Multiple regression analysis techniques are used to study the effects of therapeutic radiation exposure, number of fractions, and time on such quantal responses as tumor control and skin injury. The potential of these methods for the analysis of human blood cell responses is demonstrated and estimates are given of the effects of total amount of exposure and time of protraction in determining the minimum white blood cell concentration observed after exposure of patients from four disease groups

Lushbaugh, C. C.

Stokes, T. R.

Yuhas, J. M.

English

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John M. Yuhas, T. R. Stokes, and C. C. Lushbaugh
Bioloc_lyDivision, Oak Ridqe National laboratory, and Medical Division, Oak Riddle Associated Unlversitles_ Oak Riddle,
Tennessee 37830
INTRODUCTION
Each source of information whicn tlas contributed to our
knowledge of human responses to total body irradiation has
characteristic advantages and disadvantages. For example,
the people exposed to atomic bomb radiations in Hiroshima
and Nagasaki were random samples from a presumably nor.mal
population, but estimation of the precise radiation dose that
each individual received is difficult, and the confounding
effects of blast and heat have made it nearly impossible to
obtain an accurate dose-response relationship (_!). For the
analysis of data from patients given therapeutic exposures,
the situation is exactly the reverse: dosimatry and clinical
follow-up have been extensive, but the patients constitute a
nonrandom sample whose usefulness in making extrapolations
to the population at large may be seriously questioned. ]f
precise response patterns can be determined for a variety of
disease states, it may be possible eventually to combine these
estimates with our knowledge of the disease processes and
thereby to arrive at a rational prediction of the average radia-
tion response of normal individuals.
Toward this end, a variety of investigators have attempted
to describe the average radiation response of the patient given
total body therapeutic exposures _, 3), but none has been
able to estimate the radiation responsewithin acceptable
confidence limits. This has resulted largely from the fact
that therapeutic exposures are often complex combinations of
total exposure, number of fractions, and time between frac-
tions, and very few individual patients have received exactly
the same combination. The individuality of clinical records
pre_ents the construction of discrete "treatment grou_" for
IResearch supp6rted by the U.S. Atomic Energy Commission
under contract with the Union Carbide Corporation and by
the National Aeronautics and Space Administration.
dose-response analysis, so pooling procedures are required, such
as separating patients who received their total exposure in less
than 8 days from those who were exposed over longer periods __).
While this type of treatment may be adequate for gross responses,
it has proved to be totally unsuitable for analysis of human blood
cell responses.
Standard techniques are available (4), however, which
allow the simultaneous study of the effects of total exposure,
independent of the time factor, and the effects of time, inde-
pendent of the total exposure factor. These multiple regression
analyses have been applied successfully to the study of the effects
of exposure, number of fractions, and time on such quantal re-
sponses as tumor control (5) and skin injury (6). The present
report demonstrates the potential of these methods for the anal-
ysis of human blood cell responses and provides preliminary
estimates of the effects of total amount of exposure and time of
protraction in determining the minimum white blood cell (WBC)
concentration observed after exposure of patients from four
disease groups.
MATERIALS AND METHODS
More than 2700 clinical records of patients who had re-
ceived single or fractionated total body exposures for a variety
of diseases were collected from more than 30 participating hos-
pitals (2). Deletion of records that contained inadequate ex-
posure or response information reduced this number to approxi-
mately 1000. Additional requirements were imposed on'th_
records for the purposes of the present analysis: only those
records which were for the first treatment a patient received
were included, since we have'preiiminary indications that the
responses to second and later exposures differ slightly from the
responses to first exposures; records for patients who received
total exposures of less than 50R were deleted due to the
233
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questionable nature of the responses observed; records from
those patients in whom the minimum concentration could not
be determined with certainty were omitted Cin order to be
considered a true minimum, the concentration must persist for
a reasonable period of time or be followed by an elevated con-
centration other than the occasionally observed abortive rise
(7) "_; and disease categories in which there were fewer than
ten records were omitted. These qualifications removed all
but 518 records, which were distributed among four disease
categories: chronic myel0genous leukemia or CML (131 rec-
ords); chronic lymphatic leukemia or CLL (200 records); lym-
phosarcoma or LSAR (66 records); and diseases which have no
direct effects on the blood-forming tissuesor NORMAL (121
patients). The NORMAL group is normal only in a relative
sense and includes patients with disseminated solid tumors, as
well as patients in the late stages of nonmalignant diseases of
the bones, joints, and genitourinary system.
Data were stored and analyzed on a simple time-sharing
computer system (Call-A-Computer, Raleigh, North Carollna),
which proved entirely adequate for the requirements of this
study.
RESULTS
Table I summarizes the number of patients in each disease
category who were given single or multiple exposures. We
were unable to obtain any data on CLL patients who had re-
ceived single exposures in excess of 10OR, soa meaningful
analysis of their single-exposure response curve could not be
conducted.
Table I
Disease category Single Multiple
exposures exposures
Chronic myelogenous leukemia 15 ] 16
(CML)
Chronic lymphatic leukemia w 200
(CLL)
Lymphosarcoma 16 50
(LSAR) .
NORMAL a 92 29
Numbers of patients in each of the four disease categories
studied who received single and multiple total body exposures.
apatlents with diseases that have no dlrecteffects on blood-
forming tissues.
Table ]I summarizes the exposure and response data for
patients from the three disease categories in which a single-
exposure analysis could be performed. The mean total exposure
varies among the three diseases, reflecting the differences in
accepted treatment levels for each of the diseases.
Table II
NORMAL a CML LSAR
No. of patients 92 15 16
Mean total exposure 195R 1|7R 108R
Mean WBC at nadir 21.6% 27.7% 39.9%
Predicted tolerated exposure 19 R 18 R 34 R
Slope (WBC/E) -1.04 -0.99 -1.12
:l: .16 b + .19 b + .65
Correlation coefficient 0.572 c 0.823 d 0.419
Exposure and response data for patients from three disease
categories who were given single therapeutic exposures.
apatients without diseases which have direct effects on their
blood-forming tissues.
bP < 0.001.
cP < 0.0005.
dP < 0.005.
The data for each disease were fit to a variety of equations,
with the most satisfactory being a simple power function,
% WBC = k [ !00-] I'E] a
where % WBC is the WBC count at the nadir as a percentage of
the preirradiation levels, k is a constanb E is the midline air
exposure in Rs and a is the slope of % WBC on E.
Individual slopes were tested for significance by use of t-
tests, and the overall correlation coefficient by use of F-ratios
(4). The slopes and correlation coefficients are highly signifi-
cant for the NORMAL and CML groups (Table II), but not for
the LSAR group. In each cases however, the slope does not
differ significantly from -1.0, indicating that with response
measured as the nadir concentration of white blood cells there
is no demonstrable difference in radiosensitivity among these
three groups, once the tolerated exposure has been exceeded.
The predicted tolerated exposure is given by
Predicted tolerated exposure = EXP ( log k - log 100 ).
/v
234
Figure ] gives the plot of % WBC concentration at the nadir as
a function of radiation exposure for the three disease categories.
The displacement of the LSAR group to a higher exposure level
is not statistically significant and requires further study.
I00-_
50-
z2 O-
i-
<I
nm
_o-
5-
\
\'_LYMPHOSARCOMA
NORMAL_X _ \\
CHRONIC _ \\
2b 2bo
MLAD(R)
Figure i. Percent white blood cell concentration at the nadir
as a function of radiation exposure for patients with chronic
myelogenous leukemia (CML), lymphosarcoma (LSAR), or with-
out any disease which has direct effects on fhe blood-forming
tissues (NORMAL).
For the analyses of multiple exposures we define the time of
protraction as the number of days over which the exposure is
given. For example, a patient who received one fraction on
each of two consecutive days would have a protraction time of
two days. Table II[ summarizes the exposure and response data
for patients from the four disease categories who received mul-
tiple exposures. Mean total exposures are logically greater,
since the exposures were protracted over times of 27 to 36 days
on the average. As was the case with the single-exposure
data, the most adequate fit proved to be a power function:
%WBC= k [ I00] [E]_ET] 8,
where T is the time of protraction in days and 6 is the slope of
% WBC at a given E on T. The slope of % WBC on exposure
does not differ among the NORMAL, CML, and LSAR groups in
this multiple-exposure analysis, and it is essentially equal to
-1.0, as was observed in the single-exposure groups (Table lI).
Theoretically, the identity of slopes in the two sets of data is
expected, since by our definition the protraction time in the
single-exposure studies is one days and one raised to any power
equals one. In other words, the single-exposure data should
fit the multiple-exposure equation with T set equal to one.
This indicates, therefore, that there are no qualitative differ-
ences between the two sets of data (single versus multiple ex-
posure).
Table III
NORMAL CML LSAR C LL
No. of patients
Mean total exposure (E)
Mean duration of exposure (1")
Mean WBC at nadir
Predicted tolerated exposure
Slope (WBC/exposure)
Slope ONBC/time)
Multiple correlation coefficient
29 116 50 200
233R 152R 217R !i6R
27. 9 days 28.9 days 32. I days 36.9 days
55.2 % 44.4 % 43.8 % 52.9 %
16 R 7R 25 R i ] R
-].07 + .39 b -0.82 +. 12d -i.04 ± .22 d -0.75 ± .08 d
0.63 ± .24 c 0.39 ±. I0 d 0.23 ± . 18 0.22 ± .06 d
O.535 c O.569 e O.567 f O.583 e
Exposure and response data for multiple exposures in four patient samples.
apatients without diseases which have direct effects on their blood-forming tissues.
bp < 0.025. cp <0.01 , dp < 0.001. eP < 0.0001. fP < 0.0005.
235
TheCLL group, on the other hand, demonstrates a response
on exposure slope which is significantly less than -].0, but
which is not significantly different from the slopes observed
for the other diseases. We are unable, therefore, to demon-
strate any difference among the disease categories studied in
the slope of response on exposure.
The slope of WBC concentration on time at a given expo-
sure presents the most interesting of the results obtained from
this analysis. At a given exposure the % WBC at the nadir
increases as the 0.63 power of the number of days separating
the first and last fractions. Figure 2 illustrates this effect for
exposures of 60, 100, and 200R given over periods of 2 to 32
days. In the CML group, the slope of WBC on time, or more
loosely the recovery constant, is smaller but not significantly
below that of the NORMAL group. The recovery factor for
the two diseases which affect lymphatic tissues, LSAR and
CLL, are each approximately one-third of that observed in the
NORMAL group (P < 0.5 and P < 0.05, respectively). Figure
3 illustrates this variation in the time factor for the four groups
given |00R in 2 to 32 days.
100- "NORMAL" PATIENTS
60R
z - OOR A
0
TIME (days)
Figure 2. Percent white blood cell concentration at the nadir
as a function of radiation exposures of 60, 100t or 200R given
in 2 through 32 days (NORMAL patients).
DISCUSSION
It is quite clear from the foregoing that multiple regression
analyses can extract important information from complex expo-
sure-versus-response data. It should also be pointed out exactly
what this type of analysis cannot do. The data on which these
analyses are based cover an exposure range of 50 to |0OOR
given over i to nearly |00 days. Since we are dealing at
present with dividing cell populations which are subject to a
variety of dose- and time-dependent compensatory mechanisms,
it is clear that any inferences regarding the effects of other
exposure patterns must be confined to the range of exposures
and times from which the equations have been derived. The
analyses do not provide a means of estimating average responses
to exposures less than 50R accumulated in times in excess of
|00 days.
In the present report we have considered only two vari-
ables: total exposure and time. The number of fractions in
which the total exposure was delivered was deleted for two
reasons: it would require more space than is available to us to
discuss this factor adequately, and the number of fractions and
time of protraction are closely correlated. Even with this
simple two-factor analysis we have uncovered certain character-
istics of the radiation response which obviously merit further
study. Two observations, in particular, should be pointed out.
IOO-
o: 50-
Z
I--
¢..)
gO
20-
l MYEL. ] LEUKEMIA
TIME (days)
Figure 3. Percent white blood cell concentration at the nadir
as a function of the time over which a i00R exposure is pro-
tracted for patients from the four disease categories.
First, there is very little variation among the disease states in
regard to the sensitivity to exposure level (¢f. Tables I[ and Ill).
This might appear to contradict the well-established radiosensi-
tivity of the mature lymphocyte (8), but it should be remembered
236
that response in the present study does not refer to the rate at
which the white blood cells disappear from the circulation.
Response is measured as the lowest concentration following ex-
po6ure, independent of the amount of tlme required to reach
thls nadir. The radiosensitivlty of the progenitor compartments
is more important in the determination of the nadir concentra-
tion than is the radlosensitlvity of the mature element, and our
preliminary data are compatible wlth a conclusion of equal
radlosensitlvity in the progenitor compartment of the four dis-
ease categories.
The fact that the sparing factor associated wlth protraction
of the exposure in tlme varies as a function of the disease state
is quite clear, at least for comparing diseases that affect the
lymphatic tissueswith those that do not. This corresponds to
theoretical expectations (9) as well as to experimental data
from lower animals (1__0)regarding the effects of exposure pro-
traction on lymphatic versus nonlymphatic blood-formlng
tissues. We will continue to analyze this time factor in the
hope of determining what, if any, correlations exist bet_veen
human and lower animal responses to similar exposure regimens.
Acknowledgment.--The authors wlsh to thank Mrs. J. O. Proctor
and M. G. Hayes for their excellent assistance.
LITERATURE CITED
]. Proceedlr_s of the ]st Interdlsciplinar), Conference on
Selected Effects of a General Wart pp. 31-208. Defense
Atomic Support Agency Information and Analysls Center.
Special Report _67, 1968.
2. Lushbaugh, C.C. In Praceedin_ls of a Sympo6ium on
Dose Rote in Mammalian Radiation Biology, pp. 17-1 to
17-25. Division of Technical information Extension
USAEC Report No. TID-4500, 1968.
3. Lushbaugh, C.C. Radiat. Res., 2,_7:487-488, 1966.
4. Dixon, W. J., and F. J. Massey. Introduction to Sta-
tistical Analysis. 3rd edition. McGraw-Hill, New York,
1969. 638 pp.
S. Fowler, J. F., and B. E. Stern. Brit. J. Radiol., 36:
163-173, 1963.
6. Coutard, H. Am. J. Roent_lenol. Radlat. Ther., 2_8:
313-331, 1932.
7. Hasterllk, R. J., and L. D. Marinelli. Proceedin_ls of
the International Conference on Peaceful Uses of Atomlc
Energy, Geneva, 2: 25-34, 1955.
8. Andrews, J.R. The Radloblolc_ly of Human Cancer Radio-
_. W. B. Saunders, Philadelphia, 1968.
9. Taliaferro, W. H., L. G. Taliaferro, and B. N. Jaroslow.
Radiation and Immune Mechanisms. Academic Press, New
York, 1963.
10. Gengozlan, N., D. E. Carlson, and C. F. Gottlleb.
Fed. Proc., 2,_,8:582, 1969.
237


Multifactorial analysis of human blood cell responses to clinical total body irradiation

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