Inr. J. Radiation Onco/ogv Biol. Phys.. Vol. 7. pp. 1695-I 701 03~3016/81/121695~7~2.

~/0
Printed in the U.S.A. All rights rcscrved. I
Copyright 0 198 Pergamon Press Ltd.

0 Oncology Intelligence

RADIOBIOLOGICAL BASIS OF TOTAL BODY IRRADIATION WITH

DIFFERENT DOSE RATE AND FRACTIONATION: REPAIR CAPACITY OF
HEMOPOIETIC CELLS

CHANG W. SONG, PH.D., TAE H. KIM, M.D., FAIZ M. KHAN, PHD., JOHN H.
KERSEY, M.D. AND SEYMOUR H. LEVITT, M.D.
University of Minnesota Medical School, Box 494 Mayo, Minneapolis, MN 55455

Totalbodyirradiation
(TBI) followed by bone marrow transplantation is being used in the treatment of malignant or
non-malignant hemopoietic disorders. It has been believed that the ability of hemopoietic cells to repair sublethal
radiation damage is negligible. Therefore, several school of investigators suggested that TBI in a single exposure at
extremely low dose rate (5 rad/min) over several hours, or in several fractions in 2-3 days, should yield a higher
therapeutic gain, as compared with a single exposure at a highdoserate(26 rad/min). Wereviewed the existing data
in the literature, in particular, the response of hemopoietic cells to fractionated doses of irradiation and found that
the repair capacity of both malignant and non-malignant hemopoietic cells might be greather than has been thought.
It is concluded that we should not underestimate the ability of hemopoietic cells to repair sublethal radiation damage
in using TBI.

Total body irradiation, Dose rate, Bone marrow transplantation, Hemopoietic stem cells, Leukemia.

Total body irradiation (TBI) followed by bone marrow with 750 rad of 10 MV X rays at a midline dose rate of 26
transplantation is becoming an established modality in rad/min in a single exposure. With this protocol, TBI can
the treatment of malignant or non-malignant hemo- be completed within 30 min.
poietic disorders.2’,22.38 In the past, the most commonly Presently, dose rates ranging from 2.5 rad/min to 45
used protocol for TBI was exposing patients to 1000 rad rad/min are being used for TBI in a single or fraction-
in a single dose at dose rate of 5-8 rad/min using a 6oCo ated dose at various medical centers.22 The clinical effect
radiotherapy unit.” It should be stressed that the use of of different TBI protocols has been a controversial
such a low dose rate was not based on a radiobiological subject in recent years. Several groups of investiga-
foundation, but it was the maximum dose rate that could tors23*24*26*29.30 have stated that the capacity of bone
be obtained from the conventional @‘Co unit. Delivery of marrow stem cells and malignant hemopoietic cells
1000 rad at this low dose rate requires an arduous task of (which are the targets of TBI) to repair sublethal radia-
several hours and has a number of disadvantages. tion damage is quite limited as compared with that of
Because the already sick patients develop radiation other mammalian cells. It was concluded, therefore, that
syndrome during the treatment, the radiation process TBI in a single dose at a low dose rate (5-8 rad/min) or
should be interrupted frequently. In addition, occupying in fractions should yield a greater therapeutic gain when
a radiation source for several hours in the usual radio- compared with single dose TBI at high dose rate (26
rad/min)*3v26-29,30
therapy department severely restrains routine work. In support of their contention, the report
Since high dose rate machines, such as linear accelera- by McCulloch and Til127 that the radiation survival curve
tors, became available, several medical centers have been of colony forming units (CFU) from mouse bone marrow
using high dose rates to minimize the inconvenience had an extrapolation number (n) and quasithreshold dose
imposed on the patient and to avoid the great ado with (Dq) of 1.5 and 50 rad, respectively, is frequently
TBI for several hours at low dose rate.*‘*** mentioned. We reexamined a number of other reports on
Based on our animal experiments on the TBI with @Co the radiation response of normal and malignant hemo-
and 10 MV X rays at different dose rates for bone poietic stem cells and found that the repair capacity of
marrow death,” we at the University of Minnesota these cells is substantial. It is our opinion that the
devised a protocol in which the patients are irradiated theoretical therapeutic gain achieved by delivering TBI

Reprint requests to: C. W. Song, Ph.D. Acknowledgment-The authors are indebted to Miss Peggy
Supported by National Cancer Institute Grant # CA 15548. Teefy for help in manuscript preparation.
Accepted for publication 9 July I98 I.
1695
 1696 Radiation Oncology 0 Biology 0 Physics December I98 I, Volume 7, Number 12

Table I. Radiation response of hemopoietic cells

Do Dq
Irradiation Rad Rad n Refs

Mouse bone marrow CFU In vivo (100) (80) (2.0) 16

Mouse bone marrow CFU In vitro 105 (100) 2.5 24
In vivo 95 (50) 1.5 27
Mouse splenic CFU In vivo 62 0.97 17
Mouse femoral CFU In vivo 70 (80) 2.5 17
Mouse bone marrow CFU In vitro 62 (100) 4.0 42
Mouse bone marrow CFU In vivo 73 (90) 2.4 42
Mouse bone marrow CFU In vivo. 105 R/min 72 60 2.4 32
I 1.6 R/min 79 48 1.8 32
5.37 R/min 85 45 1.7 32
2.86 R/min 99 1.2 32
Mouse bone marrow CFU In vitro, 1750 R/hr 90. I (Z.2) 1.93 24
190 R/hr 92.9 (56.1) 1.83 24
Mouse bone marrow CFU In vitro 160 0 1.0 36
Human lymphoid cell (T,) In vitro 85 175 7.7 8
Human bone marrow CFU In vitro 137 0 1.0 36

The numbers in parentheses are estimate values.

in several fractions at a high dose rate or in a single dose was fractionated in 2 doses with a time interval of 5 hours
at 5-8 rad/min instead of a single treatment at 26 (curve B); they concluded that “early repair processes
rad/min is overestimated by other investigators. occur after whole-body irradiation of the intact mouse.”
In Table 1, the parameters of the radiation survival The recovery factor was about 2 for exogenous colony
curve of hemopoietic cells reported by a number of forming cells from mouse bone marrow (curve C), as
investigators are listed. The parameters of radiation opposed to 3-4 recovery factor for endogenous cells
survival curves for the hemopoietic cells in some of those (curve B), suggesting that perturbation of environment
studies are at considerable variance from those reported may diminish the repair capacity of hemopoietic cells.
by McCulloch and Till.” For example, Van Putten Till and McCulloch” concluded that “the survival ratio
reported that the n of the radiation survival curve for (recovery factor) at the j-hour maximum appears to be
mouse bone marrow stem cells was as large as 4 and Dq greater than would be expected from the extrapolation
was 100 rad. The Do of radiation survival curve of mouse number of 1.5 for the single-exposure curve.” This could
marrow CFU was reported to be 160 rad, although the be taken to imply that the extrapolation number of a
extrapolation number was only 1 .0.36 Pettersen et ~1.~’ single dose radiation survival curve may not necessarily
reported that mouse bone marrow stem cell population is
consisted of radiosensitive and radioresistant cells and
30- I 1 I I I I
that the Dq of the radioresistant population is greater
than 200 rad. Drewinko et al.’ demonstrated that estab- 20- Hemopoietlc Cells
lished human lymphoid cells (T,) had n and Dq of 7.7
and 175 rad, respectively; they concluded that the radia-
tion response of these lymphoid cells is remarkably simi-
lar to the response of other mammalian cells.
The capacity of mammalian cells to repair sublethal
radiation injury can be best quantitated by split-dose or
fractionated-dose experiments. In Fig. I, the repair
capacity of lymphoid cells is compared with that of
Chinese hamster cells and L cells of mice. It is clear that
the survival of lymphoid cells, including hemopoietic
stem cells, significantly increases when the radiation
0 2 4 6 8 10 12 14
exposure is split into two doses, unequivocally demon-
Hours after First Dose
strating the sublethal damage caused by the first dose of
radiation is repaired. In fact, the extent of recovery of T, Fig. 1. Recovery factor for hemopoietic cells as a function of
ceils, an established human lymphoid cell line (curve A), time between two doses. (A) Tl cells, 350 rad + 350 rad.8 (B)
Mouse splenic CFU (exogenous), 400 rad + 300 rad.j9 (C)
is greater than that in Chinese hamster cells (curve E) or
Mouse bone marrow CFU, 200 rad + 200 rad.39 (D) Mouse
L cells of mice (curve F). Till and McCulloch3’ observed splenic CFU (endogenous), 250 rad + 500 rad.6 (E) Chinese
that survival of endogenous colony forming ceils in the hamster cells, 791 rad + 731 rad.” (F) L cells, 700 rad + 509
mouse spleen increased by factors of 3-4 when radiation rad.47
 Repair capacity of hemopoietic cells ??C. W. SONG et al. 1697

present the repair capacity of sublethal radiation different kinds of CFU and that fractionated irradiation
damage. In this context, Withers45 suggested that single is less effective than a single dose irradiation in sterilizing
dose survival curves tend to provide an underestimate of the CFU.
the repair capacity of a proportion of the cells. The study by Puro and Clark3* clearly demonstrated
Chaffey and Hellman observed that the survival of that the response of mouse bone marrow CFU to radia-
hemopoietic stem cells of mice increased by a factor of tion is dose rate dependent as shown in Table 1. Kolb et
more than 2 when the irradiation was split into 2 aLz3 also studied the effect of TBI delivered with
fractions at an interval of several hours (curve D). The different dose rates on the peripheral blood counts of
study by these investigators on the effect of fractionated leukocytes, lymphocytes and platelets as well as on the
irradiation on the endocolonies inthespleenof mice is bone marrow CFU in dogs. Irradiation at 5.5 rad/min
more interesting. With fractionated radiation of 200 R was far less effective than that at 55 rad/min in reducing
per day, there was no further decrease in the endocolonies above blood cells. For example, TBI of 400 rad at 5.5
with the increase in total dose greater than 600 R; the rad/min decreased the CFU to 36%) of the control, while
efficacy of the fractionation of 250 R per day was TBI at 55 rad/min decreased the CFU to 0% of the
significantly less than that of a single dose exposure in control 35 days after the treatments. In the study by
reducing endocolonies (Fig. 2). Hellman15 recently Krebs and Jones,24 no such dose rate effect was observed
attributed the above results to repopulation of clonogenic for the CFU from bone marrow of mice. Interestingly,
cells between fractionations and repair of cellular however, there was a significant increase in LDS,,,3,, when
damage. Whatever the mechanism might be, the unrefut- the dose rate was reduced; the LD,,,,,, at 3.1 R/min and
able fact is that fractionated radiation is significantly less 20.9 R/min was 1359 R and 873 R, respectively. The
effective in reducing hemopoietic stem cell survival than difference was 486 R, which was a 55% increase over the
a single exposure. LD so,30for the higher exposure rate.
Rubin and Scarantino33 detailed the factors related to For a complete take of bone marrow transplanted after
bone marrow regeneration after irradiation and drug TBI, the host immune response should be suppressed as
treatment. Indications are that there are at least three much as possible. There is unequivocal evidence that the
immunosuppressive effect of TBI is strongly dependent of
dose rate.7.‘2 Gengozian rt al.‘* irradiated mice at
50.0 different dose rates and transplanted allogeneic or xeno-
geneic bone marrow cells. A permanent marrow graft
was obtained and the survival of mice was prolonged
when the TBI was done at 39.7 R/min or 53.4 R/min,
while the mice irradiated at 3.75 R/min rejected the
graft. In the mice receiving TBI at the low exposure rate,
1 10.01 POOR/day formation of antibody directed against graft antigen was
observed. It was concluded that “the lower the exposure
a rate, the greater the ability of the irradiated animal to
2 5.0 - mount an immune response leading to an incomplete take
or loss of the graft and subsequent formation of anti-
8
.- body.”
2 There is abundant evidence that normal or malignant
hemopoietic cells are able to effectively carry out repair
s
of DNA damage caused by ionizing radiation or ultravio-
5
r" 1.0: let light in common with other proliferating mammalian
Cel]s,%25.35The above observations are in direct contra-
diction to the assertion that “there is often no split dose
0.5 - recovery” in hemopoietic stem cells,” “there should be
relatively little effect on cell survival of dose fractionation
or of dose rate” or “both LD50,30 assay and CFU assay
indicate a limited to absent repair capacity.“30
0.2 -
With regard to malignant hemopoietic stem cells,
4/ ’ I I I I I
Peters et ~1.~’stated that the mean extrapolation number
400 600 800 1000 1200 1400
for 7 leukemias or lymphomas compiled by Whitmore
Total Dose (RI and Til14’ was I .6 (our own calculation shows that it is not
I .6, but 2.0) and concluded that “experimental leukemias
Fig. 2. Radiation survival curves of endogenous CFU in spleen
of C3H mice. The animals were irradiated in a single dose or or lymphomas share the property of their normal cells of
daily dose of 200 R or 250 R, and the colonies in the spleens origin, having smaller survival curve-shoulders.” Kolb et
were counted. Redrawn from Chaffey and Hellman.” ~1.‘~ and Lichter ef ~1.~~also expressed a similar opinion.
 Radiation Oncology ??Biology 0 Physics December 198 1, Volume 7, Number I2

In Fig. 3, we compared the radiation survival curve of

several experimental malignant hemopoietic cells with
that of Chinese hamster cells and mastocytoma cells of
mouse. The detailed parameters of the radiation survival
curves of various leukemia and lymphoma cells of mouse
are summarized in Table 2. It is apparent that the n, Dq
and Do of these malignant hemopoietic cells are not
different from those for normal or other malignant cells,
including human tumor cells,44 and are greater than those
values cited by other investigators.23~26~29”0 In Fig. 4, the
effect of split dose on the survival of malignant hemo-
poietic cells of mice is compared with that of Chinese
zn hamster cells and L cells of mice. It can be seen that the
.-c capacity of hymphoma or leukemia cells to repair suble-
> thal damage caused by the first dose is as great as that of
._
> other cells.
f Recently, Weichselbaum et ~1.~~studied the radiosen-
co sitivity of established human malignant hemopoietic cell
lines. They observed that the radiosensitivity of these
cells was heterogenous with Do and n respective of
45-165 rad and 1.1-4.0. It should be stressed that the
radiobiological parameters of these malignant hemo-
E
poietic cells were similar to the radiobiological param-
I I I I I I eters of other human tumors (Do; 139 rad. n; 1.63)
0 400 800 1200 reported by Weichselbaum et a1.44 Unfortunately, the
response of human malignant hemopoietic cells to split
Rad dose irradiation has not yet been examined. It is highly
Fig. 3. Radiation survival curves of malignant hemopoietic conceivable, however, that human malignant hemopoietic
cells. (A) Ll2lO lymphoma cells in viva (hypoxic?).” (B) cells may also be able to repair radiation damage as are
P-388 leukemia cells in vivo (1 day old).’ (C) WEHI AML the other human malignant cells.
cells in vitro, grown in 0.8% methylcel1ulose.‘3 (C’) WEHI-
It is probable that the disassociation of tumors
AML ceils in vitro, grown in plastic dish.13 (D) L5178Y
lymphoma cells in virr~.‘~ (E) L12lO lymphoma cells in viva.” depleted the repair capacity of the cells in the experiment
(F) Chinese hamster cells in vitro.” (G) Mastocytoma cells in by Weichselbaum et a1.,44 and that the actual repair
vitro.” capacity of tumor cells in situ may be much greater than

Table 2. Radiation response of malignant hemopoietic cells

Do Do
Irradiation Rad Rad n Refs

Ll210 lymphoma (spleen) In vivo 88 (108) 3.4 17

(femur) In vivo 83 (102) 3.4 17
L1210 lymphoma (i.p.) In vivo 250 (219) 2.4 19
LS 178 lymphoma In vitro 100 134 3.8 34
L5 178 lymphoma In vitro 85 130 4.7 49
Mouse leukemia In vivo 165 (181) 3.0 18
AKR lymphoma In vitro 114 0.7 5
P388 leukemia (6 day old) In vivo (300) (600) (10.0) 20
P388 leukemia (diploid) In vivo 160 (75) 1.6 3
P288 leukemia (tetraploid) In vivo 180 (204) 3.1 3
P388 leukemia In vivo 350 600 8.0 4
P388 leukemia In vitro I51 (226) 4.5 1
(1 day old) In vivo 110 (362) 26.9 1
(7 day old) In viva 411 (230) 1.75 1
5774 In vitro 116 0.67 13
WEHI- In vitro (methylcellulose) 104 (268) 13.2 13
In vitro (plastic dish) (103) (42) 1.5 13
BNML In vivo 68 (89) 3.7 14

The numbers in parentheses are estimate values.

 Repair capacity of hemopoietic cells 0 C. W. SONG et al. 1699

30 I I I I I I Table 3. Decrease in survival (log death) of BNML leukemic

cells of rats by different TBI schedules (14)
20 - Leukemia Ceils
TBI schedules Total dose
(I 1S/rad/min) tad Log death

1 x 900 rad/day x I 900 4

1 x 225 rad/day x 4 900 l-2
2 x 200 rad/day x 4 1,600 3-4

fractionated irradiation. Fractionated TBI with a total

dose of 1600 rad given by 200 rad per fraction twice a day
reduced the survival of leukemic cells by 3-4 logs, which
0 2 4 6 8 10 12 14 is substantially smaller than 5.91 logs killing estimated
Hours after First Dose by Peters,” as mentioned above.
The lung is believed to be the dose-limiting tissue for
Fig. 4. Recovery factor for malignant hemopoietic cells as a
TBI followed by bone marrow transplantation. A number
function of time between two doses. (A) 1 day old P-388 cells,
500 rad + 500 rad.* (B) 6 day old P-388 cells, 1500 rad + 1500 of investigators pointed out that the repair capacity of the
rad.* (C) AKR mouse lymphoma cells, 374 rad + 188 rad.“’ lung is greater than that of CFU of hemopoietic cells. It
(D) Chinese hamster cells, 791 + 731 rad.” (E) L cells, 700 is probably improper to compare the damage in orga-
rad + 500 rad.” nized whole lung with the depletion of the reproductive
capacity of disassociated hemopoietic cells, which is
the parameters of radiation survival curve of single cells assayed either by in vitro culture or by injection to other
in vitro indicate. It has been reported that the self- irradiated hosts. The repair capacity of endoclones in
replication of hemopoietic stem cells and certain undisrupted mouse spleen as used by Chaffey and
leukemic cells occurs preferentially in the subendosteal Helman (Fig. 2) may be a better choice for a compari-
area.” The relatively small extrapolation number of son. In this regard, it is of interest to note that dose-
radiation survival curves for CFU reported by investiga- response curve for the depletion of proliferation function
tors may be attributed, at least in part, to the disruption of type 2 lung epithelial cells in mice has recently been
of microenvironment: i.e. culturing in agar media after reported to be diphasic.28 The initial steeper portion of
removing from such a preferred area. the curve was characterized by Do of 120 rad with the
Using the parameters of a single dose radiation extrapolation number of I .O.
survival curve for mouse bone marrow stem ceils (Dq:50 It is believe that repair of sublethal damage, redistri-
rad. n: I .5) reported by McCulloch and Till*’ and the dose bution of cells through the cell cycle, and regeneration of
rate effect factors for mouse LDsolso, Peters*’ and Peters surviving cells both in normal tissues and tumors and
et a1.30 estimated the effectiveness of different TBI proto- reoxygenation of hypoxic cells in tumors take place
cols to reduce the survival of hemopoietic stem cells of during radiotherapy with conventional fractionated
mouse. They concluded that a single dose of 750 rad at 26 schedules.46 The relative importance of these four factors
rad/min would reduce the mouse hemopoietic stem ceils in the TBI in several fractions over 2-3 days is unknown.
by 3.63 logs, and that fractionated TBI with total dose of Nevertheless, it appears that the role of difference in the
1200 rad or 1600 rad using 200 rad per fraction twice a repair capacity between hemopoietic cells and other
day would reduce the survival by 4.43 logs and 5.9 I logs, tissues in TBI may not be as substantial as has been
respectively. Hagenbeek and Van Bekkum” used a rat believed.
model for human acute myelocytic leukemia (BNML) to It is not the contention of this discussion that normal or
investigate the efficacy of different TBI schedules (Table malignant hemopoietic cells are able to repair radiation
3). TBI with 900 rad in a single dose reduced the survival damage as effectively as are other normal tissues such as
of BNML cells by 4 logs and TBI of 900 rad in four daily the lung. Rather, it is intended to point out that the repair
fractions of 225 rad could reduce the survival by only I-2 capacity of hemopoietic stem cells or immunocytes may
logs. This significant difference in the efficacy of 900 rad have been underestimated. Further research on the repair
in a single dose and in fractionated doses to reduce the capacity of normal and malignant human hemopoietic
survival of leukemic cells was apparently a result of the tissues and that of the lung is urgently needed.
regeneration and repair of sublethal damage during the

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