The relative biological effectiveness of fast neutrons (42MeVd→Be) for early and late normal tissue injury in the pig

Inr J Rodrarwn Oncolog, Bwl Printed I” the L S A All r,ght\

Ph,br Vol reserved

??Symposium

8. pp

036&3016/82/12207745$03.00/0 CopyrIght D 1982 Pergamon Presr Ltd

2071~2081

II--Early

and Late Efects: Experimental

to Clinical

THE RELATIVE BIOLOGICAL EFFECTIVENESS OF FAST NEUTRONS (42MeV, .Bc) FOR EARLY AND LATE NORMAL TISSUE INJURY IN THE PIG J. W. HOPEWELL, B.Sc., PH.D.,’ D. W. H. BARNES, B.M., F.R.C. PATH.,’ D. T. GOODHEAD, B.Sc., D.PHIL.,’ J. F. KNOWLES, B.Sc., PH.D.,’ G. WIERNIK, M.D., F.R.C.R.’ ‘CRC

AND

M. A.

C.

M.Sc.,

YOUNG,

D.Ptir~.’

Normal Tissue Radiobiology Research Group, Research Institute (University of Oxford), Hospital, Oxford OX3 7LJ and ‘MRC Radiobiology Unit, Harwell, Didcot. Oxfordshire

Churchill

Early and late radiation damage has been investigated in a number of normal tissues in the pig after irradiation with single doses of neutrons produced by 42MeV deuterons on beryllium. The results have been compared with data obtained after irradiation with single doses of 250kV X rays. In the skin a low RBE value of approximately 1.2 was obtained for the early (3-9 week) epithelial reaction. For the subsequent dermal vascular response, higher RBE values in the range of 1.35-1.6 were obtained; the RBE decreasing with an increase in the neutron dose. For late skin damage, assessed by the relative reduction in the linear dimensions of an irradiated field, a RBE value of approximately 1.5 was obtained. In the kidney the RBE value, for a neutron dose level (550 cCy) at which renal function was just preserved, was 2.0. A lower value of 1.7 was found for doses resulting in a loss of renal function. The results of “‘Xenon clearance studies showed two waves of impaired ventilation function in the irradiated lung. In the acute reaction (3-9 months), at a dose level consistent with just preserving normal ventilation function. the RBE value was <: 1.2. For late Lung damage (15-24 months) the RBE value was higher, 1.4. For the rectum, methods ate presently only available for assessing acute damage. A RBE of 2.0 was found for neutron doses in the range 350-575 cGy. The RBE values for eatny endpoints in the skin, lung and gut of the pig ate comparable with those published previously for other species, including man. The values for late effects in pig skin and lung were higher than for early damage in those tissues. Radiation,

Normal tissue effects, Fast neutrons. INTRODUCTION

The results the

of an early

treatment

gested

that

of advanced there

only

randomized

clinical

head

and

was an advantage in radiotherapy.

later

studies’

not

there

is still

potential

have

value

tissues’ ies.”

However,

information This

is particularly

There

have

fibrosis that would

been

is

their

elTects

true

then

responses.”

have In most

the still

for

several after

sug-

The

the

(single

the results

initial

of

very a

of fast

late

clinical

normal reports

patients.” neutrons

been

were

predicted

pub’ished

reports

to

relative

on

clinical

stud-

obtain

more

tissue

changes.

of more

marked

Others

have

more

severe

from

the

of animal

Harwell,

acute

few

have

This

relative

products

beam

line

have

been

energy

on this

species and

by the

plota

previously.’ beam

energq

Establishment.

Details

bc the cyclotrons

This

of single

the variable

neutrons

the isodosc

doses investi-

tissucs.7.x.”

Research

reported

produced

produced

pig.

the effects

was

biological

are being

in the

bqllium.

and

that

and fractionated

out using

Energy

on

field

that

the

single

results

program

late etrects

tissues

were carried

U.K.

sizs

preliminary

doses of X rays on normal

dcuterons

neutron

and

normal

horizontal

twice

Reprint requests to: Dr. J. W. Hopewcll. A~,knoH’lrdgrnlr,nrsThe authors are indebted to members ol the scientific and technical statf of the MRC Radiobiologq Unit, Churchill Hospital Research Institute and Harwell Cyclo-

of both

at the Atomic

32McV

the

on-going

been used to examine

Irradiations

studies

describes

Early

in selected

cyclotron

than

examined:’

to examine

(RBE)

fractionated

noted

been

of ;I large

designed

has already

to photons.

have

report

neutrons.

gated

early

need

present

dose data)

efTectivcness

the

of neutrons

changes late lesions.“’

specifically

optimism

and exploit

of the effect

cRectiveness

in neutron-treated

late

from

early

described

in radiotherapy.

sirce

there

about

this

to explore

knowledge

has improved

turnorb.’

While

reinforced

of neutrons

Radiobiological

neck

involving

to be gained

use of fast neutrons

a need to continue

trial,

line

of

action the

of

fixed

for a range The

is more

presentI\

of

average than

based

in

tron Group. without whose help this stud! would not have been possible. The work W;I~ supported bq grants from the Cancer Raearch Campaign and the Medical Rcscarch Council. Accepted for publication 27 July 1982.

2077

2078

Radiation

hospitals next

at Edinburgh

generation

neutrons

and

based

investigations

doses

of

after

The

single

effects

the

used

after

regimens.

of analysis

to the study

with

skin,

kidney

lung.

to assess

An

radiation

relevant

exception

effect

and

damage

rectum;

was only

single

of the

fractionated

was the

instance after

single

to the study

clinically

used in this

of acute

:hc

produce

irradiation

doses are also applicable

irradiation type

included

methods

produced

will

FINDINGS

involving

neutrons

rectum.

However,

machines

energy.

EXPERIMENTAL The

0 B~ologj 0 Phyhich

Hammersmith.

of hospital

of this greater

Oncology

the

applicable

doses.

4

(51

(61

01

(51 I 1500

I

1000

Following neutrons,

irradiation

severity

of the dermal

months.

Pilot

skin tields I725

with

the dose tolerated

studies

with

reaction

neutrons

after

showed

that

single

with

1300 and

1500 cGy.

The skin changes

I6 weeks

after

the tirst

wave

reactions

(IO-

ble

X

ray

reaction

(3.-9

developing

weeks)

Fig.

dose

after

and

observed

severe

arc plotted

along

I.

second

For

response

the

curves*

the larger

the

of damage

level

represented

skin scores of I .5 to 2.5 (Fig. The both

earlier

tirst

wave

wave

reaction.

Only

erythema

mal,

no significant

with

absorbed average of

skin

score

neutrons

significantly X rays.

indicates

that

developed

(Figure

I);

specific

reactions,

necrosis,

an

dose effect

of

weeks)

than

X

After

after

and

second

was mini-

The dose

was

not

by 1800 cGy was

skin

scores

of

signif-

score

The

However,

paper

because

were

2.).

symbols)

indicated

of

Ih

or

relate

to

x 4 cm lields

RBE

‘average

after

neutron data

wave

reaction.

the dermis

be

practice.’

A

for der-

a higher

RBE

2).

at intervals

and comparing linear

from

the values This

obtained

this with

contraction

for the second

consistent

between

and subsequent

plotted

IO?% held

is

with

over

et al..x in Fig. 3.

Hopewell I .5 for

relationship

is

of 6. 9

them

contraction’

irradiation

of approximately

causal

sire

not

dusky/mauve

doses),

of these fields

The

erythema

of a held should

(Fig.

of a

curves

in I6 x 4 cm skin sites was assessed

with

suggested

neutron

irradiation

X ray

lack

in clinical

of I .5 was found

after

period

The

For the less severe.

the lengths

sites.

the dose effect

I .35 was obtained

(lower

was comparable

of

with

vascular

the

effects

in

late damage.h

Kidnr), 2

The

irradiated

the

is difficult.

that

reaction,

dose

developing

erythema points

(solid

9

seen

1.2. The

rays

wave

The data

in this

(Fig.

cornparable

as the

absorbed cCy)

of fields

ray

W;LVL’(3

?? ) reactions

experiments

of approximately

I2 months

time

data.

is accepted

tissue damage

irradiation

subsequent

hippuran

dusky/mauve

curves

what

of the order

control

neutron

observed

of the fields skin

I

series and no evidence

radiobiological

reaction

Late

the second

reaction

average

45%

for the proportion

are included.

necrosis

numerical

of approximately cGy

important

mal

average

produced

of average

have been plotted.

fields

that

the lir\t

values

number

in the neutron

with

value

value

(1500

The

on the combined

RBE

at

by the largest

X

RBE

in the X ray studies”

in these

effects

red erythema.”

for the curves

are based

for dermal

1 IO0 to 1500 cGy.

study

for both

with

The

reaction.

of fields

crythema

wave

from

approximately

bright

has a numer-

seen.

irradiation

si7e effect

of

response

a RBE 2070

interpretation

Therefore,

*The

from by

response

large

this

suggests

produced greater

The

in

different

This

reaction cantly

in the tirst

produced

used

was

scorch

( IO I h weeks:

wave

is given in parenthesis.

confused

necrosis

RBE

(3-9

kGy)

reaction

symbols).

wave

irradiated

effect

dermal

steep,

was less severe

dose was increased

after

(open

second

values

response

dose

the

skin

by measuring

erythema

irradiation

wave

I).

skin

X rays and neutrons,

by

in pig skin

field

compara-

wave

used).

obtained

i2rcr:qe

0 0) and second

number

for both

second

doses. (Necrosis

of I .4 to I .6 were

a numer-

with

are

ical score of 5.5 to 6.5 on the scheme the order

1 2500

in the first

using

skin scores

more

on the

doses of I 100,

assessed

The average

I6 weeks) in

absorbed

were

system.*

data the

neutron

I

f’ig.

weeks;

neutrons

16 x 4 cm fields

skin were irradiated

ical skin scoring

doses of 2

necrosis.

dose study

irradiation

3-4

of 6 x 4 cm

absorbed

Dose

by the

approximately

the irradiation

100% dermal

181

doses of X rays’ and

by the skin was limited

involving

cCiy produced

For the main

single

(16) I 2000

(281

and

the

dermal

for small

and

of the limited

drawn

by eye.

renography

described

carried

out

irradiation

at

renal

for

function

in each

tissue

was undertaken

intervals

are given

kidney of

previously.’

are also tabulated. obtained

of a single evaluation

of

in Table A RBE

the greatest was preserved

animal.

damage

by

in a similar

The

results

of

3-12

months

after

I. Equivalent

value neutron (550

way

to

renograms neutron

X ray doses’

of approximately dose at which cGy).

and “I-

2 was normal

Fast neutrons

1000

1500

for tissue injury in pig 0 J. W.

2500

2000

et al.

HOPEWELL

1000

2079

2000

1500

2500

Dose kGy) Fig. 2. Dose related change in the proportion of skin fields developing dermal necrosis or a dusky/mauve erythema (16 x 4 cm fields, A X rays, 0 neutrons; 6 x 4 cm fields, 0 neutrons; 4 x 4 cm fields, 0 X rays; combined data, A-A X rays, )_a neutrons). RBE values are given for the IO and 50% levels of incidence.

Lung

250kV

The irradiation

with neutrons

the lung in each pig involved used for x-irradiation.‘3 of

the

cyclotron

a similar

However,

generated

of a single basal lobe of size of field to that

the greater

neutrons,

penetration

compared

with

X rays, produced

maximum

variation

Ventilation

function

with

that

“‘Xenon

reduction

in the

in dose across the irradiated

an appreciable

lung.

in the irradiated

of the normal clearance.”

lung in the same animal

Function

was studied at 3 monthly x-irradiated cated

animals.

reaction

have

irradiation.ls

pigs

but more frequently

The results

of these studies

ventilation

15524 months.

been

reported

in

The results obtained

function

in indi-

after

the clearance

indices were determined

X rays

z 120% represents

and

neutrons,

a significant

Comparable mouse

waves

lung

after

over the early and late

periods in the pig have been averaged ods after

using

irradiated

the first, or early wave, after 3-9 months and

the second wave from of

in neutron

intervals,

two waves of impaired

irradiation;

lung was compared

(Table

2). Although

by different

a clearance

impairment

meth-

index

of

of ventilation

Table I. Results in renograms in pigs after single doses of neutrons (42MeV, +)

Absorbed dose (CGY) 450 550 650

750 15bo

Dose

20-00

2sbo

(cGy)

Fig. 3. Dose releated changes in the relative length of I6 x 4 cm skin fields 6-l 2 months after irradiation (D--m neutrons, A-A X rays).

850

Time after irradiation (months) Pig no. 16 8 I8 9 I2 19 IO 13 20 7

3

6

9

12

F F F F F F F F F __ ~ F NF F RF MF MF F RF RF RF NF NF NF NF MF NF NF MF F F F* NF NF NF NF MF NF RF MF

Equivalent x-ray absorbed dose (CGY)

RBE

1070

2.0

I I65

1.8

1260

I.7

*Hypertrophy of non-irradiated upper pole of irradiated kidney, due to geographical miss. F = Normal function; RF = Reduced function; MF = Minimal function; NF = No function.

2080

Radiation

Oncology

0 Biology

0 Physics

December

1982. Volume

8. Number

I?

Early (3-9 month) changes in the relative 2 (A). clearance of “‘Xenon from pig lung after X rays and neutrons 42MeV, .Re

Table

X rays

Absorbed dose (CCY)

Neutrons

No. of Clearance index animals

%

2 II6 2 IO 810 ______________________~~~~~~ 2 4 3

980 II50 1325

I21 ? 4 136 + 5 I68 t 7

Absorbed dose

No. of ani-

Clearante index

(CGY)

mals

7r

I

I

600 2 107 r 3 700 2 II2 i 4 __--_-~~~~---~-~~---~~~ 800 900

2

1

I

I35 + 2 I71 * 5

Table 2 (B). Late (I 5524 month) changes in the relative clearance of ‘l’Xenon from the lung after X rays

i

.?,

and neutrons 42MeV, .RF Neutrons

X rays

Absorbed dose (CCY)

No. of Clearance aniindex % mals

Absorbed dose

No. of ani-

(CCY)

mals

%

600 810 700 2 I05 ? 3 980 ___------_____-_____-~~~--_-~~~----~~~~~~~~~~~~~~~ 2

II50 1325

I

155 15 I41 + 7

1\ Clearante index

800 900

Broken line indicates suggested “tolerance” from Moustafa and Hopewell.”

2 2

II4 II3

I I

I38 i- 4 173 f 6

i \

* 2 + 3

level. X ray data

At the maximum dose levels consistent with preserving normal ventilation function the RBE for early effects was < 1.2. It was higher (-1.4) for late changes

2to

560 Dose

?jC

l&l3

kGy)

Fig. 4. Dose releated changes in the reduction in cellularity of the crypts in the pig rectum (arbitrary units) in the period 2-7 days after irradiation (+-+ neutrons, H y rays).

function.

(Table

2).

Rectum

Rectal biopsies were taken from individual animals at daily intervals after irradiation and from these, biopsies sections were prepared for histological analysis.” The results of this analysis indicated that in the first 7 days after irradiation, with both neutrons and cobalt -60 gamma rays, the maximim reduction in the cellularity of the rectal crypt and the time for it to repopulate was dose related. The severity of the damage to the rectal epithelium was assessed, in arbitrary units, by measuring the area under the curves created by plots of crypt cellular length against time (2-7 days). The slopes of the dose effect curves for neutrons and gamma rays suggest a RBE value of about 2 over the range of neutron doses used (Fig. 4).

CONCLUSIONS The results of the present study involving irradiation with single doses of neutrons suggest that in the skin and lung, where it was possible to measure both early and late effects in the same animal, the RBE for late damage was higher than that for early effects. A comparable result was obtained for pig skin after fractionated doses.‘” The RBE values for neutrons produced by the Harwell cyclotron can be compared with the more extensive data obtained using the Hammersmith machine4 if a factor of 1.2 is applied. This factor was derived from RBE values obtained using two machines.’ This comparison after correction indicates good agreement in the RBE values for early effects in skin, lung and gut between the two centers. This is encouraging in view of the different animal species and assay methods used. The results of experiments involving the irradiation of normal tissues in the pig with fractionated doses of neutrons are now awaited.

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neutron beams generated with I6 and 42MeV deutrons on beryllium. Brir. J. Radiol. 49: 360-366. 1976. 3. Catterall, M., Sutherland, I., Bewley, B.K.: First results of a randomized clinical trial of fast neutrons compared with

Fast neutrons

4.

5.

6.

7.

X or gamma rays in treatment of advanced tumours of the head and neck. Brif. Mea’. J. 653-656. 1975. Field, S.B.: An historical survey of radiobiology and radiotherapy with fast neutrorls. Curr. Top. Rad. Res. 11: l-86. 1976. Goodhead, D.T., Berry. R.J., Bance. D.A., Gray. P., Stedeford. J.B.H.: HigkI energy fast neutrons from the I. Physical characterisHarwell variable energy cyclotron. tics. Am. J. Roentgenol. 129: 709-716. 1977. Hopewell, J.W.: The importance of vascular damage in the development of late radiation effects in normal tissues. In Radiation Biolog_~, in C‘ancer Research, R.E. Mcyn. H.R. Withers (Eds.). N.Y.. Raven Press. 1980. pp 449 459. Hopewell, J.W., Berry, R.J.: Radiation tolerance of the pig kidney: A model for determining overall time and fraction factors for preserving renal function. Int. J. Radiat. Oncol. B&l.

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Hopcwcll. J.W., Young. C.M.A.: The effect of field si7e on the reaction of pig skin to single doses of x-rays. Brit. J. I. 19132. Radiol. 55: 356-36 IO. Hussey. D.H., Gleiscr. C.A.. Jardinc. J.H.. Raulston. G.L.. Withers, H.R.: Acute and late normal tissue effects of 50 Biolog), in C‘ancer MeV, .,,< neutrons. In Radiation

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R.E. Meyn, H.R. Withers (Eds.). N.Y., Raven Press. 1980. pp. 47 I -48X. Hussey. D.H.. Parker, R.G.. Rogers, C.C.: Evolution of dosage schedules at the fast neutron therapy facilities in the United States. 1111.J. Radial. Oncol. Biol. Phys. 2 (Suppl. 2): 225-260. 1977. Kingsley, D.. Gad. A., Catterall, M.: Adenocarcinoma of the stomach: Radiological and pathological correlation of effects of treatment with fast neutrons. Girt 17: 624-623. 1976. Moustafa. H.F.. Hopewell. J.W.: Measurement of lung function in the pig after local x-irradiation. In RadiohiologVol. I. Vienna, IAEA. ical Research and Radiorherap),, 1977, pp. 75 ~X3. Stone. R.S.: Neutron therapy and specific ionization. .4n1. J. Roentgenol. 59: 77 I 785. 1948. Travis. L.E.. Down. J.D.. Holmes, S.J.. Hobson. B.: Radiation pncumoniti\ and librosis in mouse lung assayed by respirator! frcquerq and histology. Rudiat. Rex. 84: I33143. 19x0. Wtcrnik. G.. Pcrrins. D.: The radiosensitivit) of normal human rectal mucosa to irradiation in hyperbaric oxygen. Bri/. J. Radiol. 45: 737 744. 1972. Young. C.M.A.. Hopewell. J.W.: Functional and morphological changes in pig skin after single or fractionated doses of X rays. Inr. J. Radiar. Oncol. Biol. PhJt.v. 8: I539- 1548. 19x2. Research.

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