Clinical

radionuclide

therapy

dosimetry

the

quest

for

the

Holy

Gray

Introduction

Radionuclide

therapy

has

distinct

similarities

to

but

also

profound

differences

from

external

radiotherapy

Introduction

Radionuclide

therapy

-LRB-

or

targeted

metabolic-or

molecular-radiotherapy

-RRB-

may

be

defined

as

a

radiation

therapy

that

uses

local

loco-regional

or

generally

administered

open

-LRB-

i.e.

unsealed

-RRB-

radionuclides

to

achieve

a

transfer

of

radiation

energy

to

a

pathological

target

tissue

and

by

this

means

to

exert

a

destructive

tissue

effect

This

internal-radiation

therapy

has

distinct

similarities

to

but

also

profound

differences

from

the

more

commonly

used

external

radiotherapy

-LRB-

EBRT

-RRB-

The

tissue

effect

is

expressed

as

the

absorbed

radiation

dose

in

grays

-LRB-

Gy

-RRB-

i.e.

the

amount

of

transferred

energy

in

joules

per

unit

mass

of

target

tissue

The

fundamental

use

of

this

unit

is

similar

to

that

in

EBRT

and

there

is

a

similar

relationship

between

radiation

dose

and

response

in

terms

of

cell

killing/survival

Therefore

calculation

of

the

radiation

absorbed

dose

to

a

targeted

tissue

makes

sense

at

any

point

in

treatment

In

this

respect

radionuclide

therapy

dosimetry

may

be

considered

an

inherent

part

of

radionuclide

therapy

in

principle

as

in

EBRT

In

the

literature

there

is

considerable

confusion

over

the

proper

use

of

the

term

dose

which

actually

refers

to

the

radiation

dose-in

the

SI

unit

grays

However

dose

in

the

context

of

radionuclide

therapy

is

frequently

used

when

actually

the

administered

activity-in

GBq

or

mCi

is

meant

To

avoid

confusion

the

terms

radiation

dose-and

absorbed

dose-are

used

when

indicating

Gy

and

the

term

activity

dose-when

indicating

GBq

Individual

patient

dosimetry

has

the

following

goals

-LSB-

-RSB-

To

establish

individual

minimum

effective

and

maximum

tolerated

absorbed

dosesTo

establish

a

dose-response

relation

to

predict

tumour

response

and

normal

organ

toxicity

on

the

basis

of

pre-therapy

dosimetryTo

objectively

compare

the

dose

response

results

of

different

radionuclide

therapies

either

between

different

patients

or

between

different

radiopharmaceuticals

as

well

as

to

perform

comparisons

with

the

results

routinely

obtained

with

external

radiotherapyTo

increase

the

knowledge

of

clinical

radionuclide

radiobiology

in

part

with

the

aim

of

developing

new

approaches

and

regimens

In

EBRT

the

absorbed

dose

can

be

calculated

relatively

straightforwardly

from

the

energy

loss

in

the

body

from

the

point

where

the

radiation

enters

the

body

to

the

target

Radiation

in

radionuclide

therapy

is

directed

to

its

target

by

a

vehicle

-LRB-

hence

radiopharmaceutical

-RRB-

which

exhibits

more

or

less

specific

binding

to

the

target

tissue

This

is

a

highly

dynamic

metabolic

process

both

biochemically

and

physically

within

the

time

interval

of

the

decaying

isotope

and

entails

a

much

more

complex

spatial

and

temporal

radiation

distribution

than

that

in

EBRT

Pharmacokinetics

such

as

circulation

metabolisation

target

expression

heterogeneity

and

cellular

uptake

and

release

as

well

as

radiobiological

phenomena

such

as

biological

or

physical

-LRB-

cross-fire

-RRB-

bystander

effects

-LSB-

-RSB-

play

a

determining

role

in

the

final

radiation

dose

to

the

target

EBRT

is

typically

a

fractionated

high

dose

rate

radiotherapy

in

which

episodes

of

radiation

aimed

to

cause

as

much

lethal

damage

as

possible

are

interspersed

with

episodes

of

non-treatment

during

which

repair

and

repopulation

occur

Radionuclide

therapy

is

radiotherapy

with

a

low

and

continuously

decreasing

dose

rate

which

requires

a

unique

radiobiological

approach

-LSB-

-RSB-

Integral

activities

can

be

determined

numerically

or

by

compartmental

models

-LSB-

-RSB-

and

presently

rely

heavily

on

the

detection

of

the

activity

distribution

by

gamma

cameras

Because

the

electron

range

is

inferior

to

the

spatial

resolution

of

most

molecular

imaging

devices

the

perfect-dosimetric

study

can

not

be

achieved

and

calculations

are

always

an

approximation

Using

the

temporal

and

spatial

radionuclide

distribution

data

radiation

doses

to

target

organs

have

generally

been

calculated

using

the

MIRD

formalism

formerly

used

for

calculation

of

the

biodistribution

of

diagnostic

radiopharmaceuticals

Commercially

available

software

such

as

or

the

newer

OLINDA/EXM

-LSB-

-RSB-

is

available

for

calculation

of

internal

absorbed

doses

in

organs

and

tumours

Although

these

models

make

important

assumptions

about

anatomy

-LRB-

standard

man

and

woman

-RRB-

and

radiopharmaceutical

distribution

-LRB-

uniformity

of

uptake

in

source

and

target

-RRB-

that

are

not

necessarily

valid

in

individual

patients

they

do

provide

a

practical

and

standardised

model

for

clinical

end-users

Nevertheless

to

date

the

need

for

dosimetry

to

individually

optimise

the

therapeutic

activity

to

be

administered

has

been

far

from

self-evident

Radionuclide

therapy

dosimetry

has

not

gained

wide

acceptance

as

a

clinical

tool

among

the

-LRB-

nuclear

-RRB-

medical

community

because

of

an

imbalance

between

the

accuracy

and

the

complexity

of

the

procedure

A

number

of

studies

have

even

completely

discarded

dosimetry

instead

using

fixed

activities

for

all

patients

or

activities

based

on

kg

or

body

dimensions

-LSB-

-RSB-

To

underline

that

this

is

unjustified

this

review

will

describe

the

significant

progress

that

has

been

achieved

over

recent

years

especially

in

the

fields

of

instrumentation

-LRB-

with

provision

of

clinically

useful

instruments

-RRB-

physical

modelling

and

radiobiology

Furthermore

the

EURATOM

Council

Directive

stipulated

that

in

medical

exposures

for

radiotherapeutic

purposes

including

nuclear

medicine

exposures

of

target

volumes

shall

be

individually

planned

In

this

context

the

nuclear

medicine

physician

is

at

present

confronted

with

a

dosimetric

dilemma

because

official

guidelines

and

recommendations

for

most

treatments

do

not

include

advanced

dosimetric

calculations

Therefore

this

review

primarily

aims

to

provide

the

nuclear

medicine

practitioner

with

an

up-to-date

overview

of

clinically

applied

dosimetry

techniques

in

radionuclide

therapy

For

those

working

at

a

more

basic

level

of

dosimetry

information

is

provided

on

the

clinical

application

of

methods

and

areas

of

further

development

Given

the

large

size

of

the

field

of

radionuclide

therapy

this

review

is

limited

to

those

oncology

indications

for

which

there

is

substantial

literature

concerning

dose

calculations

with

in-depth

discussion

thereof

As

it

would

be

impossible

to

cover

all

areas

of

the

complex

subject

of

dosimetry

appropriate

references

will

be

provided

where

necessary

e.g.

regarding

basic

physics

-LRB-

radio

-RRB-

biology

radiopharmaceuticals

and

preclinical

aspects

Radioiodine

therapy

in

differentiated

thyroid

carcinoma

Radioiodine

therapy

has

proven

to

be

a

safe

and

effective

method

in

the

treatment

of

patients

with

differentiated

thyroid

carcinoma

-LRB-

DTC

-RRB-

after

total

or

near-total

thyroidectomy

-LSB-

-RSB-

It

has

been

shown

to

be

useful

not

only

for

ablation

of

benign

remnant

thyroid

tissue

facilitating

subsequent

diagnostic

testing

but

also

for

treatment

of

any

remaining

cancerous

cells

either

in

the

thyroid

bed

or

at

metastatic

sites

Dosimetry

plays

an

important

role

in

answering

questions

concerning

biodistribution

since

the

biological

half-time

of

radioactive

iodine

differs

substantially

between

individual

patients

and

even

within

distinct

lesions

of

the

same

patient

It

has

proven

exceptionally

helpful

in

clinical

trials

of

new

drugs

for

example

retinoids

and

in

assessment

of

the

use

of

recombinant

TSH

-LSB-

-RSB-

as

well

as

in

the

study

of

other

questions

such

as

the

phenomenon

of

stunning

However

its

possible

role

in

extending

therapy

doses

to

the

level

of

individual

maximum

effectiveness

is

currently

less

obvious

There

is

at

present

no

consensus

on

the

activity

dose

of

to

be

administered

in

various

settings

according

to

recent

European

and

American

guidelines

-LSB-

-RSB-

largely

because

of

the

lack

of

prospective

randomised

data

In

the

majority

of

cases

GBq

-LRB-

mCi

-RRB-

is

prescribed

empirically

for

the

first

radioiodine

therapy

after

thyroidectomy

in

newly

diagnosed

DTC

to

ablate

the

remaining

glandular

tissue

Activity

doses

as

low

as

GBq

are

used

when

the

size

of

the

thyroid

remnant

is

small

as

measured

by

the

postoperative

radioiodine

uptake

in

the

neck

and/or

to

reduce

local

complications

that

could

arise

from

radiation

thyroiditis/oedema

which

has

been

reported

in

of

cases

although

usually

mild

The

effectiveness

of

this

ablative

approach

based

on

standard

activities

is

reported

to

be

about

For

the

treatment

of

residual

tumour

relapses

or

lymph

node

metastases

generally

higher

activities

of

GBq

-LRB-

mCi

-RRB-

are

used

Approaches

in

which

quantitative

dosimetry

is

performed

to

estimate

the

activity

dose

needed

to

deliver

an

effective

radiation

dose

are

scarce

in

the

literature

Maxon

and

co-workers

using

sequential

planar

scintigraphy

established

in

the

early

that

an

effective

mean

radiation

dose

of

at

least

Gy

is

required

for

successful

remnant

ablation

-LSB-

-RSB-

The

validity

of

this

recommendation

remains

unclear

as

it

conflicts

somewhat

with

clinical

experience

It

also

neglects

microdosimetry

of

radioiodine

and

dose

heterogeneity

which

may

well

determine

the

overall

response

As

far

as

metastases

are

concerned

these

authors

concluded

in

the

same

study

that

a

radiation

dose

of

at

least

Gy

is

associated

with

a

significant

increase

in

response

while

a

dose

of

less

than

Gy

offers

little

chance

of

success

In

a

later

study

-LSB-

-RSB-

they

found

that

when

metastatic

disease

was

present

only

in

lymph

nodes

a

target

radiation

dose

of

at

least

Gy

was

successful

in

of

patients

and

of

involved

nodes

When

nodal

metastases

were

associated

with

either

residual

thyroid

tissue

or

other

metastatic

foci

a

single

treatment

calculated

to

deliver

at

least

Gy

to

the

metastases

proved

successful

in

of

patients

and

of

nodes

The

aforementioned

doses

were

mean

absorbed

doses

for

the

whole

remnant

or

tumour

no

data

were

provided

on

the

dose

distribution

in

smaller

tumour

parts

It

is

also

unclear

what

causes

the

large

difference

between

radiation

dose

values

for

remnants

and

metastases

This

method

requires

sequential

measurements

with

a

scintillation

camera

and

h

after

administration

of

MBq

-LRB-

mCi

-RRB-

of

De

Keizer

et

al.

-LSB-

-RSB-

recently

calculated

thyroid

tumour

doses

with

a

similar

methodology

but

with

the

use

of

recombinant

TSH

A

tumour

dose

of

Gy

was

found

in

only

of

metastases

visible

on

post-therapy

scanning

In

of

patients

progressive

disease

was

evident

after

months

and

of

these

patients

had

radiation

doses

to

the

tumour

in

excess

of

Gy

confirming

the

existence

of

a

clinical

dose-response

relation

In

cases

of

distant

metastases

higher

amounts

of

are

given

in

single

doses

and

subsequent

cumulative

therapies

Most

centres

use

a

fixed

dose

of

GBq

-LRB-

mCi

-RRB-

but

some

use

-LRB-

much

-RRB-

higher

activity

doses

In

order

to

avoid

serious

complications

-LRB-

bone

marrow

suppression

lung

fibrosis

-RRB-

the

commonly

used

maximum

safe-administered

dose

concept

published

by

Benua

et

al.

-LSB-

-RSB-

restricts

the

blood

absorbed

dose

to

less

than

Gy

-LRB-

rad

-RRB-

and

the

whole-body

retention

to

GBq

-LRB-

mCi

-RRB-

at

h

in

the

absence

of

diffuse

lung

metastases

According

to

the

protocol

activity

concentration

in

the

whole

body

as

measured

by

should

not

exceed

MBq

-LRB-

mCi

-RRB-

after

h

when

diffuse

functioning

lung

metastases

are

present

These

measurements

can

be

camera

based

without

blood

sampling

More

recently

the

blood

dose

formula

derivation

proposed

by

Hänscheid

et

al.

-LSB-

-RSB-

has

provided

a

new

tool

for

patient-specific

blood

dose

assessment

representing

marrow

dosimetry

in

DTC

therapy

For

more

precise

dosimetry

e.g.

in

dosimetric

studies

or

for

higher

targeted

blood

absorbed

doses

sequential

blood

sampling

is

recommended

-LSB-

-RSB-

The

calculated

radiation

dose

serves

as

a

surrogate

parameter

for

the

organ

at

risk

the

bone

marrow

since

to

date

direct

determination

of

the

bone

marrow

absorbed

dose

is

not

feasible

This

method

has

been

applied

successfully

in

clinical

practice

Dorn

et

al.

-LSB-

-RSB-

used

a

dosimetric

study

prior

to

therapy

with

MBq

and

obtained

daily

images

up

to

days

They

maximised

the

administered

activity

to

an

absorbed

dose

of

Gy

to

the

bone

marrow

or

Gy

to

the

lungs

corresponding

to

the

in

EBRT

while

aiming

at

Gy

to

all

known

metastases

This

resulted

in

a

mean

of

GBq

-LRB-

mCi

-RRB-

and

a

range

of

GBq

-LRB-

mCi

-RRB-

activity

administered

per

treatment

Many

institutions

will

find

it

difficult

to

deliver

these

amounts

owing

to

radioprotection

restrictions

limiting

the

applicability

of

this

method

To

date

bone

marrow

depression

has

rarely

been

reported

while

the

rate

of

dose-related

leukaemia

has

been

estimated

to

be

approximately

after

years

Lung

fibrosis

as

a

consequence

of

micronodular

iodine-avid

metastases

has

been

reported

in

of

patients

suffering

from

pulmonary

metastases

The

downside

of

these

high-dose

strategies

may

be

an

increase

in

the

occurrence

of

these

side-effects

On

the

other

hand

assuming

this

maximum

safe

dose-to

be

an

optimal

dosing

strategy

extrapolation

to

a

fixed

activity

dose-strategy

of

GBq

-LRB-

mCi

-RRB-

as

is

widely

applied

would

and

of

patients

-LSB-

-RSB-

To

date

there

are

no

randomised

and

prospective

trials

that

directly

compare

a

low

and

high-activity

dose

strategy

in

patients

with

metastases

The

treatment

of

DTC

in

childhood

varies

substantially

from

the

standard

approach

in

adults

mainly

owing

to

the

different

tumour

biology

in

this

age

group

Usually

activities

of

MBq/kg

are

given

treatment

data

on

children

being

scarce

and

non-systematic

There

are

a

number

of

potential

drawbacks

of

dosimetry

that

may

preclude

its

use

in

many

centres

One

problem

is

the

uncertainty

of

volume

determinations

by

neck

ultrasound

shortly

after

thyroid

surgery

since

the

differentiation

between

scar

tissue

haematoma

and

thyroid

remnant

is

often

difficult

The

same

holds

true

for

the

use

of

computed

tomography

-LRB-

CT

-RRB-

magnetic

resonance

imaging

-LRB-

MRI

-RRB-

and

positron

emission

tomography

-LRB-

PET

-RRB-

in

the

evaluation

of

distant

metastatic

lesions

especially

in

the

case

of

diffuse

lung

metastases

Also

it

is

difficult

to

predict

radioiodine

kinetics

during

therapy

from

prior

diagnostic

studies

owing

to

the

large

difference

in

administered

and

measured

activity

and

potential

subsequent

biological

effects

PET

studies

using

the

cyclotron

product

if

possible

in

combination

with

PET/CT

tomography

may

prove

to

be

particularly

valuable

in

improving

treatment

planning

and

patient-specific

dosimetry

Compared

with

conventional

methods

including

CT

and

scanning

this

technique

was

found

to

be

superior

in

terms

of

lesion

detection

and

functional

assessment

-LSB-

-RSB-

Using

three-dimensional

voxel-based

dosimetry

Sgouros

et

al.

-LSB-

-RSB-

showed

a

wide

range

of

mean

absorbed

dose

values

for

individual

tumours

from

to

Gy

Unfortunately

no

correlation

with

response

was

reported

in

that

study

However

this

wide

variation

certainly

implies

that

the

assessment

of

meaningful

dose-effect

relationships

and

clinical

dosimetry

should

include

further

development

of

a

quantitative

approach

therapy

in

neuroblastoma

and

phaeochromocytoma

For

more

than

two

decades

mIBG

labelled

with

the

γ/β

emitter

-LRB-

-RRB-

has

been

used

to

treat

neural

crest-derived

tumours

essentially

neuroblastoma

and

phaeochromocytoma

both

in

relapsed

and

in

newly

diagnosed

patients

In

high-stage

neuroblastoma

the

treatment

may

represent

-LRB-

a

-RRB-

palliative

therapy

-LSB-

-RSB-

-LRB-

b

-RRB-

first-line

therapy

as

a

single

agent

or

combined

with

chemotherapy

-LSB-

-RSB-

-LRB-

c

-RRB-

consolidation

therapy

after

induction

of

a

good

partial

remission

-LSB-

-RSB-

and

more

recently

-LRB-

d

-RRB-

second-line

therapy

after

failed

induction

chemotherapy

combined

with

topotecan

and

stem

cell

rescue

in

children

with

metastatic

neuroblastoma

-LSB-

-RSB-

or

with

myeloablative

chemotherapy

and

autologous

stem

cell

transplantation

in

refractory

neuroblastoma

-LSB-

-RSB-

In

neuroblastoma

important

efforts

have

been

made

to

develop

clinically

useful

dosimetry

methods

to

predict

the

radiation

dose

to

the

red

marrow

as

the

critical

organ

for

bone

marrow

toxicity

in

order

to

apply

optimal

and

individual

dose

maximisation

in

children

with

highly

aggressive

tumours

Three

different

methods

of

activity

administration

have

evolved

from

the

experience

of

treating

such

patients

The

first

approach

developed

in

Amsterdam

the

Netherlands

is

to

give

fixed

activity

dose

fractions-of

GBq

-LRB-

mCi

-RRB-

more

recently

combined

with

hyperbaric

oxygen

or

topotecan

This

approach

has

been

proven

to

have

a

synergistic

effect

on

cell

killing

in

vitro

when

used

in

combination

with

-LSB-

-RSB-

Intervals

between

fractions

are

determined

by

blood

count

recovery

and

the

treatment

is

continued

to

maximum

response

-LSB-

-RSB-

An

advantage

of

this

method

is

its

simplicity

which

may

be

viewed

as

important

in

very

sick

children

and

in

those

who

require

prompt

treatment

especially

when

receiving

first-line

therapy

Another

important

advantage

of

lower

activity

doses

is

the

shorter

isolation

and

hospitalisation

period

required

for

reasons

of

radioprotection

which

may

be

regarded

as

highly

significant

in

these

usually

very

sick

children

with

a

grave

prognosis

As

whole-body

and

tumour

radiation

doses

are

never

calculated

any

kind

of

dose-response

assessment

and

optimisation

on

the

basis

of

absorbed

radiation

dose

is

however

impossible

Furthermore

the

relatively

low

dose

rate

of

radiation

compared

with

-LRB-

ultra

-RRB-

high

doses

may

be

viewed

as

radiobiologically

suboptimal

The

clinical

results

of

this

approach

need

to

be

verified

in

a

multicentre

phase

III

trial

that

should

include

a

dosimetric

assessment

of

the

whole-body

dose

The

second

approach

originates

from

the

United

Kingdom

where

there

has

been

a

long

tradition

of

using

pre-therapy

dosimetry

In

a

phase

I/II

study

on

advanced

chemo-refractory

stage

III/IV

patients

Lashford

et

al.

observed

that

of

patients

developed

grade

or

haematotoxicity

at

a

whole-body

absorbed

dose

of

Gy

established

from

a

pre-therapy

scan

-LSB-

-RSB-

Monsieurs

et

al.

used

prior

to

therapy

to

the

same

effect

-LSB-

-RSB-

Previously

Tristam

et

al.

had

shown

a

highly

skewed

distribution

of

tumour

radiation

doses

after

a

fixed

diagnostic

activity

-LSB-

-RSB-

Matthay

et

al.

found

a

good

correlation

between

whole-body

and

tumour

dose

-LSB-

-RSB-

As

radiation

dose

is

principally

related

to

response

this

approach

may

lead

to

a

more

standardised

whole-body

and

tumour

absorbed

dose

-LSB-

-RSB-

and

may

offer

more

possibilities

of

dose

escalation

especially

in

the

presence

of

an

altered

biodistribution

e.g.

due

to

partial

kidney

failure

or

high

tumour

load

Recently

an

ESIOP

experimental

mIBG

protocol

has

been

proposed

in

which

the

aim

is

to

deliver

a

total

whole-body

absorbed

dose

of

Gy

in

two

fractions

in

combination

with

topotecan

after

failure

of

induction

chemotherapy

Post-therapy

dosimetry

is

performed

after

a

first

fixed

fraction

of

MBq/kg

-LRB-

mCi/kg

-RRB-

with

calculation

of

the

activity

dose

to

be

administered

with

the

subsequent

second

fraction

in

order

to

arrive

at

the

desired

total

whole-body

absorbed

dose

of

Gy

The

importance

of

this

protocol

is

that

whole-body

and

tumour

absorbed

dose

can

be

estimated

and

the

relation

to

both

toxicity

and

response

can

be

established

unlike

with

the

non-dosimetry

protocols

The

schedule

of

intensification

of

mIBG

therapy

by

dose

escalation

and

radiosensitisation

with

topotecan

with

a

haematopoietic

autograft

has

been

shown

to

be

safe

and

practicable

-LSB-

-RSB-

The

next

step

will

be

to

prove

that

this

approach

will

also

lead

to

a

better

outcome

in

neuroblastoma

patients

The

third

approach

can

be

derived

from

recent

publications

from

the

United

States

in

which

patients

received

high

activity

doses

of

mIBG

on

the

basis

of

an

activity

dose

of

MBq

per

kilogram

body

weight

-LRB-

mCi/kg

-RRB-

with

stem

cell

support

if

necessary

In

an

early

study

Sisson

and

co-workers

examined

predictors

of

toxicity

and

found

the

best

correlation

to

be

between

whole-body

absorbed

dose

and

platelet

ratio

however

comparable

and

statistically

significant

correlations

were

found

with

GBq/kg

body

weight

and

body

surface

-LSB-

-RSB-

This

observation

was

supported

by

Matthay

and

colleagues

-LSB-

-RSB-

who

found

the

amount

of

-LRB-

GBq/kg

-RRB-

and

whole-body

dose

-LRB-

Gy

-RRB-

but

not

administered

activity

dose

-LRB-

GBq

-RRB-

to

be

significantly

correlated

with

platelet

and

neutrophil

nadir

In

a

recent

study

by

Dubois

et

al.

-LSB-

-RSB-

substantial

haematotoxicity

was

seen

at

MBq/kg

-LRB-

mCi/kg

-RRB-

in

a

group

of

patients

with

advanced

heavily

pre-treated

neuroblastoma

including

myeloablative

chemotherapy

in

Of

these

patients

required

autologous

haematopoietic

stem

cell

transplantation

The

resulting

median

whole-body

absorbed

dose

was

Gy

with

a

median

administered

activity

dose

of

GBq

-LRB-

mCi

range

mCi

-RRB-

Interestingly

whole-body

radiation

dose

was

shown

to

correlate

with

failure

to

engraft

platelets

or

red

cells

in

those

patients

receiving

autologous

stem

cell

transplantation

An

encouraging

response

rate

of

was

reported

however

The

same

authors

recently

established

a

maximum

tolerated

dose

-LRB-

MTD

-RRB-

of

MBq/kg

-LRB-

mCi/kg

-RRB-

with

myeloablative

chemotherapy

and

autologous

stem

cell

transplantation

-LSB-

-RSB-

The

advantage

is

that

there

is

no

need

for

planning/simulation

in

this

high-dose

protocol

which

may

increase

in

importance

if

multiple

centres

participate

Malignant

metastatic

phaeochromocytoma

is

a

very

rare

disease

but

can

be

excellently

treated

by

in

both

a

palliative

and

a

curative

setting

Literature

data

on

dosimetry

are

scarce

and

casuistic

In

Loh

et

al.

reviewed

the

literature

concerning

previously

treated

cases

-LSB-

-RSB-

They

found

a

cumulative

activity

dose

of

GBq

-LRB-

mCi

mean

α

mCi

-RRB-

in

-LRB-

mean

α

-RRB-

therapies

with

a

mean

single

activity

dose

of

GBq

-LRB-

mCi

-RRB-

Dose

prescriptions

were

as

a

fixed

activity

dose

of

GBq

-LRB-

mCi

or

mCi/kg

-RRB-

A

recent

study

was

performed

in

order

to

evaluate

the

performance

of

mIBG

therapy

with

high

activities

after

debulking

surgery

-LSB-

-RSB-

The

median

individual

cumulative

activity

dose

was

GBq

-LRB-

mCi

-RRB-

with

a

range

of

GBq

-LRB-

mCi

-RRB-

in

one

to

three

consecutive

therapies

Grade

platelet

toxicity

was

observed

after

of

therapies

and

grade

and

neutrophil

toxicity

after

and

of

therapies

respectively

All

patients

had

stem

cells

harvested

before

therapy

but

patients

showed

spontaneous

reconstitution

and

only

one

required

stem

cell

return

Response

rate

was

patients

-LRB-

-RRB-

Radiopeptide

therapy

for

neuro-endocrine

tumours

Several

clinical

trials

have

investigated

the

use

of

peptide

receptor

radionuclide

therapy

-LRB-

PRRT

-RRB-

with

a

radiolabelled

somatostatin

analogue

as

one

of

the

newly

developed

targeted

tools

for

neuro-endocrine

tumours

-LSB-

-RSB-

Individual

pre-therapeutic

dosimetry

is

necessary

for

patient

selection

and

therapy

planning

because

there

are

huge

inter-patient

differences

in

radiopeptide

uptake

in

normal

organs

and

tumour

tissues

This

may

be

related

to

varying

somatostatin

receptor

densities

on

tumour

cells

as

well

as

to

factors

such

as

tumour

volume

interstitial

pressure

and

viability

The

dosimetric

studies

that

have

been

performed

in

this

treatment

have

been

the

most

sophisticated

in

the

field

and

exemplory

for

other

types

of

treatment

Initial

studies

were

performed

with

the

radiopeptide

used

in

diagnostics

-LSB-

-RSB-

octreotide

given

in

high

activities

Results

were

encouraging

with

symptomatic

and

biochemical

responses

in

a

large

percentage

of

patients

although

objective

responses

were

rare

-LSB-

-RSB-

The

analogue

-LSB-

-RSB-

octreotide

has

been

investigated

in

various

phase

I-II

trials

-LSB-

-RSB-

lanreotide

has

also

been

investigated

-LRB-

in

the

MAURITIUS

trial

-RRB-

-LSB-

-RSB-

For

dosimetry

of

from

post-therapeutic

bremsstrahlung

images

that

substantially

lack

quality

must

be

quantified

Therefore

two

alternative

approaches

have

been

developed

as

a

surrogate

for

the

original

radiopeptide

namely

therapy

simulation

with

either

the

peptide

or

the

peptide

-LSB-

-RSB-

These

methods

are

intended

to

provide

pre-therapy

assessment

of

the

optimal

activity

administration

-LSB-

-RSB-

-LRB-

Table

-RRB-

The

variation

that

can

be

appreciated

among

the

various

combinations

in

the

table

may

be

primarily

technical/methodological

in

origin

but

also

biological

based

on

differences

in

somatostatin

receptors

and

isotope/chelator

affinity

The

reader

is

referred

to

the

respective

papers

for

more

detailed

information

Table

doses

to

principal

organs

and

to

tumour

-LRB-

Gy/GBq

SD

-RRB-

deriving

from

different

radiopeptidesStabin

-LSB-

-RSB-

Kwekkeboom

-LSB-

-RSB-

Kwekkeboom

-LSB-

-RSB-

Cremonesi

-LSB-

-RSB-

Forster

-LSB-

-RSB-

Helisch

-LSB-

-RSB-

Forrer

-LSB-

-RSB-

Therapy

-LSB-

-RSB-

octreotide

-LSB-

-RSB-

octreotate

-LSB-

-RSB-

octreotide

-LSB-

-RSB-

octreotide

-LSB-

-RSB-

octreotide

-LSB-

-RSB-

octreotideDosimetry

-LSB-

-RSB-

octreotide

-LSB-

-RSB-

octreotate

-LSB-

-RSB-

octreotide

-LSB-

-RSB-

octreotide

-LSB-

-RSB-

octreotide

-LSB-

-RSB-

α

α

α

b

α

α

Kidneys

α

α

α

α

α

α

α

α

α

α

α

α

α

α

Red

α

α

α

α

α

α

Tumour

-LRB-

range

-RRB-

a

3.9-37.91.4-313.21-19.582.1-29.52.4-41.7

aFrom

reference

-LSB-

-RSB-

bSeries

enlarged

from

the

original

one

as

in

Bodei

et

al.

-LSB-

-RSB-

Although

-LSB-

-RSB-

octreotide

-LRB-

or

lanreotide

-RRB-

and

its

imageable

counterpart

-LSB-

-RSB-

octreotide

-LRB-

or

lanreotide

-RRB-

are

not

chemically

identical

the

latter

has

been

used

for

dosimetric

simulation

based

on

the

hypothesis

that

the

similar

physical

and

biological

half-lives

yield

a

comparable

in

vivo

pharmacokinetics

and

biodistribution

especially

concerning

the

renal

uptake

which

depends

on

aspecific

phenomena

A

drawback

of

this

method

is

that

the

small

structural

modification

may

affect

the

somatostatin

receptor

binding

affinity

-LSB-

-RSB-

Regarding

biodistribution

the

organs

receiving

the

highest

predicted

absorbed

doses

in

a

first

series

of

patients

included

the

spleen

-LRB-

α

mGy/MBq

-RRB-

the

kidneys

-LRB-

α

mGy/MBq

-RRB-

and

the

tumour

-LRB-

mGy/MBq

mean

-RRB-

When

the

series

was

enlarged

to

patients

a

slightly

higher

kidney

absorbed

dose

-LRB-

α

mGy/MBq

-RRB-

was

observed

-LSB-

-RSB-

Shortcut

approaches

involving

use

of

the

commercially

available

molecule

-LSB-

-RSB-

octreotide

or

OctreoScan

have

been

proposed

-LSB-

-RSB-

Nonetheless

probably

as

a

result

of

the

quite

different

biokinetics

and

receptor

affinity

of

-LSB-

-RSB-

octreotide

and

-LSB-

-RSB-

octreotide

which

are

indeed

chemically

different

comparative

data

obtained

appear

not

to

be

sufficiently

overlapping

for

this

tracer

A

thorough

dosimetric

study

using

PET

with

-LSB-

-RSB-

octreotide

biochemically

identical

to

the

therapeutic

molecule

was

carried

out

in

patients

-LSB-

-RSB-

This

offers

substantial

advantages

in

terms

of

spatial

resolution

and

quantification

but

the

short

half-life

of

the

radionuclide

leaves

later

phases

of

the

biokinetics

to

estimates

based

on

extrapolation

The

newest

radiopeptide

-LSB-

-RSB-

octreotate

offers

further

advantages

has

a

lower

energy

-LRB-

Emax

MeV

-RRB-

and

penetration

range

-LRB-

Rmax

mm

-RRB-

emission

but

a

longer

half-life

-LRB-

days

-RRB-

The

low

abundance

gamma

emissions

-LRB-

and

keV

-RRB-

allow

for

dosimetry

and

imaging

prior

to

as

well

as

post

therapy

Moreover

octreotate

has

a

six

to

ninefold

higher

affinity

for

somatostatin

receptor

the

somatostatin

receptor

most

frequently

expressed

in

neuro-endocrine

tumours

Unfortunately

to

date

a

thorough

dosimetric

analysis

is

lacking

but

data

deriving

from

a

study

comparing

-LSB-

-RSB-

octreotate

with

-LSB-

-RSB-

octreotide

indicate

that

compared

with

-LSB-

-RSB-

octreotide

-LSB-

-RSB-

octreotate

delivers

a

lower

burden

to

organs

with

absorbed

doses

of

mGy/MBq

to

the

spleen

mGy/MBq

to

the

kidneys

-LRB-

lowered

to

mGy/MBq

with

protection

-RRB-

and

mGy/MBq

to

the

liver

Red

marrow

absorbed

dose

derived

by

the

blood

approach

ranged

from

to

mGy/MBq

-LSB-

-RSB-

Due

to

their

marked

radiosensitivity

the

kidneys

undoubtedly

represent

the

critical

organ

particularly

after

-LSB-

-RSB-

octreotide

Renal

irradiation

arises

from

the

proximal

tubular

re-absorption

of

the

radiopeptide

and

the

resulting

retention

in

the

interstitium

According

to

EBRT

studies

the

renal

maximum

tolerated

absorbed

dose

is

conventionally

considered

to

be

in

the

range

of

Gy

According

to

the

National

Council

on

Radiation

Protection

and

Measurements

-LRB-

NCRPM

-RRB-

an

absorbed

dose

of

Gy

to

the

kidneys

causes

detrimental

deterministic

effects

in

of

patients

within

years

-LSB-

-RSB-

Sporadic

cases

of

delayed

renal

failure

in

some

cases

end-stage

disease

requiring

dialysis

have

been

observed

especially

in

patients

who

have

received

an

activity

dose

of

more

than

-LSB-

-RSB-

Nephrotoxicity

is

accelerated

by

other

risk

factors

such

as

pre-existing

hypertension

or

diabetes

Given

the

high

kidney

retention

of

radiopeptides

positively

charged

molecules

such

as

L-lysine

and

L-arginine

are

used

to

competitively

inhibit

the

proximal

tubular

re-absorption

of

the

radiopeptide

This

results

in

a

reduction

in

the

renal

absorbed

dose

of

between

and

-LSB-

-RSB-

Doses

are

further

reduced

by

up

to

by

prolonging

infusion

over

h

and

by

up

to

by

prolonging

it

over

days

after

radiopeptide

administration

thus

covering

more

extensively

the

elimination

phase

through

the

kidneys

-LSB-

-RSB-

Despite

kidney

protection

renal

function

loss

may

become

clinically

evident

years

after

PRRT

A

median

decline

in

creatinine

clearance

of

per

year

was

reported

in

patients

treated

with

-LSB-

-RSB-

octreotide

and

of

per

year

in

patients

treated

with

-LSB-

-RSB-

octreotate

Cumulative

and

per

cycle

renal

absorbed

dose

age

hypertension

and

diabetes

are

considered

factors

contributing

to

the

decline

of

renal

function

after

PRRT

-LSB-

-RSB-

Clinical

experience

and

dosimetric

studies

clearly

indicate

that

the

renal

absorbed

dose

estimated

by

conventional

dosimetry

does

not

accurately

correlate

with

the

renal

toxicity

observed

in

patients

treated

with

-LSB-

-RSB-

octreotide

Consideration

of

additional

parameters

such

as

patient-specific

kidney

volume

and

distribution

of

the

radionuclide

appears

to

give

a

better

correlation

with

the

clinical

effects

-LSB-

-RSB-

Assessment

of

individual

kidney

volume

by

CT

scan

yields

a

wide

variability

when

compared

with

the

standardised

phantom

Moreover

autoradiographic

studies

performed

on

human

kidney

after

in

vivo

injection

of

have

demonstrated

that

the

majority

of

radioactivity

is

deposited

within

the

renal

cortex

mainly

in

the

juxtamedullary

region

This

leads

to

a

higher

deposition

of

energy

per

unit

mass

compared

with

conventional

dosimetry

Hence

calculation

of

the

kidney

absorbed

dose

assuming

a

homogeneous

renal

distribution

of

radioactivity

is

inadequate

New

techniques

accounting

for

the

difference

in

radioactivity

placement

in

the

kidneys

on

the

basis

of

a

CT-based

volumetric

analysis

appear

more

realistic

-LSB-

-RSB-

Even

if

predicted

absorbed

doses

are

much

lower

than

the

threshold

for

toxicity

the

other

target

organ

that

gives

rise

to

concerns

about

acute

and

permanent

toxicity

after

PRRT

is

the

bone

marrow

particularly

in

repeated

administrations

-LSB-

-RSB-

Acute

haematological

grade

or

toxicity

is

not

uncommon

especially

after

-LSB-

-RSB-

octreotide

and

sporadic

cases

of

myelodysplastic

syndromes

or

even

overt

acute

myeloid

leukaemia

have

been

reported

with

all

three

therapeutic

radio-compounds

Bone

marrow

dosimetry

is

usually

modelled

through

a

blood-based

method

in

which

an

equivalent

distribution

of

the

radioactivity

from

blood

throughout

the

bone

marrow

is

conservatively

considered

-LSB-

-RSB-

Currently

the

potential

risk

of

kidney

and

red

marrow

limits

the

amount

of

radioactivity

that

may

be

administered

Indeed

when

tumour

masses

are

irradiated

with

suitable

doses

volume

reduction

may

be

observed

-LRB-

Fig.

-RRB-

-LSB-

-RSB-

Tumour

remission

is

positively

correlated

with

high

uptake

during

-LSB-

-RSB-

octreotide

scintigraphy

Nevertheless

tumour

radiation

dose

depends

not

only

directly

on

the

administered

activity

and

the

uptake

versus

time

but

also

on

the

tumour

load

This

is

confirmed

by

clinical

data

regarding

the

response

characteristics

patients

with

a

limited

number

of

liver

metastases

respond

to

PRRT

whilst

patients

with

a

high

tumour

load

do

not

-LSB-

-RSB-

Mathematical

models

have

shown

that

is

better

in

small

tumours

-LRB-

optimal

diameter

mm

-RRB-

whilst

is

better

in

larger

ones

-LRB-

optimal

diameter

mm

-RRB-

very

small

masses

are

likely

not

to

absorb

all

the

β-energy

released

in

the

tumour

cells

by

while

larger

tumours

will

suffer

from

lack

of

uniformity

of

activity

distribution

of

Finally

differences

in

dose

rate

must

be

taken

into

account

the

longer

physical

half-life

of

means

a

longer

period

is

needed

to

deliver

the

same

radiation

dose

than

when

using

This

may

allow

more

time

for

tumour

re-population

-LSB-

-RSB-

Therefore

combination

therapy

with

and

either

simultaneously

or

in

distinct

settings

has

been

suggested

to

overcome

the

difficulties

of

real

clinical

situations

involving

different

sized

lesions

Fig.

dose-response

relationship

in

patients

treated

with

Tumour

volumes

were

assessed

by

CT

before

and

after

treatment

Tumour

dose

estimates

were

derived

from

CT

scan

volume

measurements

and

quantitative

imaging

performed

before

treatment

Data

were

further

computed

using

the

MIRDOSE

spherical

model

Reprinted

by

permission

of

the

Society

of

Nuclear

Medicine

from

-LSB-

-RSB-

Treatment

of

solid

tumours

by

radiolabelled

antibodies

Most

clinical

radioimmunotherapy

-LRB-

RIT

-RRB-

studies

have

been

performed

in

colorectal

cancer

using

antibodies

against

CEA

and

KSA

Other

tumours

studied

have

included

ovarian

cancer

-LRB-

anti-folate

receptor

-RRB-

prostate

cancer

-LRB-

anti-PMSA

-RRB-

breast

cancer

-LRB-

anti-mucin

-RRB-

glioma

-LRB-

anti-tenascin

-RRB-

and

renal

cancer

-LRB-

-RRB-

-LSB-

-RSB-

Although

at

later

time

points

after

injection

of

radiolabelled

monoclonal

antibodies

adequate

to

high

uptake

may

serve

to

delineate

deposits

of

solid

tumours

the

relatively

unfavourable

therapeutic

window

between

the

anti-tumour

effect

and

toxicity

hampers

the

introduction

of

these

agents

in

the

clinic

Solid

tumours

are

generally

more

radioresistant

than

for

example

malignant

lymphoma

The

absorbed

doses

required

to

achieve

a

response

of

tumour

deposits

are

higher

than

those

needed

to

obtain

a

response

in

malignant

lymphoma

Activity

doses

leading

to

adequate

absorbed

doses

in

tumour

deposits

therefore

result

in

significant

radiation-induced

toxicity

primarily

of

the

bone

marrow

as

the

most

radiation-sensitive

organ

myeloablation

may

be

the

goal

as

well

as

the

result

of

this

Most

studies

aim

at

administration

of

the

MTD

that

results

in

acceptable

toxicity

to

the

bone

marrow

as

the

organ

responsible

for

dose-limiting

toxicity

Several

methods

have

been

reported

for

calculation

of

the

absorbed

dose

to

the

bone

marrow

e.g.

region

of

interest

analysis

of

scintigraphic

data

or

a

model

based

on

radioactivity

in

the

blood

When

radiolabelled

antibodies

bind

to

blood

bone

and

bone

marrow

components

or

when

the

radionuclide

accumulates

in

bone

or

bone

marrow

upon

metabolisation

of

the

radionuclide-antibody

complex

calculation

of

the

red

marrow

dose

is

more

complex

than

when

using

radiolabelled

antibodies

that

lack

these

characteristics

-LSB-

-RSB-

The

use

of

a

model

for

bone

marrow

dosimetry

using

blood

activity

may

result

in

better

reproducibility

of

the

bone

marrow

dosimetry

Wessels

et

al.

-LSB-

-RSB-

observed

that

historical

variations

as

high

as

between

different

institutions

performing

marrow

absorbed

dose

calculations

could

be

dramatically

reduced

to

to

by

a

central

computing

facility

and

the

use

of

similar

methodology

based

on

the

standard

American

Association

of

Physicists

in

Medicine

-LRB-

AAPM

-RRB-

Sgouros

blood

model

-LSB-

-RSB-

In

a

study

using

murine

monoclonal

antibody

in

patients

with

metastatic

renal

cell

cancer

haematological

toxicity

correlated

with

whole-body

absorbed

radiation

dose

-LSB-

-RSB-

In

a

retrospective

analysis

of

patients

who

underwent

antibody

therapy

absorbed

dose-based

definitions

of

MTD

and

escalation

variables

proved

to

be

better

than

activity-based

methods

-LSB-

-RSB-

In

a

study

in

which

therapeutic

doses

of

-LRB-

the

chimeric

variant

of

-RRB-

were

administered

no

correlation

was

found

between

haematological

toxicity

and

either

the

radiation

absorbed

dose

to

the

whole

body

or

bone

marrow

or

the

administered

activity

-LSB-

-RSB-

Juweid

et

al.

observed

that

besides

red

marrow

dose

baseline

blood

counts

multiple

bone

and/or

marrow

metastases

and

recent

chemotherapy

are

important

factors

related

to

haematological

toxicity

after

radio-immunotherapy

-LSB-

-RSB-

making

a

dosimetric

approach

to

identify

the

optimal

radionuclide

dose

more

complicated

One

way

to

overcome

the

unfavourable

therapeutic

index

of

tumour

response

and

normal

organ

toxicity

is

to

focus

on

treatment

of

patients

with

minimal

residual

disease

For

example

patients

with

ovarian

cancer

in

complete

remission

after

debulking

and

chemotherapy

have

an

approximately

chance

of

relapse

Compared

with

results

in

matched

controls

Nicholson

et

al.

observed

an

increase

in

survival

from

to

following

intraperitoneal

administration

of

in

patients

with

ovarian

cancer

in

complete

remission

after

chemotherapy

-LSB-

-RSB-

However

a

more

recent

randomised

clinical

trial

in

patients

with

ovarian

cancer

in

complete

remission

after

debulking

and

chemotherapy

did

not

reveal

a

benefit

in

disease-free

and

overall

survival

after

treatment

with

murine

-LSB-

-RSB-

Introduction

of

did

not

delay

the

time

to

relapse

and

did

not

result

in

prolonged

survival

as

compared

with

the

control

group

One

can

argue

that

is

far

from

ideal

for

treatment

of

minimal

residual

disease

owing

to

its

high

β-energy

and

that

radionuclides

with

lower

range

emissions

such

as

have

more

favourable

characteristics

for

this

purpose

Furthermore

relatively

large

antibody

doses

were

used

which

may

have

resulted

in

saturation

of

the

epitopes

on

cancer

cells

and

subsequently

in

low

tumour-to-non-tumour

ratios

of

radioactivity

uptake

Obviously

clinical

dosimetry

could

play

an

important

role

in

explaining

these

differences

in

therapy

results

A

very

significant

advance

that

promises

to

increase

the

radiation

dose

to

the

tumour

while

reducing

that

to

the

bone

marrow

is

the

development

of

pre-targeting

strategies

In

pre-targeting

the

tumour

is

first

targeted

with

a

specific

non-radioactive

monoclonal

antibody

construct

The

antibody

construct

is

allowed

to

accumulate

in

the

tumour

and

to

clear

from

the

blood

and

non-target

tissues

Subsequently

a

small

radioactive

hapten

is

injected

which

has

high

affinity

for

the

antibody

construct

The

radioactive

hapten

targets

the

antibody

construct

while

demonstrating

rapid

renal

excretion

Examples

of

these

approaches

are

the

use

of

bispecific

monoclonal

antibodies

and

the

biotin-avidin

system

-LSB-

-RSB-

As

pre-targeting

increases

the

tumour/normal

organ

uptake

ratio

-LSB-

-RSB-

these

approaches

hold

great

promise

for

enhanced

therapeutic

efficacy

However

the

use

of

multiple

drugs

poses

the

problem

of

fine-tuning

dosing

and

timing

of

the

interval

between

injections

Optimisation

of

the

dosing

and

timing

schedule

is

needed

for

optimal

targeting

of

the

tumour

by

the

radioactive

compound

while

assuring

low

normal

organ

uptake

Robust

dosimetric

analysis

of

tumour

and

normal

organ

uptake

of

the

radioactive

small

molecule

is

a

requirement

for

the

successful

development

and

implementation

of

pre-targeting

strategies

-LSB-

-RSB-

Radioimmunotherapy

of

B-cell

lymphoma

Research

in

RIT

in

lymphoma

has

resulted

in

two

FDA-approved

radiopharmaceuticals

or

Zevalin

-LRB-

IDEC

Pharmaceuticals

and

Schering

AG

-RRB-

and

or

Bexxar

-LRB-

Glaxo

Smith

Kline

-RRB-

for

the

treatment

of

B-cell

lymphoma

-LSB-

-RSB-

Both

are

directed

against

albeit

not

against

the

same

epitope

They

are

both

approved

for

the

treatment

of

relapsed

or

refractory

follicular/low-grade

or

transformed

B-cell

lymphoma

including

rituximab-refractory

follicular

B-cell

lymphoma

in

the

US

but

only

Zevalin

is

approved

in

the

EU

and

only

for

follicular

lymphoma

Pre-treatment

with

unlabelled

monoclonal

antibody

-LRB-

preload

-RRB-

as

part

of

the

treatment

with

Zevalin

and

Bexxar

is

current

practice

as

it

leads

to

a

more

favourable

biodistribution

This

has

been

studied

in

animal

models

as

well

as

in

the

setting

of

myeloablative

RIT

-LSB-

-RSB-

The

preload

may

clear

peripheral

B

cells

from

the

circulation

improving

tumour

targeting

of

subsequently

administered

radiolabelled

monoclonal

antibodies

This

optimisation

has

been

accomplished

by

diagnostic

and

dosimetric

or

tracer

studies

On

the

other

hand

the

intrinsic

therapeutic

efficacy

of

the

antibody

is

a

confounding

factor

making

evaluation

of

the

relation

between

absorbed

dose

and

treatment

response

more

difficult

than

for

other

radiopharmaceuticals

-LSB-

-RSB-

Bexxar

has

been

developed

using

the

whole-body

absorbed

dose

as

a

substitute

for

bone

marrow

dosimetry

by

administering

a

trace

amount

of

antibody

and

determining

the

total

body

clearance

prior

to

therapy

in

order

to

calculate

the

patient-specific

injected

activity

dose

that

should

deliver

the

specified

absorbed

dose

to

the

whole

body

The

method

has

been

further

simplified

to

an

estimation

based

on

three

points

-LSB-

-RSB-

In

a

dose

escalation

study

with

absorbed

doses

to

the

whole

body

ranging

in

increments

from

to

Gy

the

MTD

was

found

to

be

Gy

in

patients

who

had

not

received

prior

high-dose

chemotherapy

with

stem

cell

support

and

who

had

platelet

counts

of

A

comparison

between

the

therapeutic

activity

calculated

on

the

basis

of

the

diagnostic

pre-therapy

tracer

study

and

the

amount

calculated

per

kilogram

body

weight

showed

that

using

the

latter

method

of

the

patients

would

have

been

either

over

or

underdosed

by

or

more

and

of

the

patients

by

or

more

Interestingly

a

correlation

between

the

duration

of

complete

remission

-LRB-

CR

-RRB-

and

the

absorbed

dose

to

the

whole

body

was

found

Patients

receiving

a

whole-body

absorbed

dose

between

and

Gy

showed

longer

CR

than

patients

receiving

between

and

Gy

-LSB-

-RSB-

In

contrast

Zevalin

has

been

developed

with

the

notion

that

dosimetry

may

be

dispensable

In

a

randomised

study

comparing

Zevalin

with

rituximab

alone

a

secondary

objective

was

to

determine

whether

dosimetry

was

required

-LSB-

-RSB-

A

tracer

dose

of

MBq

-LRB-

mCi

-RRB-

was

administered

for

dosimetric

purposes

with

the

first

infusion

followed

by

a

therapeutic

activity

dose

of

mCi/kg

-LRB-

MBq/kg

-RRB-

Zevalin

days

later

The

absorbed

doses

to

normal

organs

and

the

marrow

were

found

to

be

within

the

specified

limits

of

Gy

for

solid

organs

and

Gy

for

red

marrow

in

patients

The

median

estimated

absorbed

dose

to

the

tumour

was

Gy

-LRB-

range

Gy

-RRB-

There

was

no

significant

correlation

between

dosimetric

and

pharmacokinetic

parameters

and

haematological

toxicity

although

the

correlation

between

nadir

of

the

neutrophil

count

and

the

whole

blood

half-life

of

exhibited

borderline

statistical

significance

It

was

concluded

that

dosimetry

may

be

excluded

for

populations

of

Zevalin

patients

who

meet

certain

criteria

for

pre-treatment

platelet

count

and

percentage

of

marrow

involvement

by

tumour

A

possible

explanation

for

this

discrepancy

may

be

found

in

the

photon

energy

emitted

by

this

may

account

for

a

large

part

of

the

cross-absorbed

dose

to

the

bone

marrow

which

is

almost

independent

of

the

amount

of

bone

marrow

involvement

It

has

been

reported

that

the

self-absorbed

dose

accounts

for

of

the

whole

absorbed

dose

to

the

red

marrow

-LSB-

-RSB-

leaving

as

the

cross-absorbed

dose

Scintigraphic

assessment

of

absorbed

dose

to

the

bone

marrow

has

its

shortcomings

owing

to

over

and

underlying

tissues

as

well

as

to

the

local

variability

in

bone

marrow

involvement

by

the

disease

targeted

It

is

especially

difficult

to

use

pharmacokinetic

data

for

calculation

of

the

absorbed

bone

marrow

dose

since

bone

marrow

involvement

is

a

strong

confounder

Other

important

issues

are

the

bone

to

bone

marrow

ratio

and

variable

values

for

the

activity

concentration

in

the

blood

and

red

marrow

-LSB-

-RSB-

A

fixed

ratio

between

blood

and

bone

marrow

has

been

used

in

bone

marrow

dosimetry

based

on

blood

radioactivity

levels

-LSB-

-RSB-

However

it

has

been

suggested

that

the

red

marrow

to

blood

ratio

is

not

fixed

but

increases

continuously

up

to

h

post

injection

in

both

patients

and

rats

-LSB-

-RSB-

Furthermore

haematological

toxicity

like

tumour

response

is

a

deterministic

effect

of

radiation

characterised

by

a

sigmoid

rather

than

by

a

linear

dose

relationship

-LSB-

-RSB-

A

sigmoid

relationship

may

be

discernible

in

a

reasonably

homogeneous

population

but

is

likely

to

be

more

difficult

to

identify

if

the

population

is

heterogeneous

The

bone

marrow

reserve

may

be

more

relevant

to

the

magnitude

of

toxicity

than

is

the

absorbed

dose

Another

particular

challenge

to

haematology

RIT

dosimetry

may

be

tumour

regression

during

energy

deposition

as

is

frequently

the

case

in

rapidly

responding

lymphoma

This

may

lead

to

underestimation

of

absorbed

dose

since

dose

is

per

definition

energy

per

unit

mass

-LSB-

-RSB-

The

opposite

will

be

the

case

if

the

tumour

grows

during

energy

deposition

To

avoid

this

pitfall

repeated

volume

assessments

during

therapy

would

be

necessary

or

alternatively

one

could

use

voxel-based

dosimetry

which

is

likely

to

be

less

sensitive

to

changes

in

mass

Myeloablative

RIT

at

the

MTD

for

normal

organs

is

by

definition

dependent

on

dosimetry

Dose-limiting

organs

may

be

the

lungs

kidneys

or

liver

In

high-dose

RIT

using

the

mouse

antibody

tositumomab

the

lungs

were

found

to

be

the

dose-limiting

organ

in

of

patients

and

the

kidneys

in

the

remaining

patient

-LSB-

-RSB-

The

opposite

was

found

when

the

pharmacokinetics

of

the

chimeric

rituximab

were

studied

i.e.

the

kidneys

were

found

to

be

the

critical

organ

-LSB-

-RSB-

These

differences

may

be

due

to

the

significant

difference

in

half-life

between

the

antibodies

the

chimeric

and

murine

antibodies

having

half-lives

of

h

and

h

respectively

The

MTD

for

myeloablative

was

established

to

be

Gy

to

the

lungs

Studies

of

myeloablative

RIT

using

are

ongoing

and

encouraging

results

have

been

reported

-LSB-

-RSB-

In

several

experimental

studies

Auger

emitters

have

been

therapeutically

superior

to

β

emitters

when

taken

to

the

MTD

-LSB-

-RSB-

This

is

likely

to

be

due

primarily

to

lower

bone

marrow

toxicity

but

is

perhaps

also

attributable

to

the

deposition

of

more

energy

in

single

cells

or

small

tumour

cell

clusters

Auger

emitters

would

thus

be

advantageous

in

an

adjuvant

setting

in

leukaemia

but

they

may

also

be

superior

where

there

is

tumour

bulk

The

challenge

is

how

to

estimate

absorbed

dose

in

single

cells

but

one

may

begin

in

patients

with

a

significant

amount

of

circulating

tumour

cells

that

can

be

studied

ex

vivo

-LSB-

-RSB-

Interestingly

Kaminski

reported

that

in

a

number

of

patients

who

relapsed

following

RIT

the

relapse

occurred

only

at

sites

previously

not

known

to

be

involved

with

tumour

-LSB-

-RSB-

this

indicates

a

possibility

that

small

tumour

manifestations

receive

lower

absorbed

doses

than

expected

on

the

basis

of

antigen

density

and

tumour

diameter

-LSB-

-RSB-

Discussion

As

stated

by

DeNardo

-LSB-

-RSB-

claims

for

specific

dosimetry

have

to

demonstrate

that

the

frequency

of

excess

toxicity

and/or

tumour

underdosing

significantly

decreases

Dosimetry

should

provide

a

quantification

procedure

that

is

primarily

of

additional

benefit

over

empirical

fixed

dosing

with

or

without

visual

scintigraphic

assessment

In

standard

oncology

practice

a

new

therapeutic

agent

undergoes

phase

I

II

and

III

testing

before

becoming

a

standard

treatment

In

a

phase

I

study

the

maximum

tolerated

dose

is

established

and

side-effects

recorded

Dosimetry

should

play

an

essential

role

in

this

phase

and

establish

a

threshold

dose

above

which

clinically

significant

side-effects

occur

In

phase

II

the

new

radionuclide

therapy

is

evaluated

in

terms

of

effect

on

tumour

response

and

survival

Here

dosimetry

should

enable

the

determination

of

a

clinical

dose-response

relationship

In

phase

III

the

new

therapy

is

compared

with

the

standard

one

At

this

stage

dosimetry

helps

to

elucidate

the

clinical

effects

in

a

larger

patient

group

e.g.

it

may

be

observed

that

some

subgroups

have

a

better

or

worse

result

Moreover

multicentre

trials

offer

the

opportunity

to

compare

results

in

different

institutions

and

countries

as

well

as

provide

the

opportunity

to

standardise

the

dosimetry

procedure

in

a

larger

context

Evidence-based

medicine

entails

randomised

and

prospective

trials

However

after

years

of

treating

thyroid

cancer

patients

international

guidelines

still

can

not

provide

a

consensus

on

the

amount

of

radioiodine

that

should

be

given

Undoubtedly

the

need

for

randomised

trials

will

increase

in

the

coming

years

as

in

other

areas

This

underlines

the

importance

of

stepping

up

scientific

efforts

to

include

optimal

dosimetry

not

only

as

an

inherent

part

of

radionuclide

therapy

but

also

as

an

inherent

part

of

these

studies

In

this

context

there

was

a

remarkable

recent

editorial

in

the

Journal

of

Clinical

Oncology

-LSB-

-RSB-

discussing

the

limitations

of

the

body

surface

principle

that

forms

the

basis

for

chemotherapy

dosing

Indeed

the

bioavailability

of

chemotherapy

and

hence

the

dose

to

the

target

suffers

from

a

similar

metabolic

variability

as

is

observed

for

radionuclides

and

this

variability

seems

to

be

more

important

than

can

be

accounted

for

by

the

body

surface

in

square

metres

as

the

sole

parameter

Interesting

parallels

may

be

drawn

for

translational

research

for

example

in

pharmacokinetic

modelling

and

molecular

imaging

Many

modern

gamma

cameras

are

optimised

for

photons

below

keV

and

are

less

suitable

for

radionuclide

therapy

dosimetry

if

higher

energy

photons

are

involved

SPECT

overcomes

the

problem

of

superimposition

of

target

and

other

activity

but

spatial

resolution

at

depth

is

always

worse

than

in

planar

imaging

so

quantification

has

to

rely

on

more

or

less

representative

phantom

models

-LSB-

-RSB-

PET

has

a

times

higher

sensitivity

for

a

given

spatial

resolution

that

is

typically

mm

This

is

a

major

advantage

over

SPECT

in

pharmacokinetic

dynamic

modelling

Correction

for

attenuation

has

become

relatively

easy

with

the

new

PET/CT

and

SPECT/CT

cameras

but

other

correction

factors

e.g.

for

scatter

linearity

and

calibration

are

also

critical

Partial

volume

effects

are

a

major

issue

in

the

quantification

of

small

tumours

and

occur

at

below

about

twice

the

spatial

resolution

This

is

thus

more

of

a

problem

for

SPECT

-LRB-

spatial

resolution

for

mm

-RRB-

than

for

PET

-LRB-

spatial

resolution

mm

-RRB-

Finally

as

discussed

in

the

radiopeptide

section

the

radionuclides

used

for

dosimetry

must

show

similar

biochemical

and

physical

behaviour

to

those

used

for

therapy

As

previously

highlighted

the

use

of

PET

and

PET

dosimetry

-LSB-

-RSB-

has

been

a

landmark

development

PET/CT

and

SPECT/CT

and

molecular-radiopharmaceutical

developments

offer

major

opportunities

for

radionuclide

therapy

dosimetry

-LSB-

-RSB-

Further

improvements

in

the

performance

of

these

cameras

and

hence

dosimetry

can

be

foreseen

Also

the

proliferation

of

microsystems

such

as

micro-PET/SPECT/CT

MRI

is

allowing

dynamic

in

vivo

animal

research

increasing

our

knowledge

of

radiopharmaceutical

biodistribution

improving

quantitation

and

permitting

early

selection

of

therapeutic

radiopharmaceuticals

Table

lists

some

of

the

most

important

methodological

issues

involved

in

performing

accurate

dosimetry

today

Table

Methodological

issues

in

performing

clinical

dosimetry

Diagnostic

tracer

and/or

therapeutic

activity

study

Planar

and/or

tomographic

-LRB-

SPECT

and/or

PET

-RRB-

quantification

Dynamic

and/or

multiple

time

point

activity

sampling

Linearity

of

detector

response

in

low

and/or

high

activity

Correction

factors

for

attenuation

scatter

and/or

partial

volume

effects

Nuclear

medicine

and/or

radiological

volume

and

response

Standard

-LRB-

MIRD

-RRB-

and/or

simulative

-LRB-

Monte

Carlo

-RRB-

modelling

Tissue

heterogeneity

and/or

spatial

resolution

limits

Treatment

of

minimal

residual

disease

and/or

partial

volume

effects

Disease-induced

and/or

therapy-induced

changes

in

parameters

Macro

and/or

microdosimetry

techniques

Animal

and/or

human

dosimetry

data

Radiobiology

is

a

science

in

itself

Nevertheless

up

to

now

very

little

consideration

has

been

given

to

the

effects

of

radionuclide

therapy

at

the

cellular

and

molecular

level

-LSB-

-RSB-

Rather

extrapolations

have

been

made

from

EBRT

despite

the

fundamental

differences

in

radiation

kinetics

The

majority

of

observations

in

EBRT

have

been

made

under

the

condition

of

a

high

dose

rate

while

clinical

radionuclide

therapy

entails

a

decreasing

low

dose

rate

The

effect

of

fractionated

EBRT

is

primarily

influenced

by

the

R

's

of

radiobiology

repair

of

DNA

damage

repopulation

of

tissues

re-oxygenation

of

tumour

and

redistribution

in

the

cell

cycle

In

radionuclide

therapy

with

its

decreasing

dose

rate

tumour

DNA

repair

takes

place

simultaneously

with

sublethal

damage

Bystander

effects

i.e.

radiation-like

effects

in

unhit

cells

may

be

of

significance

in

low-dose

low

dose

rate

radiotherapy

-LSB-

-RSB-

Furthermore

it

is

becoming

increasingly

apparent

that

the

physical

paradigm

of

direct

cell

killing

by

double-strand

DNA

breaks

is

insufficient

Non-DNA

targets

such

as

cell

membrane

or

RNA

may

also

be

critical

to

target

cell

death

or

dysfunction

Moreover

new

molecular-targeted

oncology

treatments

may

not

produce

direct

cell

death

but

rather

alter

biochemical

pathways

or

cellular

homeostasis

that

may

interact

with

classical

radiation

targets

or

produce

new

radiation

targets

-LSB-

-RSB-

In

this

paradigm

the

concept

of

radiation

dose

may

need

re-definition

and

the

future

radiation

dose

may

be

determined

in

terms

of

the

biological

and

functional

changes

produced

and

observed

such

as

by

blood

markers

and

by

PET

SPECT

and/or

MRI

Biologically

effective

dose

-LRB-

BED

-RRB-

is

a

concept

which

has

been

successfully

applied

to

radionuclide

therapy

through

the

landmarking

studies

of

Barone

et

al.

-LSB-

-RSB-

using

DOTATOC

and

kidney

toxicity

BED

is

the

product

of

the

total

physical

dose

multiplied

by

the

relative

effectiveness

which

takes

into

account

radiobiological

parameters

such

as

dose

rate

radionuclide

decay

and

tumour

cell

repair

time

and

allows

direct

quantitative

comparison

with

EBRT

It

should

be

noted

that

late-responding

normal

tissues

and

slow-growing

tumours

allow

easier

modelling

than

early-responding

normal

tissues

and

fast-growing

tumours

because

of

repopulation

during

treatment

in

the

latter

Nevertheless

this

may

be

regarded

as

a

major

development

stimulating

further

research

-LSB-

-RSB-

aimed

towards

the

creation

of

a

firm

fundamental

basis

for

radionuclide

radiotoxicity

and

radiodosimetry

In

future

it

looks

as

if

we

shall

no

longer

be

looking

at

a

Holy

Gray

but

rather

at

the

worldly

BEGray

In

conclusion

recent

developments

in

molecular

medicine

PET/CT

and

SPECT/CT

cameras

and

radiobiology

offer

major

scientific

and

clinical

opportunities

in

radionuclide

therapy

dosimetry

However

only

prospective

randomised

trials

with

adequate

methodology

can

provide

the

evidence

that

applied

clinical

dosimetry

results

in

better

patient

outcome

than

is

achieved

with

fixed

activity

dosing

methods

O B I O O O O O O O O O O O B I O O O O O O O O O O O B O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

radionuclide therapy
radiotherapy
thyroid carcinoma
solid tumours
lymphoma

radiation dosimetry
neuro-endocrine tumours
radio-immunotherapy