Cki,w_~ Jmraa/of Cancer Research 5(1):19-23, 1993.

THE EARLY RESPONSE OF PIG SKIN TO FRACTIONATED DOSES

OF 35 MeV P-Be FAST NEUTRONS IRRADIATION

Wang Junjie t ~ i ~ . ~ , , Di Wei ~ Li Yagang

Department of Radiation Oncolo~, First Teaching Hospital,

Beijing Medical University, Be/ring 100034

Shen Wenjiang ~ 3 ~ ] :

Department of Radiation Oncology, Beifl'ng Institute for Cancer Research, Beijmg 100034

Tang Jinghua ) ~ q ~ Chang Weike ~ ' ~

Department of Neutron, High Energy Physical Insti~ute, Chinese Academy of Sciences, Belting 100039

The early responses of pig skin to fraeflonated doses of

fast neutrons (35 Mev P--~B) were determined. A neutron

fractionation scheme comprised of 12 fractions in 42 days.

The lowest doses of I, II, HI degree erythema of pig skin by

irradiation were 16 .38 , 17.32 and 19.78 Gy respectively.

The EDs0 Values for moist desquamation was 23 .40 Gy.

The mean latency of early pig skin damage was prolonged

with the decreasing of total do~e. The degree and the

incidence of early pig skin damage were associated with total

dose.

These results for fast neutron therapy facility can be

extrapolated to the human situation with a high degree of

confidence, so that the neutron dose which would yield

acceptable skin damage in patients may be determined using

the data presented here.

Key words: Fast neutron, Erythema, Moist desquamation.

The radiobiological rationale for the use of

fast neutrons in radiotherapy has been extensively

discussed. These radiobiological considerations and

the favourable results of a randomized clinical trial

formed the basis for an extention of the clinical use

of neutrons in the mid of the late 1970s , l involv ing

numerous centers throughout the world. In 1989,

a 35 Mev fast neutron facility was made in our

country. It is important to perform a number of

preclinical radiobiological investigations, which

include establishing the tolerance levels of normal

tissues to radiation. Studies are described here in

which pig skin was subjected to fractionated

neutron radiation, and the initial epidermal

reaction of erythema, dry and moist desquamations

were assessed. Pig skin in structurally similar to

human skin. 2,3 Its response to photon is

comparable to that seen in man ~'s and it was

established as an animal model for the assessment

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of radiation-induced damage. 6,~

MATERIALS A N D METHODS

Animals

The large white pigs (one male and too

female ) were used throughout the exper iment ,

with weighing approximately 2 0 - 25 Kg. At the

begining of the studies, five sguare fields, taking

the size of 5 X 5 cm, were delineated on the right

f lank of the pigs (Figure 1) as close as possible to

the middle. Four fields were irradiated and the

fifth served as a control for growth during the

experiment. Fields wer separated at least 7 cm a

part.

Fig. 1. Field arranged on minature pigs.

Anaesthesia

The pigs were anaesthetized with Ketamine

(15 m g / K g ) , in about 10 minutes before

irradation.

Irradation

The fractionation pattern is that used for most

of the patients receiving neutron therapy. All

neutron irradations of pig skin fields were

performed on the Neutron Therapy Department of

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High Energy Physical Inst i tute, Chinese Academy

of Sciences. The neutron of 35 Mev protons on a

BerUium target of thickness. Full charged partical

build-up was provided by a 6 X 6 square of A 137

Tissue-equivalent plastic of thinckness 1 cm, again

taped to the skin. Measurement of the cross-plane

profile of the fast neutron beam, at a depth of 2

cm in water with a 5. 3 X 5. 3 cm field showed that

10 cm off-axis the dose was still 2 % of the centre

axis dose, but then it droped gradually to 1% at

about the 25 cm of f -ax is , where it remained at this

lever up to 46 cm of f -ax i s , the gramma dose was

4 ~ of ail the total dose, the distance from target

to skin surface was 137 cm, the variat ion in dose

rate from the center to the edge of the field was less

than 2 ~ . Pigs lay on their abadomen and a

vertical radiation beam was used. Details of the

fract ionat ion, number of fields and radiation mode

are given in Table 1.

Tab/e 1. / ~ e fract/onat/on s c ~

Total dose No. of Radiation mode

(Gy) fields

P-Be neutron irradiation 19.8 3

12 fractions/42days 22. 0 3

24.6 3

27. 0 2

Irradiation was given two days per week on

Tuesdays, Fr idays for 6 weeks. A fractionation

scheme was originally envisaged for therapy.

Observation

The pigs were penned individually and the

irradiation skin fields were scored visually for

damage. The severity of the skin reaction was

accessed using a scoring system,7'8 at least four

observers recorded separately the epidermal

response of e ry thema, dry and moist

desquamation. The ear ly epidermal reactions were

assessed weekly for 9 weeks. The incidence of

moist desquamation over 9 weeks was used as an

endpoint. Quantal responses were used for probit

analysis to establish dose -e f fec t curves and to

Calculate EDs0 Values ( ~ 8~). The EDs0 Value is

the dose required to produce a resvonse in 50°~ of

the number of skin fields.

Tab/e 2. P/g sk/n reach/on: scot/rig system

0. normal

1. Faint erythema

2. Moderate erythema: Bronzing or white flakes when healing <50°~ fields

3. Marked erythema: Bronzing or white field ~ 5 0 %

4. Dermal oedema or paper skin over whole field

5. Moist desquamation <=20~ of fields

6. Moist desquamation ~ 5 0 % of fields

?. Moist desquamation ~ 8 0 % of fields

8. Complete moist desquamation of fields

9. Definite epidermal necrosis

10. Definite dermal necrosis

RESULTS

Mean Latency for the Development of Early Skin

Damage after Fast Neutron ( 3 5 Mev P - - ~ B )

Irradiation

Table 3 shows the results of irradiation two

times weekly in 12 fractions. The mean latency for

the development of ear ly skin damage was

shortened with increasing total dose.

Table 3. Mean latency of the development of early skin damage

after fast neutron irradiation (days, ~ :h s~ )

Fractionation Fractional dose

(Fractions/days) (Gy)

The degree of pig skin damage

I I ! V

12/42

1.65 30. 32±2. 91 31" 41" --

1.85 27 .00+1.00 35. 67-4-2.33 41.00:h0. 00 46"

2.05 25.00~0. 00 32.33+1.33 38.00/ :0 .00 44. 00+1.18""

2.25 23 .32+2.33 29 .67+3.28 36 .54+1.50 42 .50~2.58""

" 1 field * "2 fields

The days are after the first irradiation.

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Mean Doses of Early Skin Damage after Fast

Neutron

Table 4 presents the results of irradiation twice

weekly in terms of degree of early skin damage,

which is associated with total dose . The higher

the total dose , the more sever the pig skin

damage.

Table 4. Mean doses for the development of early pi 9 skin damage

after fast neuron 35 Mev P-B (Gy, zq-sl)

Fractions/days Fractional dose The degree of pig skin damage

I I l V

t.65 t7.01d=.32

1.85 16.384-0.53

12/42 2. 05 17. 604-1.15

2.25 17.67±1.48

17.32" 19. 78" --

21. 254-0. 92 22. 194-0. 02 22. 17"

21. 594-0. 66 24. 604-0. 01 24. 614-0. 02" "

21. 054-0. 35 26. 154-0. 86 27. 01:/=0. 01" "

* 1 field * * 2 field

The incidence of Moist Desquamation after

Irradiation

The dose-related changes in the incidence of

moist desquamation after irradiation with

fractionated doses of fast neutrons are shown in

Figure 2 . The increment in dose was required to

i0(

.,'t

X

3'o Dose ( Sy )

Fig. 2 Isoeffect curves for moist desquamation

in pig skin after irradiation with fractionated doses

of fast neutron (35 Mev). Error bars indicate ( z +

sD.

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increase the incidence of moist desquamation

greatly. When the total dose reached a certain

scope, the incidence of moist desquamatibn was no

more significant relation to the increasing of total

dose.

DISCUSSION

Pig skin damage produced by fas~ neutron

were qualitatively similar to that produced by

gamma-rays and X-rays . 9 Irradiation of the skin

with fast neutrons produced two distinct waves of

radiation response similar to those previously

reported. 9 Depending on the radiation dose, the

first wave reaction was characterized by erythema

and , after higher doses, by erythema together with

moist desquamation. The erythema reaction of I

and II pig appeared at the third week after first

irradiation, then developed moist desquamation;

the damage of III pig was characterized by dermal

desquamation and accompanied by ocdema, then

developed moist desquamation. The mean latency

of moist desquamation appeared at the sixth week

after first irradiation. This result was qualitatively

similar to that observed by Hopewell. 9 The degree

of early skin damage was associated with total

dose. With the increasing of total dose, the

incidence and the degree of early pig skin damage

would increase significantly.

The EDs0 Values obtained for moist

desquamation can also be compared with those

reported EDs0Values of 24 .78 (42 Mev p___~Be)9

and 2 4 . 7 8 Gy (66 Mev P--~Be)l°respect ively for

the early skin response, after 6°Co and 250KV-X

rays irradiation The ED50 Values were 64. 569 and

61. 08 Gy. 9 It can be infered that the lower dose

irradiation of fast neutron will bring about sever

damages.

The moist desquamation period of pig skin

lasted 7 - - 14 days , then scrabed, droped,

gradeually replaced by newborn skin. The late

damage of pig skin required to be observed and

reported intensively.

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