Download The Use of Body Surface Area as a Criterion of

The Use of Body Surface Area as a Criterion
of Drug Dosage in Cancer Chemotherapy*
DONALDPINKEL
(Department of Pediatrics, Roswett Park Memorial Institute
and
University of Buffalo School of Medicine, Buffalo, N.Y.)
The relationship between body surface of
animals and various parameters of their physiol
ogy has been observed over many decades. Rubner
(17), in 1883, pointed out that small animals
utilized relatively more oxygen and produced rela
tively more heat than larger animals. He explained
that smaller animals had relatively larger surface
areas than larger animals and demonstrated that
oxygen utilization and caloric expenditure were
similar for various mammalian species and differ
ently sized members of the same species when com
puted on the basis of body surface (2). These
observations have been confirmed and extended
to man by many investigators, and it has long been
standard practice to express human basal metabol
ic rate in terms of body surface area rather than
body weight (8).
Dreyer and Ray (6, 7) found that the ratio of
blood volume to body weight in rabbits, guinea
pigs, and mice decreased with increasing animal
weight, but that the relation of blood volume to
body surface area was constant. Gibson and Evans
(11) found surface area useful for estimation of
normal blood volume. Griffin et al. (12) measured
plasma volume, "available thiocyanate space,"
and total circulating plasma proteins in normal
adults and found better correlation of these data
with body surface area than with either height or
weight. Baker and Kozoll (1) determined plasma
volumes and total blood volumes in 150 normal
adults using iodinated human serum albumin
labeled with I131and hematocrit determination.
The ratio of blood volume to body weight was not
constant, but a direct linear relationship was
found to exist between body surface area and
blood volume, and the authors concluded that
surface area was the single most useful basis for
deciding the normal total blood volume of an
individual.
* Supported in part by funds contributed to Health Re
search, Inc., by the New York State American Legion Auxilia
ry, and by United States Public Health Service Grants CY8527 and CY-3900.
Received for publication February 28, 1958.
Grollman (13) determined the cardiac outputs
of normal 20-30-year-old individuals in the basal,
resting condition and noted that his results corre
lated well with the body surface areas of the
subjects.
The relation between renal function and body
surface area has been discussed by Smith (18). The
total number of glomeruli and kidney weights in
various species of mammals is directly proportion
al to their surface areas but not their weights.
Furthermore, although the ratios of kidney weight
to body weight are much different for the rat, the
dog, and man, their ratios of kidney weight to sur
face area are almost identical. The Addis urea
excretion ratio varies directly with kidney weight
in the rat, the rabbit, and the dog, and with the
calculated kidney weight in man, so that one may
construe a direct relationship extending through
several mammalian species of this renal function
measurement and body surface area. Urea 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 time.
In clinical medicine it has been found practical
to use body surface area to gauge the needs of
patients for parenteral fluids and electrolytes (21).
Thus, the normal water requirement of the young
infant demanding approximately 100 ml/kg of
water for daily maintenance and the adult needing
only 50 ml/kg daily are both met by administra
tion of approximately 2 1 of water/sq m of body
surface daily. The caloric requirements of infants
and children, which generally are progressively
lower in relation to body weight with increasing
age, are almost identical for all ages and weights
when related to body surface area.1
Crawford et al. (3) divided a number of patients
into four groups according to their surface areas
1G. B. Stickler and D. Pinkel, Calculation of Nutritional
Allowances for Infants and Children on the Basis of Body
Surface (submitted for publication).
8.53
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Cancer Research
854
and gave all the same dosage of sulfadiazine. Blood
sulfonamide levels were obtained at similar times
after administration and were found to have a
linear relationship to the sulfadiazine dosage. This
experiment was repeated with acetylsalicylic acid,
and again this relation was obtained. They also re
ported the successful clinical use of surface area as
the criterion of drug dosage in infants and children
for a wide range of medications.
On the basis of the foregoing information, it was
considered that body surface area might be useful
as a standard of drug dosage in cancer chemo
therapy studies in laboratory animals and in man.
Vol. 18, August,
1958
tive member of each animal species and for humans
were calculated.
RESULTS
In Tables 1, 2, 4, and 5 it can be seen that the
doses per unit of body weight of mechlorethamine, methotrexate, actinomycin D, and TSPA
are greater in smaller animals than in larger ones,
and higher in children than in adults. The doses
per unit of surface area are nearly similar for all
species and for all ages of humans. The usual dose
of 6-mercaptopurine (Table 3), when expressed as
mg/unit of body surface area, is higher in human
TABLE 1
MECHLORETHAMINE
DOSAGE
Subject
Mouse
Hamster
Rat
Man
Weight
(kg.)
0.018
0.050
0.25
70.0
Surface area
(sq. m.)
0.0075
0.0137
0.045
1.85
Total dose
(mg.)
0.072
0.15
0.5
21-28.0
Total dose/kg
(mg.)
4.0
3.0
2.0
0.3-0.4
Total dose/sq m
(mg.)
96
10.9
11.1
ll.S-15.1
TABLE 2
METHOTREXATE
DOSAGE
Subject
Weight
(kg.)
Mouse
0.018
Rat
0.25
Infant
8.0
Older child
20.0
Adult
70.0
* Generally accepted doses for
Surface area
(sq. m.)
Dose/day(mg.)0.0270.1251.25*2.5*5.0*Dose
kg/day(mg.)1.50.50.150.120.07Dose/sq
m/day(mg.)3.62.83.13.12.7
0.0075
0.045
0.4
0.8
1.85
infants, children, and adults, respectively.
MATERIALS AND METHODS
The available data concerning the appropriate
therapeutic dose ranges of mechlorethamine,
methotrexate, 6-mercaptopurine, actinomycin D,
and triethylenethiophosphoramide
(TSPA) in
humans and in certain laboratory animals were
gathered from the literature (4, 5, 9,10,14-16, 20).
Surface areas for the laboratory animals were
calculated according to Meeh's formula (8) :
A = K X W*
where "A" represents surface area expressed in
sq. cm., "K" is a constant for each animal species,
and "W" is the weight in gm. The weights used in
the formula were representative of each species
that is commonly utilized in chemotherapy screen
ing programs. Surface area for man was deter
mined from nomograms constructed according to
the formula of Dubois (8).
From the available information, the dosages per
unit of surface area of each drug for a representa-
adults than children. This might be correlated
with the observation that adults are generally in
clined to develop earlier and more severe toxicity
than children when given 6-mercaptopurine in a
dosage of 3 mg/kg of body weight. Conversely,
the dose per square meter in infants and children
is lower, which correlates with 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 animal, it has long been customary to
use body weight as the main criterion. However,
since the activity of most drugs depends on their
role in some physiologic process or function, it
would seem more reasonable to use a criterion
which correlates better with known parameters of
mammalian physiology. As explained above, body
surface area appears to be such a criterion.
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PINKEL—Body Surface Area in Cancer Chemotherapy
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 with impaired renal function
have an increased susceptibility to these agents.
One objection to the use of body surface area in
measuring 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
times. This same 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
used—a criterion that does not correlate as well
with those physiologic
parameters
that are
measurable at present.
Another objection is the difficulty in measuring
body surface. For practical reasons, a formula
must be used which utilizes weight and a constant
in animals, and weight and height in man. The
reliability of Meeh's and of Dubois' formulas has
855
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 among individuals and species. The determi
nation of body surface areas by these formulas is
neither arduous nor time-consuming.
For animals,
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 similarity in the
dosage per unit of surface area of methotrexate,
mechlorethamine,
actinomycin D, and TSPA for
TABLE 3
6-MERCAPTOPURINE DOSAGE
Surface area
(sq. m.)
0.0075
0.045
0.48
0.4
childAdultWeight(kg.)0.0180.2510.08.020.070.0
0.8
1.85
Dose/day(mg.)0.645.060.025.0
m/day(mg.)8511112568
SubjectMouseRatDogInfantOlder
50.0
68
200.0Dose/kg/day(mg.)40206*8t3tatDose/sq
108
*From dog toxicity data of Philips et al. (15); represents daily dosage for two weeks that
did not cause fatal toxicity.
t 3 mg/kg daily to the nearest 25 mg. is the generally accepted dosage in humans for all
age groups.
TABLE4
ACTINOMYCIN
D DOSAGE
Weight
Subject (kg.)
Mouse
0.018
Child
20.0
Adult
70.0
Surface area
(sq. m.)
0.0075
0.8
1.85
Total dose
(Mg.)
18
1600-1920
5250
(M.)
Total dose/sq
(Mg.)
1000
80-96
75
2400
2000-2400
2840
Total
doseAg
m
TABLE5
TRIETHYLENETHIOPHOSPHORAMIDE
(TSPA)DOSAGE
Subject
Mouse
Rat
Man
Weight
(kg.)
0.018
0.25
70.0
Surface area
(sq. m.)
0.0075
0.045
1.85
Dose/day
(mg.)
0.036
0.125-0.25
5-10
DoseAg/day
(mg.)
2
0.5-1.0
0.07-0.14
Dose/sq m/day
(mg.)
4.8
2.8-5.6
2.7-5.4
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856
Cancer Research
certain laboratory animals and man is described.
This is in contrast to the dissimilarity in the dos
ages per unit of weight for these compounds
among laboratory animals and man, and among
humans of different ages.
It is suggested that cancer chemotherapists
consider the applicability of body surface area
as a criterion of drug dosage in their laboratory
and clinical studies.
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The Use of Body Surface Area as a Criterion of Drug Dosage in
Cancer Chemotherapy
Donald Pinkel
Cancer Res 1958;18:853-856.
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