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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

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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.

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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

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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.

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1958;18:853-856.Cancer Res

Donald Pinkel

Cancer ChemotherapyThe Use of Body Surface Area as a Criterion of Drug Dosage in

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