cancer res 1958 pinkel 853 6
TRANSCRIPT
-
8/10/2019 Cancer Res 1958 Pinkel 853 6
1/5
The Use of Body Surface Area as a Criterion
of D rug Dosage in C ancer C hemotherapy*
DONALDPINKEL
Depar tmen t o f Pedia tr ic s , Roswet t Park Memorial Ins ti tu te
an d
Un iv er si ty o f Bu ff al o S choo lo f Medi ci ne , Bu ff al o, N .Y .
The relationship between body surface of
anim als and various param eters of their physiol
o gy h as b een o bserv ed o ve r man y d eca des. R ub ner
(17), in 1883, pointed out that small animals
u tilized relativ ely more o xy gen a nd p ro du ced rela
tiv ely more h eat th an larg er an im als. H e ex plain ed
that sm aller anim als had relatively larger surface
areas than larger anim als and dem onstrated that
oxygen u tilization and calo ric expenditure w ere
sim ilar fo r v ario us mammalian sp ecies an d d iffer
en tly siz ed members o f th e same sp ecies w hen com
puted on the basis of body surface (2). These
observations hav e been confirm ed and extended
to m an by m an y investigato rs, and it h as long been
stan dard p rac tice to e xp ress h uman b asal m etab ol
ic rate in terms of body surface area rather than
body w eigh t (8 ).
Dreyer and Ray (6, 7) found that the ratio of
blood volum e to body weight in rabbits, guinea
pigs, and m ice d ecreased w ith increasing an im al
weight, but that the relation of blood volume to
b od y s urface area w as co nstan t. G ib so n an d E van s
(11) found surface area useful for estim ation of
n ormal b lo od v olume . G riffin et al. (1 2) measu red
plasm a volum e, available thiocyanate space,
and total circulating plasm a proteins in norm al
adults and found better correlation of these data
with body surface area than with either height or
w eight. B aker and K ozoll (1) determ ined plasm a
volum es and total blood volum es in 150 norm al
adults using iodinated human serum albumin
lab eled w ith I1 31 a nd h emato crit d eterm in atio n.
The ratio of blood volum e to body weight w as not
constant, but a direct linear relationship was
found to exist between body surface area and
blood volum e, and the authors concluded that
surface area w as the single m ost useful basis for
deciding the normal total blood volume of an
individual.
* S upported in part by funds contributed to H ealth R e
s ea rc h, I nc ., b y t he N ew Yor k S ta te Ameri ca n L eg io n Aux il ia
ry, and by U nited States Public H ealth Service G rants C Y-
8527 and CY-3900.
R ec eiv ed f or p ub lic at io n F eb ru ar y 2 8, 1 95 8.
G ro llm an (13 ) determ ined the cardiac outp uts
o f n ormal 2 0-3 0-y ear-o ld in div id uals in th e b asal,
resting co ndition and noted that his results corre
lated well with the body surface areas of the
subjects.
The relation betw een renal function and body
su rface area h as b ee n d iscu sse d b y Smith (1 8). T he
total num ber of glom eruli and kidney weights in
v ario us s pe cie s o f mammals is d ire ctly p ro po rti on
al to their surface areas but not their weights.
F urth ermore, alth ou gh th e ratio s o f k id ney w eig ht
to body weight are m uch different for the rat, the
dog, and m an, their ratios of kidney w eight to sur
face area are almost identical. The Addis urea
ex cretio n ratio v aries d irectly w ith k id ney w eig ht
in the rat, the rabbit, and the dog, and with the
calculated kidney w eight in m an, so that one m ay
con strue a d irect relatio nship extendin g through
several m ammalian species of this ren al function
m easurem ent and body surface area. U rea clear
ance and glomerular filtration rate have been
shown to be proportional to body surface area in
children. The same holds true for adults, and
Smith concludes that the comparison of renal
function on the basis of surface area cannot be im
proved at the present tim e.
In clin ical m edicin e it has been found p ractical
to use body surface area to gauge the needs of
p atie nts fo r p are nte ra l flu id s a nd e le ctro ly te s (2 1).
Thus, the norm al w ater requirem ent of the young
infant dem anding approxim ately 100 ml/kg of
w ater for daily m ainten ance and the adult needing
only 50 m l/kg daily are both m et by adm inistra
tion of approximately 2 1 of water/sq m of body
su rface d aily . T he calo ric req uiremen ts o f in fa nts
and children, w hich generally are prog ressively
low er in relation to body w eight w ith increasing
age, are alm ost identical for all ages and w eights
w hen related to body surface area.1
C raw fo rd et al. (3 ) d iv id ed a n umber o f p atien ts
into four groups according to their surface areas
1G. B . S tic kle r a nd D . P in kel, C alc ula tio n o f N utritio na l
A llow ances for Infants and C hildren on the B asis of B ody
Surface (submit ted fo r publ ica tion) .
8.53
Research.on December 12, 2014. 1958 American Association for Cancercancerres.aacrjournals.orgDownloaded from
http://cancerres.aacrjournals.org/http://cancerres.aacrjournals.org/http://cancerres.aacrjournals.org/ -
8/10/2019 Cancer Res 1958 Pinkel 853 6
2/5
85 4
Cancer Research
Vol. 18, August, 1958
an d g av e all th e same d osag e o f su lfad iazin e. B lo od
su lfo namid e lev els w ere o btain ed at sim ilar tim es
after adm inistration and were found to have a
lin ea r re la tio ns hip to th e s ulfa dia zin e dos ag e. This
e xp erimen t was re pe ate d w ith a ce ty ls alic ylic a cid ,
and again th is relation w as obtained . T hey also re
p orted th e su ccessfu l clin ical u se o f su rfac e area as
th e criterio n o f d ru g d osag e in in fan ts an d ch ild ren
fo r a w id e ran ge o f med icatio ns.
O n the basis o f the foregoing inform ation, it w as
considered th at body surface area m ig ht b e useful
as a standard of drug dosage in cancer chemo
th erapy studies in laboratory anim als and in m an.
tiv e member o f e ach an im al sp ecies an d fo r h uman s
were calculated.
RESULTS
In Tables 1, 2, 4, and 5 it can be seen that the
doses per unit of body weight of mechloretha-
m ine, m ethotrexate, actinom ycin D, and TSPA
are greater in sm aller anim als than in larger o nes,
and higher in children than in adults. The doses
per unit of surface area are nearly sim ilar for all
species and for all ages of hum ans. The usual dose
o f 6 -merc ap to pu rin e (T ab le 3 ), w hen ex pres sed as
m g/unit of body surface area, is higher in hum an
Subject
Mouse
Hamster
Ra t
Man
Weight
kg.
0.018
0.050
0.25
70.0
TA BL E 1
MECHLOR ETHA MINEOSAG E
Sur fa ce a re a
( sq . m .)
0.0075
0.0137
0.045
1.85
T otal d os e
(mg.)
0.072
0.15
0.5
21-28.0
T ot al d os e/k g
(mg.)
4 0
3 0
2.0
0 3 0 4
T otal dose/sq m
(mg.)
10 9
11 1
ll S 15 1
TABLE 2
METHOTREXATEOSAGE
Weight Surface area
Subject (kg.) (sq. m .)
Mouse 0.018 0.0075
Rat 0.25 0.045
Infant 8.0 0.4
O lder child 20.0 0.8
Adult 70.0 1.85
* Gene ra ll y a cc ep te d dos es f or i nf an ts , c hi ld re n, a nd adu lt s, r es pe ct iv el y.
Dose/day(mg.)0.0270.1251.25*2.5*5.0*Doseg/day mg. 1.50.50.150.120.07Dose/sq
/day(mg.)3.62.83.13.12.7
M ATERIALS AND METHODS
The a vailab le d ata co ncern in g th e ap pro priate
therapeutic dose ranges of m echloretham ine,
m eth otrex ate, 6 -m ercap to pu rin e, actin omycin D ,
and triethylenethiophosphoram ide (TSPA ) in
hum ans and in certain laboratory anim als were
g ath ered from th e literatu re (4 , 5 , 9 ,1 0,1 4-1 6, 2 0).
Surface areas for the laboratory anim als w ere
calculated according to M eeh's form ula (8 ) :
A = K X W*
w here A represents surface area expressed in
sq. cm ., K is a constan t for each anim al species,
and W is the weight in gm . The weights used in
the form ula w ere representative of each species
th at is common ly u tilized in ch emoth erap y screen
ing program s. Surface area for man was deter
m ined from nomogram s constructed according to
the form ula of D ubois (8).
F rom th e av ailab le in fo rmatio n, th e d osag es p er
unit of surface area of each drug fo r a representa-
adults than children. This m ight be correlated
w ith the observation that adults are generally in
c lin ed to d ev elo p e arlier an d more sev ere to xicity
than children w hen given 6-m ercaptopurine in a
dosage of 3 m g/kg of body weight. Conversely,
the dose per square m eter in infants and children
is low er, w hich correlates w ith the observation
that young children are inclined to tolerate 3
mg/kg for long periods without evidence of
toxicity.
DISCUSSION
In estimating the appropriate amount of a
compound to be administered to a patient or a
laboratory anim al, it has long been custom ary to
use body w eight as the m ain criterion. H ow ever,
since the activity of m ost drugs depends on their
role in som e physiologic process or function, it
would seem more reasonable to use a criterion
w hich correlates better w ith know n param eters of
mammalian p hy sio lo gy . A s ex plain ed ab ov e, b od y
surface area appears to be such a criterion.
Research.on December 12, 2014. 1958 American Association for Cancercancerres.aacrjournals.orgDownloaded from
http://cancerres.aacrjournals.org/http://cancerres.aacrjournals.org/http://cancerres.aacrjournals.org/ -
8/10/2019 Cancer Res 1958 Pinkel 853 6
3/5
P INKEL Bod y S urface A rea in C an cer Chemoth erap y
85 5
Since methotrexate, 6-mercaptopurine, and
actinomycin D are excreted by the kidneys, it is
possible that their dose/sq m relationship is in
large part due to the correlation of renal function
with body surface area. Clinical experience indi
cates that individuals w ith im paired renal function
have an increased susceptibility to these agents.
One objection to the use of body surface area in
m easuring drug dosage is the variation in physical
and chemical activities among various species,
among different individuals within the same
species, and in the same individual at different
tim es. T his sam e objection applies to any criterion,
however. The advantage of surface area still
stands out, since any differences in tolerated drug
dosages, for example, are true differences and not
artefactual as they may be when body weight is
useda criterion that does not correlate as well
w ith those physiologic parameters that are
m easurable at present.
A nother objection is the difficulty in m easuring
body surface. For practical reasons, a formula
must be used w hich utilizes weight and a constant
in animals, and weight and height in man. The
reliability of Meeh's and of Dubois' formulas has
been contested, but they do give rough approxi
mations and should be accepted not as methods of
precise measurement of surface area but as a
means of achieving more nearly correct compari
sons am ong individuals and species. The determ i
nation of body surface areas by these formulas is
neither arduous nor tim e-consum ing. For anim als,
the constant, K, may be obtained from the
Handbook of Biological Data, and the square of
the cube root of the weight can be obtained from
a logarithm table. For humans, the height and
weight are used to estimate surface area from the
nomogram constructed according to the formula of
Dubois.
It is the policy of this Pediatrie Service to use
body surface area as the criterion for dosage of
certain anti-cancer chemotherapeutic agents as
well as for all other drugs and parenteral fluids.
SUMMARY
The rationale for the use of body surface area
as the criterion of dosage in anticancer chemo
therapy has been outlined. The sim ilarity in the
dosage per unit of surface area of methotrexate,
mechlorethamine, actinomycin D, and TSPA for
TABLE 3
6 -MERCAPTOPUR INE DOSAGE
Surface area
( sq . m . )
0.0075
0.045
0.48
0.4
0.8
1.85
* From d og to xic ity da ta o f P hilip s et al. (1 5); rep res en ts da ily d osag e fo r tw ow e ek s th at
d id not c au se f at al t ox ic it y.
t 3 m g/kg daily to the nearest 25 m g. is the generally accepted dosage in hum ans for all
age g roups.
SubjectMouseRatDogInfantOlder
childAdultWeight(kg.)0.0180.2510.08.020.070.0
Dose/day(mg.)0.645.060.025.0
50.0200.0Dose/kg/day(mg.)40206*8t3tatDose/sq
m/day(mg.)8511112568
68
10 8
Weight
Subject (kg.)
Mouse 0.018
Child 20.0
Adult 70.0
TABLE4
ACTINOMYCINDOSAGE
Surface area
( sq . m . )
0.0075
0.8
1.85
T ota l d os e
(Mg.)
18
1600-1920
5250
T otal doseA g
M.
1000
80-96
75
Total dose/sq m
(Mg.)
2400
2000-2400
2840
Subject
Mouse
Ra t
Man
TABLE5
TRIETHYLENETHIOPHOSPHORAMIDETSPA)DOSAGE
Weight Surface area Dose/day DoseAg/day
(kg.)
0.018
0.25
70.0
Surface area
( sq . m . )
0.0075
0.045
1.85
(mg.)
0.036
0.125-0.25
5-10
(mg.)
2
0.5-1.0
0.07-0.14
Dos e/s q m /d ay
(mg.)
4.8
2.8-5.6
2.7-5.4
Research.on December 12, 2014. 1958 American Association for Cancercancerres.aacrjournals.orgDownloaded from
http://cancerres.aacrjournals.org/http://cancerres.aacrjournals.org/http://cancerres.aacrjournals.org/ -
8/10/2019 Cancer Res 1958 Pinkel 853 6
4/5
85 6
Cancer Research Vol. 18, A ugust, 1958
certain laboratory anim als and m an is described.
This is in contrast to the dissim ilarity in the dos
ages per unit of weight for these compounds
am ong laboratory anim als and m an, and am ong
h uman s o f d ifferen t ag es.
It is suggested that cancer chem otherapists
consider the applicability of body surface area
as a criterion of drug dosage in their laboratory
and c li ni ca l s tud ie s.
REFERENCES
1. B AK ER ,R . J.; K OZOL L,D.; and M EY ER, K. A. The Use
o f S urfa ce A re a a s a B asis fo r E sta blish ing N orm al B lo od
Volume. S urg ., G yn . Obs t., 1 04 :1 83 -8 9, 1 95 7.
2. B ES T, C . H ., an d TAYLOR,N . B . The P hy sio lo gi ca l B as is o f
M ed ic al P rac tice , p . 5 25 , 4 th e d. B altim ore: W illia ms
Wilkins , 1945 .
3 . CRAWFORD ,.; TERRY,M .; a nd ROUBKE,G. Simplif ication
o fD r ug Dos ag e C alc ula ti on b y App lic at io n o f t he S ur fa ce
Area P ri nc ip le . P ed ia tr ic s, 5 :7 83 -9 0, 1 950.
4 . D iP AOLO ,J. A .; MOORE,G . E .; an d N IEDBALA,T. F. Ex
p er iment al S tu di es w it h Ac ti nomyc in D . Canc er Re se ar ch ,17 :1127 -34 , 1957 .
5. . The Influence of Actinomycin D on Animal and
H um an T um ors. Proc. Am. A ssoc. C ancer R esearch, 2:
195, 1957 .
6 . DREYER,G ., a nd RAY,W . The B lo od Volume o fMammal s
as D eterm ined by Experim ents upon R abbits, G uinea
Pigs and M ice and Its R elationship to the B ody W eight
and to the Surface A rea E xpressed as a Form ula. Phil.
T ra ns . R oy al S oc . L on do n, s . B , 2 01 :1 33 -6 0, 1 91 0.
7. . Further Experiments upon the Blood Volume of
M am mals and Its Relation to the Surface Area of the
Body . I bi d., 2 02 :1 91 -2 12 , 1 912.
8 . DUBO IS ,E . B asal M eta bo lism in H ealth an d D is ea se, p p.
1 25 -4 4. P hi la de lp hi a: Le a F eb ig er , 1 936.
9. FA RB ER ,S.; T OCH, R.; S EARS,E .; and PINKE L, D . A d
v an ces in C hem oth erap y o f C an ce r in M an . A dv. C an ce r
Re se ar ch , 4 :1 -7 1, 1 956.
1 0. GBLLHOHN,A ., a nd HIRSCHBERG, . ( ed s. ). I nv es ti ga ti on
o f D iv er se S ys tems f or C an ce r Chemo th era py S cr ee nin g.
C an ce r R es ea rc h, S up pl. N o. 3 , 1 95 5.
1 1. G IBSON ,J ., a nd EVANS,W ., J R. C li nic al S tu di es o f B lo od
V olum e; R elation of Plasm a and T otal B lood V olum e to
Venous P re ss ur e, B lood Ve lo ci ty Ra te , P hy si ca l Measur e
m ents, A ge and Sex in 90 N orm al H um an B eings. J. C lin.
I nv es ti ga ti on , 1 6: 317-28 , 1 937.
1 2. GR IF FIN,G .; ABBOTT,W .; PRIDE ,M . ; MUNTWYLER , .;
MAUTZ,F .; a nd GRIFFITH ,L . P la sma Vo lume, Avai la bl e
(T hioc yan ate ) V olum e a nd T otal C ircu latin g P la sm a
P rote in s in N orm al A du lts. A nn . S urg ery, 1 21:3 52-6 0,
1945.
1 3. GROLLMAN ,A . P hy sio lo gica l V aria tio ns in th e C ard ia c
O utput of M an. V I. The V alue of the Cardiac O utput of
th e N orm al In div id ua l in th e B as al, R esting C on ditio n.
Am . J . P hy sio l., 9 0: 21 0- 17 , 1 92 9.
1 4. P EHSONEUS ,G .; HALLJDAY , . L .; M cKENZiE , D .; an d
WILLIAMS,. H . E ff ec t o f a S er ie s o f E th yl en im ine De ri va
t iv es a ga in st Me ta st as iz in g Mammary Adenoc ar ci noma o f
th e R at . P ro c. S oc . E xp er . B io l. M e d., 8 1:6 14 -1 6, 1 95 2.
1 5. P HIL IP S, F . S .; S TERNBERG ,S. S.; H AM IL TON,L.; and
CLARKE,D . A . T he T ox ic E ffe cts o f 6 -M erca pto pu rin e
a nd Re la te d Compounds . Ann. N .Y . Acad . S c. , 6 0 :2 83 -9 6,
1954.
16. PIN KE L, D . A ctinom ycin D in C hildhood C ancer. Proc.
Am . A ss oc . C an ce r R es ea rc h, 2 :3 35 , 1 95 8.
1 7. RUBNER,M . T Je be r d en E influ ss d er K rp ergr s seu f
S to ff - u nd Kraf twe ch se l. Z ts ch r. f . B io l., 1 9: 535-68 , 1 883.
18. SM IT H, H. W . T he K idney, Structure and Function in
H ealth an d D isea se , p p. 4 95 , 5 43 , 5 62 . N ew York: O xford
Un iv er si ty P re ss , 1 951.
19. SPE CTOR ,W . S . (ed.). H andbook of B iological D ata, p.
1 75 . P h ila de lp hi a Lon do n: W . B . S au nd er s Co., 1 95 6.
2 0. SUG IURA,K ., and STOCK,C . C . Studies in a T um or Spec
tru m. III. T he E ffe ct o f P ho sp ho ramide s o n th e G row th o f
a V ariety of M ouse and R at T um ors. C ancer R esearch,
1 6: 38 -5 1, 1 955.
2 1. TALBOT,N .; CRAWFORD ,.; a nd BUTLER,A . Homeo st at ic
Lim its to Safe Parenteral Fluid Therapy. N ew Eng. J.
Med. , 2 48 :1 100-1108 , 1 953.
Research.on December 12, 2014. 1958 American Association for Cancercancerres.aacrjournals.orgDownloaded from
http://cancerres.aacrjournals.org/http://cancerres.aacrjournals.org/http://cancerres.aacrjournals.org/ -
8/10/2019 Cancer Res 1958 Pinkel 853 6
5/5
1958;18:853-856.Cancer Res
Donald Pinkel
Cancer ChemotherapyThe Use of Body Surface Area as a Criterion of Drug Dosage in
Updated version
http://cancerres.aacrjournals.org/content/18/7/853Access the most recent version of this article at:
E-mail alerts related to this article or journal.Sign up to receive free email-alerts
SubscriptionsReprints and
[email protected] atTo order reprints of this article or to subscribe to the journal, contact the AACR Publications
Permissions
To request permission to re-use all or part of this article, contact the AACR Publications
on December 12, 2014. 1958 American Association for Cancercancerres.aacrjournals.orgDownloaded from
http://cancerres.aacrjournals.org/content/18/7/853http://cancerres.aacrjournals.org/content/18/7/853http://cancerres.aacrjournals.org/cgi/alertshttp://cancerres.aacrjournals.org/cgi/alertsmailto:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]://cancerres.aacrjournals.org/http://cancerres.aacrjournals.org/http://cancerres.aacrjournals.org/mailto:[email protected]:[email protected]://cancerres.aacrjournals.org/cgi/alertshttp://cancerres.aacrjournals.org/content/18/7/853