International

Cancer

Research

Low Dose

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EDITED

BY

Workshop

Rate Teletherapy J.

FRANK

WILSON

long

The International Cancer Research Workshop on Low Dose Rate Teletherapy was held in Lake Geneva, Wisconsin, May 4 and 5, 1978. Proceedings will be published later. Inquiries regarding the Proceedings as well as for reprints of this section should be directed to J. F. Wilson, Department of Radiation Therapy, Medical College of Wisconsin, 8700 West Wisconsin Avenue, Milwaukee, Wisconsin 53226. This project was supported by funds provided in part by the International Cancer Research Data Bank Programme of the National Cancer Institute, National Institutes of Health (U.S.) , under contract no. NOl-C0-6534l with the International Union Against Cancer.

exposures

therapeutic curves for ciable of the

initial survival

As becomes

dose-rates

the of

of

dose-rate shallower to

is and in

an

doses

in culture, dose-rate

interest

approximates

of the for cells

accumulation

irradiated at high

low

varies and

the

reduced, the slope the shoulder becomes dose-rate

exponential

dose-rate effect which accumulate

in

the survival have an appre-

tele-

function

with repair

of

the cell sublethal

dose.

system; radia-

effectively, and small for cell systems that do not. curves for low dose-rate irradiations can be made much by the concurrent application of a modest level of hypertherin.ia. A six hour exposure at 41#{176}C, given during or immediately

Considerations

damage

after

irradiation,

although

it

low

dose-rate

For

cells

steepens

does

not

of

with

there

cycle

radiosensitivity sublethal damage, their which cells accumulate

as a result of

of

with

accumulation is cell population posure following

therapists of

Findings

or

There

cultured

in

low

low dose-rate excellence” for

to,

is evidence

vitro

that

dose-rate

radium some

from

cells

a num-

accuimilate

irradiation.

implants

types

to cycle

This

of

as

of x-ray

tumors.

This

at

of an implant, b) the low dose-rate energy is deposited continuously

superiority

distribution,

dose-rate cacy

from low

On

regimens. with low

be needed rate beam the

a

the

other

to prove teletherapy

hand,

theory. Thus it lation

the justified

of

Dg:

Phillips San

sublethal

damage.

ship

and

cause

will

the

also diation

of

may

if the

the the dose

by

low

reported

eff i-

factors, resulting then beam teletherapy to conventional multi-

some

of

have

the

at

principles

been

a greatly

Dq

be

dose

elucidated

in

trials will of low dose-

improved

result

of

Radiation

Oncology,

94143)

in radiobiology, and based on multitarget equation: potential

mammalian

cells.

Dq for D

is

de-

D0ln (1t. the accumuimportant

to accumulate

and/or repair subtime-dose relationfractionation effects. Be-

input

into

rate

and

depends

on

any

radiation

the RBE. by tissue

rate,

measured

CA

concept survival

ability

dose

the

(Div.

the following width of the in

a major

changes in is influenced

quality,

Dq

is

predict

size

predict The Dq

the

It

old cell

by the

damage

it predicts

lethal

TL

Francisco,

It is expressed is a measure of

because

by

that If

localized

shared

controlled clinical cost and inconvenience

whether are

California,

of

the

be

However,

The Dq is a relatively from the formula for

rives

of not

se, as a dose-rate

low

the fact 7 weeks.

level.

Importance of

c) to

result will

At the present time dose-rate irradiation

studies.

clinical

Univ.

The

is

advantages

teletherapy.

radiobiological

The

implants

their

dose-rate, in contrast

of implants stems from radiobiological the protracted continuous exposure, dose-rate could prove to be superior

fraction associated

at

in

of

then

at high 7 days

a cx-

Many radiotreatment

the

human

characteristic result of which

intermittently is delivered

the

repair

fractionated distribution

than dose

two,

to cellular irradiation.

and their ability to time, and the extent phase of the mitotic

exposure.

cells

a continuous

of

comparable

reflected in an increased radiosensitivity as judged by their response to an acute a long irradiation at low dose-rate.

“par

alleged

Historical Perspectives of Clinical Radiotherapy at a Low Dose Rate. Pierquin B The Potential for Clinical Exploitation of Low Dose Rate Teletherapy. Suit HD, Brown BW, Soriano A Current Results of an E.O.R.T.C. Trial Comparing Low Dose Rate and Classical Fractionated Treatments of Base of Tongue Epitheliomas. Baillet F Clinical Applications of Hyperfractionated (HFI) (8 and 16 fractions per day) Concentrated Irradiation. Castera D, Loirette M, Dutreix J Clinical Experience with Low Dose Rate Therapy at the Rotterdarn Radiotherapy Institute. Kuipers Tj Low Dose Rate Teletherapy of Unresectable Carcinoma of the Pancreas. Results of a Pilot Study. Wilson JF

factor

alleged superiority of implants over conventional beam therapy may be due to a) the localized dose

rather total

Considerations

a

of gamma-rays on a cycling cell factors. These include the in-

of

regard

choice

by

than,

of the cells mitotic cycle at a sensitive

prolonged

studies

or M during

curve

cells. Hyperthermia and to be an effective combination.

any

shorter

given dose-rate on a number

trinsic

in C2

prove

is a further dose-rate effect due can take place during a protracted

which of a depends

survival kill

may

a m.itotic

time,

proliferation

ber

the

itself

irradiation

The efficacy population

Response of Bone Marrow and Tumor Cells to Acute and Protracted Irradiation. Thbiana M, Boisserie G Variations in Radiosensitivity and in Dose Rate Effects Among Various Types of Cultured Cells, Turnours and Normal Tissues. Barendson GW Effects of Single and Fractionated Doses Applied at Low-Dose Rates on Rat Skin and R-l Rhabdomyosarcoma. Kal HB The Dose Rate Factor of In Vivo Continuous Low Dose Rate Irradiation of Tumor and Normal Tissues. Fu KK Modification of Gastrointestinal Death in Mice Exposed to Whole and Partial Body Exposures of Low Dose Rate Irradiation. Swartz HM, Reichling G, Stark R, Been A, Wilson JF Clinical

the

Survival steeper

Dose-Rate Effects in Radiation Therapy and Radiation Biology. Hall EJ The Importance of 0 . Phillips TL Implications of Initial Portion of the Survival Curve for Low Dose Rate Teletherapy. Elkind MM Tissue Responses to Multiple Small Doses of Irradiation. Withers HR Comparison of Low Dose Rate and Fractionated Irradiation for the Early Reactions of Skin and Intestinal Mucosa. Dutreix J, Loirette M, Boisserie G, Warnbersie A, Stienon-Moes MR Alteration of Cellular Proliferation in Various Cell Lines Exposed to Low Dose Rate Irradiation. Bedford JS Laboratory

the

survival

The magnitude it is large

tion

for

shoulder. curves

At

therapy,

exposure

Current

necessary

range. For cells acute x-ray exposures

smaller.

CONTENTS

Theoretical

on

type,

chemical

indirectly

quality, cell

agents, in

vivo

age, and

by

it

will

hypoxia,

ra-

hyperthermia.

determining

the

rads

recovered per fraction when a 2-fraction exposure is compared to a single fraction exposure. The value of D2 - Dl in this situation is

THEORETICAL Dose-Rate

Hall EJ Surgeons

equal

to

the

Dq.

Using

this

is seen to increase from lung, 400 for small intestinal

CONSIDERATIONS

Dq

Effects in Radiation Therapy and Radiation (Radiological Res. Lab. , College of Physicians of Columbia Univ. , New York, NY 10032)

Biology: and

131 :1105-1110,

© 1978 American

Roentgen

December

Ray Society

1978

and 845 for esophagus. Cells are known to have

zero

Dq

repair small

A very wide spectrum of dose-rates has been used In experimental radiobiology and clinical radiotherapy. The range of interest for low dose-rate teletherapy spans from about 50 to 200 rad/hour. Repair of sublethal damage can take place during the

Am J Roentgenol

ney,

thermia,

during under

severe

shoulder at

mitotic hypoxia;

or absent least

Radiation occurring with

1105

the

above

quality increasing

technique,

135

rads

the

for

mucosa,

bone

700

for

indirectly

marrow

derived

to 375

brain,

715

for

for

kid-

little or no shoulder and essentially phase; are known to show very little and

are

shoulder

known

under

to

demunstrate

conditions

a very

of hyper-

42-43#{176}C. influences LET.

For

the Dq, with decreasing example, the estimated

0361-803X/78/1200-1

Dq’s Dq

105 $00.00

LOW

1 106 based

on

either

intestinal cobalt,

or

tion,

or

D1

-

data

cells

4 MeV

0 rads

plateau

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D2

crypt

to

carbon

estimated

at

Dose rad/minute,

rate influences the Dq drops

from 200

peak,

around

rads

neon

radiations.

150

extrapolated

decreases

radiation

for peak

or

DOSE

for

survival

curves

350

for

rads

helium

plateau

or

Conversely,

15

RATE

peak

peak,

MeV

using

duce

Certain chemical or inhibit the

‘37Cs

the Dq in that for intestinal

from

and

370

to

agents may also repair of sublethal

for

EMT6

show

tumor

influence damage.

hours

the

to

zero.

before

Dq

irradiation.

and

a Dq

the Dq as they reMost a8ents cause

Cyclophosphamide

bleomycin,

Two-dose

at

a dose

survival

reduced

D

with

duction

i

survival

the

of

ratios

has

100

mg/kg,

confirm

the

drugs

mentioned

above,

ratio

occurring

with

1 0

cells.

a small effect on the 0 however, with D ‘s for 13’Cs from 350 rads to around 300 i’ad with actinomyin, adriamycin, 5-fluorouracil, methotrexate, cis-platinum, and vincristine no

the

bleomycin

satisfactory.

doses

are

given

tions

are

sufficiently

tions,

and

repairable additional

the

has

killing

by

injury

small

been

dose

enough

each

curve

rads

is

the curve has give results

all

from

the

D0

to show

frac-

is slope Also,

is

non-

results Using for

in these

the

the dose Although

no

dose range most

of cell

mecha-

from exponential. agreement with

Other these

values. Thus

it

radiobiology

apply dict

can

be

seen

as

applied

to certain

newer

the

ability

situations

useful

in

of

that to

the

formulae

cells

Dq

is

to

for

cell

repair

term

though

it

survival.

sublethal

can

predicting

important

even

arise clinically the effects which

which

an

radiotherapy,

in

It does

damage

under

This CA-ll138.

not pre-

may

investigation

of

Low

Dose

Early Reactions of Loirette M, Boisserie

Dose

of

Rate

Argonne

the

Initial

Teletherapy:

National

Lab.

,

Portion

of

the

Survival

Elkind MM (Div. Biological Argonne, IL 60439)

Curve

for

& Med.

Low

France)

and

Brussells

rate teletherapy may teletherapy to larger

and

smaller

doses.

Accordingly,

Res.,

is

logical

to

think

of

fewer

cells

are

killed.

The

resulting

part

by

change

in

shape

of

the

tion

NIH

grant

The at

Stienon-Moes

MR

irradiation

for

(Centre

des

Tumeurs,

the

isoeffect

total

dose

of

more

precisely

sublethal

to

injuries

less

when

cell

the

frac-

dose

size

increases

becomes is

to

a maximum

sufficiently

entirely

due

which

small

to

direct

treatment,

the additional which is related

the isoeffect dose 13 Gy (single dose) abdominal irradiation

from after

dose to

reached

the

lethal

systems considered this situation size is less than 2.00 Gy.

Disregarding repopulation, and

is

that

killing

events.

For

is achieved

needed to the overall

when

cell

compensate time of

increases for human skin desquamato 22 Gy (maximum) and for LD 50/5 on mice, from 12.50 Gy to 22.00

Gy. For

dose

continuous

irradiation

to increase

the

cellular

repair

a

have

random

place

been

repair

expects

with

taking

Calculations assuming

one

monotonously

during

made

of

the

isoeffect

irradiation on

a

sublethal

time

the

total

on account

2 component

cell

injuries;

they

model allow

com-

puting

the isoeffect dose as a function of the irradiation time. Experiments have been carried out on mice with abdominal irradiation: the LD 50 at 5 days increases with the irradiation time

from

(14

h.).

puted

can no

12.40

Gy

These

values

values.

(acute

Thus,

be explained

the

by

dose)

to

in

excellent

are

dose

the

skin

treating

desquamation

the

total

with

role of irradiation

kVp).

equivalent

h.)

and

the

Gy

(at 12 Reactions by 15.00

time

and

there

dose

up

is

to

to 12 hours

much

less

explained

compared supported

the

relative

dose

because

rate. some

efficacy

of

If

events

low

dose

the

beginning

of

are

repaired

during

rate

the

teletherapy

to conventional fractionated teletherapy. by the U. S. Department of Energy.)

fication in

a

dicted

by

Thus

Responses

of

to radiotherapists

tissues

to

but

doses

are

of

difficult

about

200

rads

to quantitate.

are

of

Most

inter-

tis-

age

in 3 days) the

distribution

up

irradiation

the

total

it is mechanisms

advantage

conventional

of

injuries: events. can bring

of curietherapy. suggested for

The role of desquamation

attention.

Gy. The skin to low dose rate

an

time

experia modi-

accumulation

of

is 22.00

skin

time injuries

necessary play an the

fractionation

repair of sublethal by directly lethal and reoxygenation

some

dose

irradiation sublethal

to 12 hours

therapeutic to

with

For

than

24

hours

Gy,

the

of

cells

(actually

value

pre-

computation.

radiobiological A

respect

cell phase.

for this 24 hour by the repair of

times

other

Tissue Responses to Multjple Small Doses of Irradiation: Withers HR (Sect. Experimental Radiotherapy, Univ. of Texas System Cancer Ctr. , M. D. Anderson Hosp. and Tumor Inst. , Houston, TX 77070)

the

3 x 8 hours

tion

(Work

of

sensitive

human

the observed value is 13.00 Gy acute dose were delivered in 12 hours

determining

reduced

steep,

is

by

fields

times

acute hour to Gy

Gy corn-

mechanisms. been compared

irradiation

13.00

the

irradiation

injuries

other have

22.00

with

supraclavicular

For

to

from the calculation instead of 20.50. to those produced

(6

of sublethal

bilateral

(250

dose

expected 15.00 Gy comparable

Gy

agreement

increase

repair

evidence for any significant Low dose rate and acute

simultaneously

20.20

exposure, the total dose required to sterilize a tumor--or to produce a given level of damage in normal tissue--will be larger than predicted on the basis of the shape of the acute-exposure survival curves of the respective cells in question. As in other unconventional mudes of radiation therapy, therefore, a differential in the influence of repair on the initial slopes of the survival of normal tissue cells versus tumor tissue cells may be the factor

with

less

of

irradiation.

is, as suggested by other hypothetically ascribed to

change

the

for the

dose was 20.50 more sensitive

becomes

the

when

irradiation than predicted; this ments reported at this meeting,

will

curve

UCL

in-

whereas the predicted necessary therefore appears to be somewhat

curve

the

Dutreix J, Villejuif,

When the overall time is kept be ascribed to the additional

fractions,

accumulation

fraction

biological fraction

tion days

A,

between

to

total

each

Irradiation

diminishes.

fraction

sur-

vival curve is generally attributed to a flattening of the mid- to large-dose portion of the curve because the initial negative slope is customarily assumed to represent a contribution to cell killing from so-called “single-hit” action. Single-hit effects do not require the accumulation of damage for expression; hence, they are assumed not to be modifiable by reducing the dose rate. A theorem of T. A. Hall--overlooked for many years--indicates that exponential, so-called “single-hit” survival can result when absorption events are accumulated in the target in a particular way. The relevance of this theorem in the context of potentially lethal damage and its repair was recently discussed. In particular, it was pointed out that repair competence may play a major role in influencing the sensitivity of cells exposed to radiations of different qualities. The applicability of these considerations to therapy depends upon if, and in which direction, the initial slope of a survival

due

size

the

Fractionated

fraction number. dose increase can

repair

killing

and

and Intestinal Mucosa: (Institut Gustave-Roussy,

G

Wambersie

with the

cellular

the

radiobiology involved as a projection of the radiobiology of acute, single exposures to hyperfractionation. This approach leads to the inference that the initial shape of the single-cell survival curve critically influences the shape of the isosurvival curve (i.e. , the dependence of total dose, TO, to reach a given level of survival on the number of fractions, N). In particular, if the single-cell survival curve has a zero initial slope, the isosurvival curve TD increases with N without limit. But if the initial slope is negative--such that the beginning of the curve is described by a negative exponential--TO rises to a plateau. The level of this plateau decreases with increasing steepness of the initial slope (or the smaller the D0 of the initial slope). It is well known that the shape of a single-cell survival curve depends upon the dose rate of the radiation exposure. Even if cell division during exposure is discounted, at a low dose rate repair of sublethal damage will occur during exposure, and hence

Rate

Skin

fractionated

creases constant

be viewed as an extension of and larger numbers of smaller

it

in

Belgium)

,

For

dose fractionation Low

supported

a range

Comparison

Implications

was

and, therefore, can be would occur at low dose

rates.

eat

will if

through

(single-hit)

diverge general

frac-

of

fraction

value

over rads.

the

dose

curve curve.

dose fractionation a certain effect.

non-repairable

begun that

If

killing

crypt cells, 350 and 450

200

is over

number

dose

of

which

slope of a surif the higher

large

survival survival

that

that

jejunal between

doses

of

fractions. a

from

estimated

for lies

200

single none

survival

requiring

injury, then further dose requirement for

nisms, methods

of

equal

small,

are

a

re-

multiple

sublethal

fractions

curve rads,

cis-plati-

slope

from used,

repaired, the multifraction the initial slope of the

it

greatest

be

may be estimated from the over a range of higher doses

as

if

completely approximate

injury must

The

of dose/fraction curve measured

dose

detectable methods

range vival

survival 140-210

num.

of

manifest

alternative

methods

of

and

not

and

the

influence

findings

with

reduced BCNU, given

reduces

will

entirely

argon

as dose rates approach crypt cells from 400 to

0 rads

WORKSHOP

rads,

irradia-

and

neutrons

only

two

sues

for

cesium,

rads.

rads

on

TELETHERAPY

the isoeffect while for

dose irradia-

to consider that important role.

curietherapy cannot

schedule be

ascribed

some with to

the

in both cases the cells are killed It is not likely that repopulation an advantage for the short duration other radiobiological mechanisms, (and other experiments), requires

is

LOW

DOSE

RATE

TELETHERAPY

Alteration of Cellular Proliferation in Various Cell Lines Exposed to Low Dose Rate Irradiation: Bedford JS (Colorado State Univ., Dept.

of

Radiology

and

Radiation

Therapy,

Fort

Collins,

CO

80521)

CFU5

survival

Downloaded from www.ajronline.org by 218.94.80.10 on 10/06/15 from IP address 218.94.80.10. Copyright ARRS. For personal use only; all rights reserved

cells

and hr.

The

cell

was

examined

for

delay.

HeLa

in

could the

be

repeated

by

per

was

every At

rates

during

G2 phase

absence

of

10

cell

the

Gl

to

rad/hr.

,

e.g.

much of

shorter 37

higher

the

than

Chinese

doubling

rad/hr.

survival

SO

37

rad/hr.

division

,

is

does

hamster

time not

of

10

inhibit

V79

hours

the

cell than

line

rads/hour as

collected. radiation;

does

increase

in

HeLa, cell

Labeling the mitotic

a

val

cells during

Survival hypoxic of

a

5%

dose

the

in

is

dose

significantly

survival

of

influenced

by

the

stem

dose

cells

rate

for

(CFU5)

dose

is

rates

of

the

surviving

stem

continuous

irradiation

the

LD5O

ranging

cells.

is

slowly

increased

when

the irradiation duration increases up to 4 hours (dose rate 3 rads/min.); the LD50 is increased with respect to the LD50 for acute single dose. The ratio (1.15) is close to the ratio 1.2 served of

3

for

4

and

rads/min.

8 there

fractions. is

This

already

little

suggests cell

that

at

killing

the by

types

of

tissues, supply

cycle

or,

more

Studies different

have

The

of to

irre-

an

show lOs;

acute

The dose

irradia-

time interdependent.

no evidence cells from

curves

with

of acutely

10

tumor, and

to

20%

the

acute

irradia-

in

Dose

Rate and

of

Effects

Normal

Among

Tissues:

Organization

for

Health

Netherlands)

types

tissues

of

the

types

of

tumours

as

considerable

well

as

variation

among

has

for unlimited structure and

different

been

to single and fractionated low dose rate treatments. by the responsiveness of

observed

doses

of

These constituent

proliferation or that function of normal

cell proliferation and host responses

radiosensitivity

of

that

survival curves radiosensitivity

doses

of

rad

per

100

kinetics, can also

at

slopes of 5.

cultured

and

differences

to

fraction,

cells

carcinomas

large

for X-rays. amount to

by the initial least a factor

100

of

experimental

demonstrated

dose

cells

in culture The

can

be

are

For large least a

single factor

200

responses

rad,

play

a

at

from

sarcomas

in

observed

rats

between

the

doses differences of three. For are

of survival curves Since the effectiveness

administered

cells

tumours

rate

which

genic

tion the

e.g.

from

culture

have

capacity

results tion of

short

in

determined

which

may differ small doses

of intervals

adequate

experimental

derived

in

syngeneic

been

studied

by

of

the

from with

of

constituent

and

as

to

delay,

after

studied.

rat

give

respect

growth

cells

have very

tumours

experimental

animals

analysis

of these studies cells that were

to treatments at low dose to be at least as large survival curves of the

of

to

their cure

solid

responses rate

culturing

shown that tumours resistant in vitro,

tumours,

rise

in

or

to clono-

vitro.

The

grown by inoculado not always

a large resistance in vivo with respect to growth delay or respect to doses required to obtain eradication, although in cases, e.g. a ureter squamous cell carcinoma, a good correlais obtained. cells cultured

fractionated respect

caused

to With

growth respect

high

and

among cord

different in rats,

low

in

It relative fraction,

Institute

dose rate shows that

tiveness

over

tumours

rates,

types assessed

to

4-6

be

considerable

per over dose

the

effect rate

of is

unit

tissues variation

and

the

dose

increasing

and the

with

for of 4-6

Doses

Experiments of

single

have and

been

carried

fractionated

out

to

doses

to

weeks For

spinal a large

numbers and a other

fractions

central

at

observed

of

of normal irradiated.

and

of

treatments, rad per depend on

tissue

at

that

Low-Dose

Rates

(Radiobiological

investigate applied

of

large tissues

nervous

low dose rate with 200-300 weeks, will

MB

with

irradiation also

increasing

Applied

and R-l Rhabdoinyosarcoma: Kal TNO, Rijswijk, The Netherlands)

cell

resistant

is

of the

on the type site to be

Fractionated

accelerated

tolerance of paralysis,

numbers than

is concluded that an advantage to fractionated daily treatments administered over periods of

Single

weeks,

periods of several rate were observed.

smaller

tumour treated critical for

rat rhabdomyosarcoma, resistant, but with

relatively

of tissues. For through evaluation

in

dose

the type of is considered

potentially

e.g. a extremely

delay or eradication. to tolerance of normal

dose

administered reduction

skin,

tumours, are not

extending the

in effectiveness

fractions effect of e.g.

For other in vitro

treatments

proliferation

changes

a

in

irradiation,

show with some

derived

transplanted

decrease an ob-

accumula-

likely,

the were

time tended

experimental

Tumours

but other factors, e.g. oxygen and nutrients,

of

of

cell

and

part.

Skin

the

data

a

cells accumulated cells were in G2

continuous

and

cells that have the capacity are required to maintain the

on Rat

of

of

Inst.

with respect to responses ionizing radiation and to differences are determined

Effects

phase

this

Cells,

Rijswijk,

different

in

radioresistant

a dose

technique

after

survival

For

Cultured

normal

system.

a

biphasic

(Radiobiological

TNO,

tion of sublethal injuries. If there were not any other mechanism involved, this ratio should not increase for longer periods of irradiation. Actually when the period of irradiation is further cxtended up to 21 hours, the ratio increases up to 1.46 and is much higher than expected from the repair of sublethal injuries. This increase cannot be explained by hemopoietic cell repopulation because this hypothesis would require a doubling time of 2 hours. Two other explanations deserve discussion: reassortment of cells slow repair process that might be related to repair of lethal damage. Anyhow the discrepancy between the effects of low irradiation on LD50 and hemopoietic stem cell survival

1.47,

in G1 phase. is observed is

considerable differences in responses rates. These differences are expected differences among the initial slopes

not

We have assessed the LD5O at 30 days after total body irradiation on BALE/c mice with a fractionated irradiation up to 8 fractions (in 48 hours) and with a continuous irradiation up to 21 hours (unpublished data). For the fractionated irradiation, the total dose levels off at 920 rads when the fraction number increases (the dose increased by a factor 1.2 with respect to the single fraction acute irradiation LDSO: 720 rads). There is no dose increase between 4 fractions and 8 fractions. This observation is consistent with a full repair of sublethal injuries between fractions and the absence for fractions of 115-230 rads of cell killing due to an accumulation of sublethal injuries. For

is to

to allow all sublethal damage to be repaired, is expected to be equal to that of treatments at dose rates of 50-100 rad per hour, it can be inferred that different types of tumours may also show

600 rads/min to 30 rads/hour. However the interpretation of CFU5 survival is complex because radiation does not only kill the CFU5 but also triggers the differentiation and the proliferation of the surviving cells. For instance for very low dose rates (40 to 80 rads/day) the initial slope is equal to that observed for higher dose rates, but subsequently a plateau is observed, probably due to an increase in the rate

rate

with increasing initially but

whereas

rela-

2472)

kinetic cloning

the ascites 61% of the

accumulated accumulation

effectiveness

of

GW

Among

from

proliferative

the

vitro

decreased dropped

hypoxic.

dose (NCTC

If

the

rate

Cells to Acute and Protracted G (Institut Gustave-Roussy,

hemopoietic

in

Radiosensitivity

Types

Barendson

of

The

the

yielded

the

in

Various

mainly by at

and Tumor Boisserie

an

CFU,

small.

Variations

even

FINDINGS

Response of Bone Narrow Irradiation: Tubiana N, Villejuif, France)

studied;

by

damage.

of

low

tumor

cells from solid tumors to a survival level of

being

difference tion

in

tumors cells

fractionated

LABORATORY

also

indices indices

temporarily which this

curves of cells down

Research

at 154 rad/hr. , one cell doubling occurs. The survival curves for dose rates of 74 to 270 rad/hr. are similar. In the pig kidney cell line, which has a doubling time similar to that of HeLa cells (28 hours), more cell division occurs at 37 rad/hr. than occurs In HeLa cells. The survival curves are similar for dose rates of 37 to 270 rad/hr. In summary, it appears that when continuous Irradiation to some cell lines slows or stops cells in their progression through the cell cycle, the redistribution that occurs in the cell cycle can counteract the effect produced from repair of sublethal damage to the extent that In some cases the low dose rate is more effective in cell killing than is the higher dose rate. This phenomenon may be important in the response of tumors and normal tissue to low dose rate teletherapy.

CURRENT

rate versus for LD50.

controls),

has

number;

was measured

medullary

instead

experimental

(versus

tion,

prevented

which

an

phase

of

also. However, as the dose rate is lowered, more cell division occurs. The cell survival curves of log phase HeLa cells cluster together at low dose rates but separate at higher rates. The dose rate of 37 rad/hr. is more effective in cell killing than are the higher rates as a result of the redistribution of cells in more sensitive phases during the lower dose rate exposure. in

of

irradiated

rates

However,

rate

of

for

cells

37 rad/

4 hours.

dose

high dose that observed

to

response

cell

criterion marrow

without

such that a 148 rad

,

similar The

good

irradiation After 40 hr

pattern

doses

rad/hr.

a

bone

Under continuous at a rapid rate.

an accumulation This

not

cover. in G2

At

S phases

division.

37

270

cycle.

fractionated

equivalent

HeLa

to

and

preceded cell

administering

from

one

through

the

the

mitotically-synchronized

dose

doses in

in

hour

of

various

progressed

a delay

mitosis

dose

dose

cells

Then

cells

progression for

hyperfractionated

the

,

cycle

is

one counts nucleated tive efficiency of value

In six different mammalian cell lines, a detailed life cycle analysis has been performed during low dose rate exposure to determine the redistribution during the cell cycle in an attempt to explain variations in low dose rate survival among the lines.

1107

WORKSHOP

the at

effec-

different

LOW

1108 dose

rates

tumour applied rays

tumour

skin

at

of

the

in

the

effectiveness decreasing

and

at

3)

normal

cell

no

dose

75

to

per

rate

are

of

was

R-l

the

gamma

rad/h

sublethal

progress

through

their in

dose

the

137

irradiation

the

10%

1)

decreased

is repaired

G1

S phases

The

G2+M.

in

and

vivo

results

show

a

and

that

1)

by

low

into for

sublethal

damage

is

occurred essential

a more

radiosensitive

irradiation. assessment

A of

repaired

continuous

that the 4) cells

phase

cell

of

the

skin transplantation radiation induced

Continuous irradiation at a dose rate of sparing effect per unit dose as compared of

during

so rapidly constant and

ir-

reactions dose ing

growth delay as compared with low dose rate. No significant

provides a large irradiation with

per

rate that

unit

of 340 animals

dose

were

rad/h were

observed

when

as compared anaesthetized

with with

treatments

of

differences

doses

were

ture Ethrane and oxygen was used as an anaesthetic applied at the lower dose rate were more efficient implying that protracted use of Ethrane interferes

at

providthe mix-

The

therapeutic

of about observed This

100 for

might

gain

observed

tion

Dose

indicate

Rate

that

Factor

of Tumor

Francisco, Low

and

Div. dose

clinically

single

the

of

In

Normal

of

dose

Vivo

rate

about

Low

Fu KK

Oncology,

irradiation of

of

Continous

Tissues:

Radiation

because

rates

the

is

(Univ. San

assuming

increased

Dose

use

San

increasing

importance

interstitial

94143)

radio-

that

the

order

variation

to

of

factor

protracted

quantify

the

variation

dose

rate,

I would

like

(DRF)

which

is the

ratio

exposures

DRF

that

of

effectiveness

with

to

introduce

the

term

of

the

for

acute

result

in

the

same

Isoeffect

dose

for

acute

Isoeffect

dose

for

protracted

doses

biological

dose

and

effect:

the

there the DRF

the In

is will

greater sparing be smaller for

therapeutic order

to

ratio evaluate

of normal the normal

will the

be

greater

potential

than

then tumor

1.

advantages

of

low

dose

rate teletherapy, the DRF’s for the E’6 tumor and mouse jejunal crypt cells and bone marrow CFU’s were determined from their dose response curves for in vivo continuous irradiation with Cesium 137 at .54, .92, 4.5, 36, and 274 rad/min. For the tumor, DRF’s were also determined from dose response curves to in vivo continuous

irradiation

with

Californium

252

neutrons

at

78

low

to

Whole

Swartz College of

tract

dose

the

body

rates

(2.2

deaths whole and

irradiation

half

of

the

that

the

quite not

the

the

long

sparing

diminished These results

clinical

tract

limit

tolerable effects be

to

to con-

acute rate

is

method, no rad/min and 6.3 compared

to

by

partial that

using suggest on

the

89 it

irra-

radiation

radiation of

for

pertinent They

dose

by avoiding

the

tract

were

limitations

term

gastrointestinal

1300

rad

tract when

of our experimental dose rates of 2.2 were

body 2600

are subjects.

gastrointestinal

of

the

of

increased

rates

were:

2.2 rad/min or 6.3 rad/min. higher LD5016 values. Re-

data human

overcome

that

Perspectives

therapy in the the

B

of

(Service France)

utilization

radiotherapy with 1930’s,

as with

dose.

low-dose

It

rate

irra-

investigated.

curietherapy

and

a Low

prolonged

permitted

to

in

clini-

in

COUTARD, dose, but weeks

development

become

to allow delivery Euphemistically,

curie-

several

Renewed me

Henri

only radiation over

Dose

Univ.

(LDR) except

teleradiotherapy, delivery of a

of LDR time.

6 weeks” with

irradiation

technique.

192

at Hospitalo

exploited

remained

Iridium

than in treated

rate

fully

fractionated

with

rather patients

dose

been

time

Radiotherapy

Radiotherapie,

Concerning the slow

treatment

classical

low

not

radium. studied

Clinical de

of has

overall

days 3000 of tumor, for the

of for

gastrointestinal or

experimental teletherapy

effect was irradiation.

currently

Pierquin Creteil, The

Tissue. than than

dose

patients

Exposed

to

interesting possibilities dose in a very short total

tissue tissue

low

CONSIDERATIONS

Rate: Mondor,

exposure.

Tumor DRFNormal

If

with

compared

gastrointestinal

that of

Mice

the

lower

greatly

these

to

essential

Historical

exposure

DRF -

of

possible

diation

of

clinical

impracticality

rad/min

of is

may

of

rate

the

The DR.F decreases with decrease of biological effect as the dose rate decreases. For a given dose rate, the therapeutic ratio is equal to the ratio of DRF’s for tumor and for normal tissue at the same dose level: Ratio

tolerance

radiation

whole

the

89

Both

now

low

dose

ongoing

of

rad/min)

rad for yielded

only

provide rate

This sparing than whole body

cal

Therapeutic

of

rad/min. rather

is

the

the

in

to

for

rad/min.

reactions

than of the

effects on gastrointestinal the LD5016 following either

Within the limitation was observed between

diation

than

with low

Dose Rate Irradiation: Wilson, JF (Medical

(90

lowered. difference

be

greater

of

gain

against

Low A,

The

rad at rad/min.

results low dose

of

was

cells

immobilization

rate

5O/6

1600 6.3

or

firm effects

comparable

small intestine is volume, low dose

use

by

Death

of Been

versus 2200 and thorax

irradiation

CA

.92,

therapeutically increased sparing the

.92

.69,

4.5,

exposures.

approximately: 2.2 rad/min

of California,

but

hemopoietic

administered

dose

approximate

CLINICAL In

was

sults

tumors.

and

body

the

were

36,

10

at

53226)

acute

rad/h

Irradia-

of

significantly

CFU’s

therapeutic

and

rad/min or 6.3 rad/min). were assessed by determining

These use of

jejunal

level

at

not

Thus, if the the treatment

verified

potential

Exposures Stark R, WI

at an

for

the

DRF’s

at

Califor-

malignant lymphomas, leukemias, Whether low dose rate teletherapy in the treatment of other types

be balanced

exposure

X-irradiation

The

be

the

at

was

Cesium

rad/min. with

irradiation

the

support

Gastrointestinal

Body G,

be

Rate

to

at

level. 4.5 rad/min.

the

with 36

DRF

type,

radiation.

For

137

marrow

of

0.9 to

tissue

treatment.

rad/min the head

increased

also

the

Milwaukee,

,

of

would

must

of

Partial Reichling

Wis.

sparing management transplants. advantageous

of

.78

tumor

bone

to

irradiation

EMT6

the

needs

rad at 89 Shielding

therapy and external beam total body and partial body irradiation in the treatment of malignant lymphomas, leukemias, disseminated and localized carcinomas, and in bone marrow transplants. In general, the biological effectiveness decreases with decrease of dose rate for a given dose of radiation. When low dose rate irradiation is used as a form of teletherapy, for it to be more advantageous than teletherapy with conventional dose rates, it is necessary that there is greater sparing of normal tissues than of

rate

a

and MM,

partial

Francisco,

of

of

Modification

dose

100

in the marr be more

time

form

to

be more advantageous irradiation. The

less

However,

at

telecobalt therapy cannot of therapeutic gain.

but

teletherapy

this

the

the

in

CFU’s,

137

2)

of

rad/hr.

Cesium

marrow

Cesium

for

irradiation

studies.

of mice

rates

that

neoplasms

treatments dose repair

doses

bone

for

DRF

malignant

unit

rad/h as compared to acute irradiation could not be fractionated irradiation at a dose rate of 340 rad/h.

presently used in clinical to 340 rad/h without loss

The

for

bowel rate

the per with

processes.

the with

78

.53

with

rate,

.54

change

and

from

0.54 from

no

the jejunal crypt cells. limiting normal tissue in

protracted

doses

applied

from

for dose

rate

in skin

acute irradiation Nembutal. When

that the

from

was

at the 10% survival 137 irradiation at

the

teletherapy and in bone would also

1.8.

tumour at the

different

dose

Tumour growth delay and severity of skin injury of the rat foot were used as endpoints to evaluate the effectiveness of four daily doses of X-rays applied at a dose rate of 340 rad/h as compared with four daily doses at high dose rate. Treatments of doses administered at the high dose rate were more effective in inducing applied

1.88

levels,

small

during

technique has been damage to rat skin.

85 rad/h to acute

For

and

dose

4) quality

ranging 17.6

ranged

rate irradiation would conventional dose rate

fraction are accu-

cycle

DRY

.54 rad/min. With Cesium

dose

varied

There between

the

1)

and

rates

cells/circumference

1.88

tu-

with:

dose,

DRF

dose

level.

irradiation

cells,

1.0,

varied

or the

at

to 36 rad/min. at

through

tumor,

survival

252

crypt

damage and

nium

T6

surviving

on cell survival were present in the range of dose rate irradiation was less effective a factor of 1.45 as compared to acute irradiation 2)

that

factor

For

that

DRF’s

endpoint

X-

effects

3) reoxygenation cells remains

a

show

The

irrare-

irradiation

irradiated

vitro.

The

radiation

progression

was

of

acute

rad/hr.

3) biological

were

doses

and

cells

continuous

to

in

daily

WORKSHOP

17.6

of

rays

rad/min.

tumour

TELETHERAPY

induction

gamma

rad/h

340

4-75

assayed

radiation, of hypoxic continuous employed

of during

340

of

RATE

for

X or Four

of

rate on

2)

and

of

rad/h. rate

dose

delayed

indicating

mulated

150

dose

rhabdomyosarcoma

rad/h,

unit

unit

vitro

doses

a dose

rate,

continue

survival

150

in

experiments

rates

R-l

to

a

at

per

but

rat

40

at

dose

cells

rate The

mour

of

vitro

dose

R-l

survival Single

performed

with

applied

rates

administered were

sults

cell

responses.

dose

were

diations

Downloaded from www.ajronline.org by 218.94.80.10 on 10/06/15 from IP address 218.94.80.10. Copyright ARRS. For personal use only; all rights reserved

on

and

DOSE

aware of a “6000

. Based on experience with Iridium 192 between 1960 and

in

of

the

very rad

high in 6

more 1970

than and

especially my experience with over 250 patients treated to large target volumes for cervical lymph node recurrences, I acquired the clinical conviction that LDR to a dose of 1000 rad and up to 2000

rad

the

tumor,

sensitive

daily even and

was

well

when

tolerated

entirely

locally

by poorly

radiocurable.

the

taken in January, 1970 patients who presented

of irradiating by with very advanced

sites. of 30

an

and

Since 100+

there is rad/hour,

isoeffect I was able

normal

tissues

oxygenated, On

this

remained basis,

the

telecobalt LDR, tumors in head

plateau to treat

between these

the first

but

that radio-

risk

was

several and neck dose rates patients

LOW

with

daily

doses

approximating

900

rad

DOSE

delivered

over

at the rate of 1.5 to 2 rad/minute. Eight years (1970-1978) with 120 patients thus treated, more had oral cavity or oropharyngeal lesions has led conclusions:

Downloaded from www.ajronline.org by 218.94.80.10 on 10/06/15 from IP address 218.94.80.10. Copyright ARRS. For personal use only; all rights reserved

1.

The

most

LDR

is

practical as

recommendable

a split-course

method

consisting

of

of

RATE

8 to

TELETHERAPY

9 hours

of experience than half of whom to the following

3.

The

series

of 4.

effect

on

LDR

in

Necroses

the did

classical

5. 6.

7.

8.

9.

the

skin

is

very

reduced;

0.25

the OERTC study comparing LDR with classical irradiation. The effect on the tumor at short and medium tion appears much more efficacious: (factor same not

of

3250

vs.

2.3

in

fractionated

more

fractionated

frequently

time

than

General

Hosp., Harvard Biomathematics,

(Dept. of Univ. of Texas, Cancer

Medical M.

Houston,

Management,

TX

School, D. Anderson

77030)

Massachusetts

and

Soriano Hosp.

rads

hr’,

single

dose

and

comparable

to

those

using

the

more

02114),

Brown

is

factor

which

has

contributed

to

in

the

range

of

for

radiation

low

dose

superior

rate

field

or

protracted

problems

administered

at

50-100

treatment. This would mean therapy techniques would not surely be a tendency to employ parallel

opposed

technique

where

would

contiguous

areas

portals.

be

difficult

were

to

be

single

hit,

single

target

and

Equation

for

survival

e1111/1)O[l

-

the

single

hit

is:

_e_’t)O)”l

(1

-

multi-target,

fraction

the proportion of energy absorbed in production of nondamage. In an analysis of the performance of this model no detected advantage of the continuous low dose rate over highly fractionated irradiation (small dose per fraction). For example, at dose rates of the order of 50-100 rads per hour or dose per fraction of 100 rads or less the total dose required to achieve a survival fraction of l0 would be the same for

the

two

approaches

(n

values

of

4-10,

repair

half

time

for

re-

pair of damaged site of f60 mm). The highly fractionated or the continuous low dose rate irradiation may be more effective than conventional fractionation schedule because of the OER or more favorable age density distribution or the use of shorter overall time but radiobiologically they appear to be approximately equivalent. These new approaches are potentially very interesting and

certainly

*Thi

BW

systems

quite high dose are approximately

the

doses

where u reparable there was irradiation

irradia-

afterloading

i.e.

dose

S

and Tumor Inst., A (Director of Boston, MA 02114)

continuous

traditional

i.e.

treatment

inactivation.

rate

intracavitary therapy. This clinical finding indicates that the advantage of the intracavitary was not the consequence of a low dose rate but rather the superior dose distribution which made feasible the administration of high total doses. All of the cxperience of radiation therapy has shown that where dose distribution has been improved such that higher total doses could be empioyed, the tumor control probability is increased. Our own interpretation of the results of interstitial therapy is that the predominant

techniques, the low

those

the

tion, short overall treatment time (3-8 days), and treatment volume confined to the palpable tumor and its immediately surrounding normal tissues. Clinical experience has demonstrated Unequivocally that external beam therapy combined with low dose rate intracavitary therapy for carcinoma of the uterine cervix has yielded superior results to that which can be obtained using very aggressive external beam techniques alone . However , recent resuits from centers employing remote control for their intracavitary therapy but utilizing rates have obtained results which apparently

of

treated; for example, head and neck carcinoma (primary plus lover neck), ca of the breast (chest wall and supraclavicular regions). The effectiveness of radiation given continuously at various dose rates or as fractionated high dose rate irradiation was considered by reference to a model which features a combination of

question being considered in this symposium is: would results of external beam radiation therapy be improved by employing low dose rates, viz. l-3 rads min given in series of quite protracted exposures? The stimulus for this question is a widely held clinical opinion that the best results achieved in radiation therapy are those obtained using interstitial therapy. The physical characteristics of the latter feature dose rates of 40

immobilization,

single

for

Dose Rate TeleMassachusetts

,

day

simple

Boston, MA Hospital

General

per

with

The clinical

approximately

of

Further,

of Low Medicine,

fractions

6-9 hrs per radiation there would

technique.

Clinical Exploitation (D.pt. of Radiation

several

rad hr1 for a total of that highly sophisticated be readily feasible and

Soft tissue sarcomas appear very radiosensitive to LDR (11 of 12 locally controlled). The small intestine appears very tolerant of LDR. Four patients treated for pancreatic cancer tolerated irradiation without nausea or diarrhea, however, treatment was via relatively small portals measuring approximately 10 x 12 x 6. We must study further the optimization of this technique and explore the possibility of finding the optimal dose rate. It is hoped that it will be the highest possible low dose rate to allow treating more patients daily per therapy machine. As of May, 1978 we have confirmed that our last several patients have tolerated well doses of 800 rad given at 2.5 to 3 rad/minute. Studies conducted in close conjunction with our radiobiological colleagues will permit us to better determine the optimization of dose rate as a function of the radiosensitivity of each normal or tumor tissue. This optimization equally applies to the notion of “split” course radiotherapy: when should a split occur and of what duration? Comparative trials should be organized and conducted to compare LDR vs. hyperfractionated irradiation vs. neutron therapy. I propose a meeting for this purpose in 1980 or 1981 in Creteil. Such a meet will assemble a small group of representatives of the teams of clinicians and radiobiologists interested in these irradiation modalities.

The Potential for therapy*: Suit MD

example,

term observaof 2 in favor

study). occur

For

rads per fraction. There appear to be several significant technical problems inherent in the use of the prolonged exposure periods which are necessary in low dose rate external beam therapy. Specifically there would almost of necessity be some decrement in the quality of the dose distribution pattern over that which could be achieved with high dose rate conventional external beam therapy technique. Treatment volume would have to be relaxed in order to be certain that the target volume was covered during all of each protracted radiation sessions. This would be the consequence of a prolonged

rad separated by a 3 week rest interval, delivering 800 rad daily at a dose rate of 1.5 rad/minute. Total dose therefore equals 6500 rad calculated at our reference isodose, habitually 90% of the dose at the center of the target volume. 2.

sensitive phases of the cell replication cycle. It is almost certainly true that both of these advantages would, however, obtain for irradiation given in multiple fractions of small doses. 50-100

administering

two

1109

WORKSHOP

results

the better dose distribution and not the low dose rate. There would be two radiobiologic advantages which may be a feature of low dose rate continuous irradiation. These are: 1) a reduced oxygen enhancement ratio, 2) greater opportunity for radiation inactivation of cells as they pass through the more

warrant

work

was

a

serious

supported

clinical

in part

investigation.

by DREW

Grant

#CAl33ll.

Current Results of an E.O.R.T.C. Trial Comparing Low Dose Rate and Classical Fractionated Treatments of Base of Tongue Epitheliomas: Baillet F (Service de Radiotherapie, Centre Hospitalo Univ. Henri Mondor, Creteil, France) This trial was preceded by rate irradiation of 70 patients Creteil. Initially forty-five (T ) 4 cm. in all cases except

preliminary studies of low dose on the service of Pierquin at patients with advanced ENT tumors 3) were treated with one of two techniques both employing the low hourly dose rate of 0.8 to 1.8 Gy per hour to a daily dose of 6 to 8 Gy. Technique A consisted of

70

Gy

as

a

single

course;

Technique

B of

65

to

70

Gy

as

a

split-

course with a rest interval of 3 weeks at mid-course. Fifteen patienta were treated with Technique A; 30 with Technique B. Cutaneous reactions with Technique A were extremely mild but no visible reaction occurred with Technique B. Marked mucosal reactions occurred in 14 of 15 with Technique A vs. 4 of 30 with Technique B. Complete disappearance of tumor at 3 months was observed in 33 of 45 patients. Tumor disappearance was essentially the same with either technique (60% Technique A vs. 54% Technique B). Necrosis has occurred in 15 of 25 patients who have not relapsed (6/11 T3, 9/14

T4).

Seven

of

nine

occurred

with

Technique

A

compared

to

8

dose rate irradiation was concluded to be safe if given as a split-course and produce tumor disappearance more frequently than expected with classical fractionated irradiation. On this basis the current trial was organized in January, 1976 comparing Technique B vs. of

16

with

classical

Technique

B.

fractionated

Based

date

16

patients,

this

irradiation

tered as 5 fractions of 2 Gy volume is made at 45 Gy with with low dose rate technique To

on

8 in

data,

of

70

low

Gy

total

per week. Reduction fractionated therapy to shield the cervical

either

arm

of

the

study

dose

to

adminis-

of irradiated and at 35 Gy spinal cord. have

completed

treatment with the following observations: cutaneous reactions graded from 0 to 3 were greater by a factor of 10 with the fractionated

schedules. dose rate of

technique.

8 patients

4 of

8

Mucosal

reactions

were

Tumor disappearance occurred more technique, 75% vs. 50% at 3 months.

treated

treated with

with the

the

low

fractionated

dose

rate

technique.

identical

frequently In April, technique Necrosis

for

both

with 1978

low 5

are

alive, occurred

1110 in

LOW

one

fourth

rate group sis

and

of

3 of

0/8

in

the

patients

the the

in

8 patients

either

are

fractionated

DOSE

group.

alive

In

without

technique

RATE

the

low

relapse

group.

The

TELETHERAPY

dose

or necro-

poor

prog-

nostic influence of preexisting ulceration appears to be overcome with the low dose rate technique, there being only 3 relapses in 5 cases who had initial ulceration, 3 of 3 treated with the fractionated technique. Our preliminary conclusion is that a better result is being obtained with low dose rate irradiation in such

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cases. Clinical Applications of Hyperfractionated (HFI) (8 and 16 fractions per day) Concentrated Irradiation: Casters D and Loirette M (Centre J. Godinot, Reims, France) Dutreix J (Institut C. Roussy, Villejuif , France) In a comparative study measuring human skin desquamation 16 fractions of 0.45 Gy per day given at 30 minute intervsls over 3 days was found to be biologically equivalent to reactions produced by 2 x 8.5 Gy in 3 days, to 27 Gy given as fractionated irradiation over 3 weeks and to the low dose rate schedule of 22 Cy given at 0.92 Cy per hour (2 x 4 hours daily). In a second preliminary therapeutic study 11 patients with advanced head and neck lesions were treated for palliation with 250 kV XRays giving 16 fractions per day to total skin doses of 26 to 30 Gy. Moderate to brisk dry desqusmation peaked at 25 days and was repaired at 40 days; mucositis peaked at 10 days and was repaired by 20 days. Tumor regression was appreciable at 10 to 20 days. This sequence of reactions was similar to that observed with concentrated irradiation given in 2 fractions of 9 Gy in 3 days. In 5 patients a second series was given after a rest interval of 3 to 6 weeks; in 2 there was no evidence of local disease at the time

consecutive

of

death

at

20

months.

In

a

third

clinical

study

56

patients

with

WORKSHOP

received 6-8 Gy a day. Five fractions per week were given. The total dose for pelvic tumors was usually 50-60 Gy, applied in two equal courses separated by an interval of 2-3 weeks. Sarcomas of a limb received a total dose of 60-70 Gy. During the first portion of the study, lower total doses were applied. The

long

reasonable

series

had

laryngeal

edema;

1

re-

of patients

has been compared previously treated with conventional fractionation (70 Gy/7 weeks) treated through similar portals. With the NFl schedule early mucosal reaction was greater but of shorter duration. Xerostomia was more marked and late cervical fibrosis was more frequent but was asymptomatic. Local control of the primary tor was superior with NFl (4 failures vs. 14) but control of lymph node metastasis was less (9 failures vs. 3). The survival rate at 6, 12, 18 and 23 months is higher for NFl (63% vs. 30% at 23 months) suggesting a benefit with Nil but a clinical trial is necessary for confirmation. Fatal complications of hemorrhage or extended necrosis were similar with the two schedules (7 NFl vs. 10 conventional). Clinical

experience

Radiotherapy tisch

Inst.

,

with

Low

Dose

Institute:

Kuipers,

Rotterdam,

The

Rate Tj

Therapy (Rotterdamsch

at

the

Rotterdam

Radiotherapeu-

Netherlands)

In a pilot study, 66 sites in 63 patients have been treated low dose rate telecobalt therapy in order to advance knowlof therapeutic indications and contra-indications for this type of treatment. Mainly palliative results have been strived after. The poor prognosis of recurrent gynecological malignancies seemed to justify the admission into this pilot study of patients suffering from this type of disease. Case reports from a few other centers mentioning some favorable results in non-gynecological sarcomas, were the reason for also including various malignant soft tissue tumors. Most of the leiomyosarcomas, however, originated from the myometrium. Patients remained in the treatment room for 5-6 hours per day and were repositioned every 20-30 minutes. Short rest intervals were allowed for nourishment and elimination. The dose rate at the centre of the tumor was 1.0 - 1.2 Gy/hour. Treatment was given through anterior and posterior pelvic portals measuring as large as 14 x 14 cm. to a dose of 5 Gy, whereas sarcomas of a limb with edge

was

not

always

well

supported;

vaginal at

dose

In

other

irradiation achieved

had

recurrent

initial

without

application

the

cases,

as

following

treatment,

complications

given

only

a

if

about

50%

the

of

surface.

Recurrent ovarian carcinoma usually requires a high dose in a large volume. Therefore, external low dose rate irradiation is not the treatment of first choice, yet some palliation was achieved in a few such patients. Overall,

twenty-two

recurrent

carcinomas

of

the

cervix,

twelve other gynecological or urologic tumors and fourteen soft tissue sarcomas were treated yielding a total of forty-eight evaluable sites. In these, excellent or good palliation was noted in sixteen, twelve obtained moderate palliation and twenty responded poorly. Eleven severe complications were encountered.

of

quiring tracheotomy. This to a series of 54 patients

patients

time

was

tolerance

months

Four

palliation

post-operative

Wig.,

3 patients.

treatment

rate of severe complications. surgery and post-operative

head and neck tumors (9 T2, 43 T3, 4 T4-NON1, 34 N2N3, 22) were treated with cobalt 60 teletherapy with curative intent given as 8 fractions per day of 0.90 Gy at 2 hour intervals over 5 consecutive days repeated after a 2-week rest interval. This resulted in administration of 7.2 Gy per day, 36 Cy per series and 72 Gy total dose. Practically all primary lesions remain clinically controlled except for 4 clinical suspicions of recurrence. In 9, node residua required surgical excision which healed without complication or subsequent recurrence. Brisk mucositis was repaired at 2 months in 75% of cases; it has persisted more than 4 in

daily

therefore, in a number of patients treatment was partially given with conventional megavoltage methods precluding evaluation. Poor selection of patients early in the study resulted in a total of 18 non-evaluable cases. Remarkable reduction of tumor volume (up to 90% and more) was observed in the leiomyosarcomas. The best results were seen in the two patients with a recurrent mixed-mesodermal tumor: one of them appears to be free of tumor more than three years after low dose teletherapy. The results show that for a carcinoma of the cervix, recurrent following full course of initial radiotherapeutic treatment, the addition of low dose rate teletherapy results in a high

Dose Rate creas. Results

Low

coon

and

Teletherapy of a Pilot

Milwaukee,

WI

of Unresectable Study: Wilson

JF

Carcinoma (Medical

In the United States today pancreatic fatal malignancy following carcinoma large bowel, there being only 1% overall

years.

Two pancreatic

significant cancer

of the College

Panof

53226)

have

barriers been

to the

cancer is the of the lung, survivorship

progress notorious

in radiation difficulty

4th most breast at five therapy in

accurately localizing such lesions and the proximity of critical organs which tolerate irradiation poorly, principally small bowel, kidney, liver and spinal cord. Experience during the past 20 years has shown clearcut dose dependency of local control confirming that tumor doses of less than 3500 to 4000 rad conventionally

administered

are

probably

ineffectual.

Clinical

and

experimental studies strongly suggest the sparing effect of low dose rate irradiation is different for different organs but particularly for the gastrointestinal tract which seems to show remarkable adaptability and can tolerate higher doses of radiation than were previously thought possible if delivered at lower dose rates. Six patients have been evaluated for inclusion in a pilot study; four have actually completed treatment (2 excluded due to mental incompetence). Patients received cobalt 60 teletherapy through portals measuring an average of 12 to 14 cm2 with an SSD varying between 68 and 75 cm. to give a dose rate of 95 rad per hour at the center of the tumor. Minimum total tumor doses of 5300 to 6150 rad were administered. Such irradiation was

extremely

well

tolerated

by

patients

producing

minimal

or

no

acute side effects during treatment. Karnofsky performance status improved in one patient and did not change in the other three. Cutaneous reactions were extremely mild consisting of only an cxtremely faint erythema at the end of treatment. One patient died of disseminated cancer after 28 weeks. Postmortem examination confirmed

a

profound

radiation

effect

in

the

tumor;

minimal

or

no

radiation effect was evident in the irradiated adjacent intestine, skin or kidney. Profound histological changes were also noted within the liver substance characterized by marked hepatocellular damage in conjunction with an unusual bile duct proliferation suggesting an individual adaptability to low dose rate irradiation of various cell lines within a single organ. This phenomenon is currently being studied further in a laboratory model. Of the remaining three patients, one is alive with disease at 26 weeks; local recurrence is suspected in another at 12 weeks and the fourth is doing well 10 weeks postirradiation.