Local

therapy

of

cancer

with

free

This

is

a

position

paper

about

the

therapeutic

effects

of

locally

applied

free

in

the

treatment

of

cancer

Local

therapy

therapy

of

cancer

was

originally

introduced

as

a

systemic

therapy

This

therapy

led

to

about

objective

responses

Systemic

therapy

however

was

very

toxic

due

to

the

vascular

leakage

syndrome

Nevertheless

this

treatment

was

a

break-through

in

cancer

immunotherapy

and

stimulated

some

interesting

questions

Supposing

that

the

mechanism

of

treatment

is

both

proliferation

and

tumoricidal

activity

of

the

tumor

infiltrating

cells

then

locally

applied

should

result

in

a

much

higher

local

concentration

than

systemic

application

Consequently

a

greater

beneficial

effect

could

be

expected

after

local

application

-LRB-

peritumoral

juxtatumoral

intratumoral

intra-arterial

intracavitary

or

intratracheal

inhalation

-RRB-

Free

Many

groups

have

tried

to

prepare

a

more

effective

formulation

than

free

Examples

are

slow

release

systems

insertion

of

the

gene

into

a

tumor

cell

causing

prolonged

release

However

logistically

free

is

much

easier

to

apply

hence

we

concentrated

in

this

review

and

in

most

of

our

experiments

on

the

use

of

free

Local

therapy

with

free

may

be

effective

against

transplanted

tumors

in

experimental

animals

and

against

various

spontaneous

carcinomas

sarcomas

and

melanoma

in

veterinary

and

human

cancer

patients

It

may

induce

rejection

of

very

large

metastasized

tumor

loads

for

instance

advanced

clinical

tumors

The

effects

of

even

a

single

application

may

be

impressive

Not

each

tumor

or

tumor

type

is

sensitive

to

local

application

For

instance

transplanted

lymphoma

or

lymphoma

were

not

sensitive

in

our

hands

Also

the

extent

of

sensitivity

differs

In

Bovine

Ocular

Squamous

Cell

Carcinoma

-LRB-

BOSCC

-RRB-

often

a

complete

regression

is

obtained

whereas

with

the

Bovine

Vulval

Papilloma

and

Carcinoma

Complex

-LRB-

BVPCC

-RRB-

mainly

stable

disease

is

attained

Analysis

of

the

results

of

local

therapy

in

cases

of

cancer

in

human

patients

shows

that

there

were

Complete

Regressions

-LRB-

CR

-RRB-

Partial

Regressions

-LRB-

PR

-RRB-

Stable

Disease

-LRB-

SD

-RRB-

and

Progressive

Disease

-LRB-

PD

-RRB-

In

all

tumors

analyzed

local

therapy

was

more

effective

than

systemic

treatment

Intratumoral

applications

are

more

effective

than

peritumoral

application

or

application

at

a

distant

site

Tumor

regression

induced

by

intratumoral

application

may

be

a

fast

process

-LRB-

requiring

about

a

week

-RRB-

in

the

case

of

a

highly

vascular

tumor

since

induces

vascular

leakage/edema

and

consequently

massive

tumor

necrosis

The

latter

then

stimulates

an

immune

response

In

less

vascular

tumors

or

less

vascular

tumor

sites

regression

may

require

months

this

regression

is

mainly

caused

by

a

cytotoxic

leukocyte

reaction

Hence

the

disadvantageous

vascular

leakage

syndrome

complicating

systemic

treatment

is

however

advantageous

in

local

treatment

since

local

edema

may

initiate

tumor

necrosis

Thus

the

therapeutic

effect

of

local

treatment

is

not

primarily

based

on

tumor

immunity

but

tumor

immunity

seems

to

be

useful

as

a

secondary

component

of

the

induced

local

processes

If

local

is

combined

with

surgery

radiotherapy

or

local

chemotherapy

the

therapeutic

effect

is

usually

greater

than

with

either

therapy

alone

Hence

local

free

application

can

be

recommended

as

an

addition

to

standard

treatment

protocols

Local

treatment

with

free

is

straightforward

and

can

readily

be

applied

even

during

surgical

interventions

Local

treatment

is

usually

without

serious

side

effects

and

besides

minor

complaints

it

is

generally

well

supported

Only

small

quantities

of

are

required

Hence

the

therapy

is

relatively

cheap

A

single

application

of

million

U

costs

about

Euros

Thus

combined

local

treatment

may

offer

an

alternative

in

those

circumstances

when

more

expensive

forms

of

treatment

are

not

available

for

instance

in

resource

poor

countries

Systemic

therapy

of

cancer

Rosenberg

and

co-workers

were

the

first

to

treat

cancer

with

They

showed

that

renders

white

blood

cells

cytotoxic

in

vitro

These

cells

were

coined

Lymphokine

Activated

Killer

cells

-LRB-

LAK

cells

-RRB-

Rosenberg

and

co-workers

treated

transplanted

lung

metastases

in

mice

Injection

of

plus

LAK

cells

clearly

reduced

the

number

of

metastases

in

the

lung

-LSB-

-RSB-

Next

these

authors

treated

consecutive

patients

with

different

types

of

advanced

cancer

for

whom

no

effective

treatment

was

available

In

patients

objective

responses

were

obtained

after

treatment

with

and

LAK

cells

-LSB-

-RSB-

Obviously

this

paper

attracted

worldwide

attention

as

it

was

a

breakthrough

in

immunological

treatment

of

cancer

In

further

studies

systemic

application

of

with

or

without

LAK

cells

appeared

useful

in

patients

with

metastasized

renal

cell

carcinoma

and

metastasized

melanoma

In

both

conditions

about

objective

responses

were

obtained

that

is

about

complete

and

about

partial

tumor

regressions

-LSB-

-RSB-

Repeated

cycles

of

systemic

administration

were

required

to

achieve

systemic

tumor-inhibitory

effects

Grande

et

al.

-LSB-

-RSB-

recently

reviewed

the

therapeutic

effects

of

systemic

therapy

Systemic

application

required

bolus

injections

of

given

every

h

at

a

dose

of

IU/kg

body

weight

for

at

least

days

These

high

doses

were

very

toxic

as

systemic

therapy

induces

a

generalized

vascular

leakage

syndrome

-LSB-

-RSB-

In

addition

the

preparation

and

application

of

LAK

cells

was

cumbersome

indeed

Supposing

that

the

tumor

infiltrating

leucocytes

have

to

be

stimulated

by

we

and

other

groups

decided

to

focus

on

local

therapy

that

is

application

at

the

site

of

the

tumor

-LRB-

peritumoral

juxtatumoral

intratumoral

intra-arterial

intracavitary

infusion

or

inhalation

-RRB-

Since

local

application

requires

smaller

doses

of

than

systemic

treatment

less

complications

were

expected

Locally

applied

relatively

small

doses

of

leads

to

much

higher

concentrations

at

the

site

of

the

tumor

and

to

much

lower

concentrations

elsewhere

in

the

body

Conclusion

The

development

of

systemic

therapy

was

a

break-through

in

cancer

immunotherapy

We

supposed

that

the

drawbacks

of

systemic

application

might

be

overcome

by

local

application

Effectiveness

of

local

versus

systemic

therapy

Subject

The

therapeutic

effectiveness

of

local

versus

systemic

application

Data

Silagi

et

al.

-LSB-

-RSB-

studied

mice

with

melanoma

or

sarcoma

using

combined

cyclosphosphamide

and

Cyclophosphamide

was

always

applied

systemically

Cyclophosphamide

alone

had

no

therapeutic

effect

but

combined

treatment

of

cyclophosphamide

and

showed

a

synergistic

effect

When

either

tumor

was

implanted

s.c.

at

day

and

treatment

was

given

at

the

site

of

the

tumor

beginning

days

later

of

the

mice

were

cured

Only

were

cured

when

was

administered

i.p.

Conversely

with

i.p.

treatment

of

i.p.

tumors

of

the

mice

were

tumor-free

on

day

as

compared

with

only

with

s.c.treatment

Vaage

-LSB-

-RSB-

tested

the

therapeutic

effects

of

daily

injections

of

U

of

human

against

the

syngeneic

immunogenic

mammary

carcinoma

implanted

s.c.

into

mice

A

local

therapeutic

effect

was

observed

after

injecting

tumors

even

with

doses

as

low

as

U

of

per

injection

Systemic

treatment

however

required

at

least

U

per

injection

for

obtaining

discernable

results

Belardelli

et

al.

-LSB-

-RSB-

treated

mice

with

s.c.

transplanted

highly

metastatic

Friend

leukemia

non-metastatic

Friend

leukemia

lymphoma

and

fibrosarcoma

In

all

these

tumor

models

peritumoral

injections

of

were

more

effective

in

inhibiting

tumor

growth

than

systemic

treatment

Anderson

et

al.

-LSB-

-RSB-

studied

the

therapeutic

effects

of

in

mice

with

sarcoma

pulmonary

metastases

When

mice

were

treated

once

daily

with

free

on

days

and

after

tumor

inoculation

the

intrathoracic

route

was

superior

to

the

i.p.

or

s.c.

routes

Maas

et

al.

-LSB-

-RSB-

treated

mice

bearing

i.p.

and

s.c.

lymphoma

If

was

injected

i.p.

then

in

of

the

mice

i.p.

tumors

regressed

completely

and

in

tumors

regressed

completely

both

i.p.

and

s.c.

When

mice

had

only

a

s.c.

growing

tumor

and

was

injected

i.p.

then

in

only

of

the

mice

tumors

regressed

completely

Dubinett

et

al.

-LSB-

-RSB-

transplanted

s.c.

Line

alveolar

carcinoma

cells

in

Balb/c

mice

On

the

third

day

following

tumor

implantation

mice

received

injections

of

twice

daily

either

by

i.p.

or

intratumoral

injection

days/week

for

weeks

Intratumoral

injection

of

significantly

reduced

the

tumor

volume

increased

the

median

survival

time

and

resulted

in

a

cure

rate

However

no

long-term

survivors

were

among

the

i.p.

treated

mice

Jacobs

et

al.

-LSB-

-RSB-

investigated

human

patients

with

nasopharyngeal

carcinoma

Local

treatment

was

combined

with

standard

irradiation

therapy

Sixty

three

of

the

patients

showed

a

disease

free

survival

during

the

next

years

whereas

only

of

the

controls

treated

with

irradiation

alone

were

still

disease

free

after

years

Interestingly

these

results

contrast

with

those

of

Chi

et

al.

-LSB-

-RSB-

who

applied

single

modality

systemic

therapy

They

concluded

that

no

response

was

observed

So

apparently

local

application

is

more

effective

than

systemic

application

It

is

important

that

these

results

of

Jacobs

et

al.

and

Chi

et

al.

were

obtained

in

spontaneously

occurring

tumors

not

with

transplanted

tumors

Local

should

even

preferably

be

given

intratumorally

as

application

adjacent

to

the

tumor

is

far

less

effective

Jacobs

et

al.

-LSB-

-RSB-

compared

the

effect

of

peritumoral

and

intratumoral

therapy

in

mice

with

s.c.

transplanted

lymphoma

Intratumoral

was

significantly

more

effective

than

peritumoral

Krastev

et

al.

-LSB-

-RSB-

treated

patients

with

various

gastrointestinal

tumors

with

intratumoral

and/or

intraperitoneal

therapy

Six

patients

had

a

clinical

response

All

six

belonged

to

the

group

of

seven

patients

who

received

intratumoral

therapy

No

objective

responses

were

obtained

in

patients

treated

only

with

intraperitoneal

In

an

early

review

Bernsen

et

al.

already

concluded

that

locoregional

treatment

was

more

effective

than

systemic

treatment

-LSB-

-RSB-

Since

then

an

overwhelming

amount

of

research

has

corroborated

this

conclusion

Conclusion

The

data

show

that

local

therapy

and

in

particular

intratumoral

application

is

more

effective

than

systemic

therapy

Local

therapy

leads

to

systemic

therapeutic

effects

even

curing

metastatic

disease

Subject

Obviously

a

major

problem

of

cancer

therapy

is

inducing

regression

of

metastases

Immunotherapy

of

cancer

is

an

attractive

concept

as

systemic

immunity

may

indeed

cure

metastases

Consequently

many

groups

have

concentrated

on

the

systemic

therapeutic

effects

of

local

therapy

Data

Maas

et

al.

-LSB-

-RSB-

have

shown

that

i.p.

injections

of

can

cure

mice

with

a

large

burden

of

i.p.

transplanted

and

greatly

disseminated

lymphoma

This

implied

that

tumor

metastases

can

be

successfully

treated

with

local

therapy

In

more

detailed

studies

tumor

cells

were

injected

in

mice

both

i.p.

and

s.c.

on

the

flank

resulting

in

i.p.

and

s.c.

tumors

-LSB-

-RSB-

About

of

the

mice

treated

i.p

with

rejected

both

the

i.p.

tumor

and

the

large

distant

s.c.

tumor

In

contrast

similar

i.p.

treatment

cured

only

of

the

mice

bearing

only

a

s.c.

tumor

Thus

it

was

shown

that

can

induce

systemic

tumor

rejection

when

injected

at

the

site

of

tumor

growth

This

tumor

rejection

was

specific

as

mice

that

were

rejecting

i.p.

and

s.c.

lymphoma

did

not

reject

mastocytoma

Vaage

-LSB-

-RSB-

tested

the

therapeutic

effects

of

against

intramammary

implants

of

an

immunogenic

syngeneic

mammary

carcinoma

Peritumoral

injected

had

almost

equal

local

and

systemic

therapeutic

effects

whereas

systemically

injected

was

not

therapeutically

effective

at

all

Immunity

also

explains

the

long

lasting

absence

-LRB-

months

-RRB-

of

bladder

carcinoma

recurrences

in

two

treated

patients

who

previously

had

a

and

years

history

of

recurrent

bladder

cancer

-LSB-

-RSB-

Van

Es

et

al.

-LSB-

-RSB-

showed

that

peritumoral

injections

of

in

a

transplanted

rabbit

carcinoma

model

can

induce

complete

regression

of

the

treated

tumors

as

well

as

untreated

contralateral

tumors

in

four

out

of

rabbits

Also

metastases

in

the

draining

regional

lymph

nodes

of

both

treated

and

untreated

primary

tumors

regressed

in

three

of

these

animals

So

local

treatment

of

a

tumor

led

to

systemic

effects

curing

untreated

tumors

at

a

distant

site

as

well

as

metastases

in

the

draining

lymph

nodes

of

both

the

treated

and

the

untreated

tumors

A

second

challenge

with

tumor

cells

of

the

cured

animals

was

rejected

Jacobs

et

al.

-LSB-

-RSB-

transplanted

in

mice

tumors

at

two

different

sites

Rejection

of

the

intratumoral

treated

tumors

was

stronger

than

rejection

of

the

untreated

tumors

Systemic

immunity

is

also

likely

in

patients

with

nasopharyngeal

carcinoma

treated

with

radiotherapy

and

intratumoral

application

-LSB-

-RSB-

Addition

of

to

the

standard

radiotherapy

reduced

the

number

of

loco

regional

and

distant

recurrences

In

line

with

these

observations

is

the

finding

that

local

or

generalized

effector

dysfunction

of

the

immune

system

can

be

reversed

by

exposure

in

patients

with

advanced

cancer

-LSB-

-RSB-

Conclusion

Local

therapy

can

also

cause

systemic

therapeutic

effects

probably

due

to

immune

reactivity

-LSB-

-RSB-

Therapeutic

effects

of

local

therapy

against

transplanted

tumors

in

laboratory

animals

-LRB-

Tables

-RRB-

Subject

For

studying

the

potential

therapeutic

effects

of

anticancer

drugs

one

has

to

start

in

animal

models

using

transplanted

tumors

as

well-performed

and

well-interpreted

studies

in

animals

have

predictive

value

regarding

the

therapeutic

effectiveness

of

a

drug

in

human

cancer

patients

-LSB-

-RSB-

Table

therapeutic

effects

of

local

application

on

transplanted

tumors

results

published

by

other

groupsTumorsSpeciesRoute

of

applicationTherapeutic

effectReferencesCarcinomasMammary

carcinomasMousePeritumoral

-LSB-

-RSB-

Transitional

cell

carcinomaMouseIntratumoral

-LSB-

-RSB-

Lung

carcinomaMouseIntratumoral

-LSB-

-RSB-

Prostate

carcinomaRatIntratumoral

-LSB-

-RSB-

SarcomasMC-induced

sarcomasMousePeritumoral

-LSB-

-RSB-

HeJ

fibrosarcomaMousePeritumoral

-LSB-

-RSB-

sarcomaMousePeritumoral

-LSB-

-RSB-

lymphomaMousePeritumoral

-LSB-

-RSB-

MiscellaneousMyeloma

site

-LSB-

-RSB-

MelanomaMouseTumor

site

-LSB-

-RSB-

Friend

leukemiaMousePeritumoral

-LSB-

-RSB-

HPV

associated

tumorMouseTumor

site

-LSB-

-RSB-

We

have

included

data

of

all

papers

that

we

have

found

on

therapeutic

effects

of

local

application

of

free

to

transplanted

cancer

in

animalsA

well-recognized

problem

with

a

Table

like

this

one

is

that

usually

positive

results

are

published

in

contrast

to

negative

results

So

there

is

a

positive

publication

bias.The

message

of

Table

is

not

that

all

transplanted

tumors

are

sensitive

but

that

positive

therapeutic

effects

have

been

obtained

in

many

different

models

and

many

different

tumor

types

Clear

therapeutic

effect

Many

cures

were

obtainedTable

effect

of

local

application

on

transplanted

tumors

results

from

our

groupTumorOrgan

typeSpeciesPredictive

modelRoute

of

applicationTherapeutic

effectReferencesCarcinomasLine

pig

Intratumoral

-LSB-

-RSB-

Peritumoral

-LSB-

-RSB-

MOTTeratomaMouse

Intratumoral

-LSB-

-RSB-

MC-ASNBreastMouse

Peritumoral

-LSB-

-RSB-

MC-BCBreastMouse

Peritumoral

-LSB-

-RSB-

Peritumoral

-LSB-

-RSB-

Intratumoral

carcinomaHead

and

NeckRabbit

Peritumoral

-LSB-

-RSB-

Recently

arisen

Intratumoral

-LSB-

-RSB-

Intratumoral

-LSB-

-RSB-

Intratumoral

-LSB-

-RSB-

SarcomaMecho

FibrosarcomaMouse

Intratumoral

Intratumoral

-LSB-

-RSB-

Intratumoral

-LSB-

-RSB-

Intratumoral

Intratumoral

Intratumoral

Intratumoral

Intratumoral

-LSB-

-RSB-

This

Table

presents

all

results

obtained

with

models

tested

by

our

group

so

there

is

no

selection

bias

-LRB-

in

contrast

to

Table

-RRB-

therapeutic

effects

just

measurable

therapeutic

effects

are

clear

animals

can

be

cured

from

extensive

tumor

loadsThe

four

negative

models

were

only

tested

in

a

few

experiments

until

we

were

convinced

that

therapeutic

effects

were

not

obtained

in

our

hands

Three

of

the

four

negative

models

were

not

published

for

obvious

reasons

On

the

other

hand

lymphoma

in

syngeneic

mice

is

our

standard

model

since

the

paper

of

Maas

et

al.

-LSB-

-RSB-

Numerous

studies

were

performed

with

this

model

The

therapeutic

effect

of

local

application

was

always

clear

Data

As

early

as

in

Bubenik

and

co-workers

-LSB-

-RSB-

established

that

peritumoral

injections

of

rat

lymphoid

suppressed

or

markedly

inhibited

the

growth

of

methylcholanthrene-induced

sarcomas

in

syngeneic

mice

An

equally

effective

inhibition

of

murine

sarcoma

transplants

in

syngeneic

recipients

could

be

obtained

with

crude

lymphoid

rat

with

purified

of

murine

lymphoid

origin

and

with

molecularly

homogeneous

human

recombinant

-LSB-

-RSB-

Maas

et

al.

-LSB-

-RSB-

injected

mice

i.p.

with

cells

and

days

later

these

mice

were

treated

with

i.p.

injections

At

the

time

of

injection

the

transplanted

tumor

had

greatly

expanded

by

growth

infiltration

and

metastasis

A

mouse

of

gram

developed

in

days

a

tumor

load

of

at

least

g

about

tumor

cells

Nevertheless

about

of

these

mice

were

cured

by

This

was

a

very

important

step

forward

in

immunotherapy

of

cancer

The

therapeutic

effects

were

dose-dependent

These

data

were

confirmed

in

more

elaborated

studies

by

Bernsen

et

al.

-LSB-

-RSB-

and

by

Everse

et

al.

-LSB-

-RSB-

Tables

and

summarize

the

therapeutic

results

of

local

application

to

transplanted

tumors

Table

displays

the

results

obtained

by

other

groups

and

Table

results

by

our

group

Both

Tables

show

that

local

therapy

may

be

effective

in

a

broad

range

of

tumor

types

such

as

carcinomas

-LSB-

-RSB-

sarcomas

-LSB-

-RSB-

a

myeloma

-LSB-

-RSB-

lymphomas

-LSB-

-RSB-

leukemia

-LSB-

-RSB-

a

mastocytoma

-LSB-

-RSB-

and

HPV

associated

tumor

-LSB-

-RSB-

Obviously

not

all

cancers

are

sensitive

to

therapy

Our

group

studied

the

effect

of

local

therapy

in

models

of

transplanted

tumors

-LRB-

Table

-RRB-

In

models

positive

therapeutic

results

were

obtained

applied

in

breast

cancers

was

only

moderately

effective

In

four

models

no

therapeutic

effects

were

obtained

namely

murine

stomach

carcinoma

-LSB-

-RSB-

murine

MOT

teratoma

-LSB-

-RSB-

murine

lymphoma

-LSB-

-RSB-

and

murine

lymphoma

-LSB-

-RSB-

Why

some

tumors

are

sensitive

to

local

therapy

and

other

tumor

models

do

not

show

any

response

remains

hitherto

an

enigma

The

data

summarized

in

Tables

and

demonstrate

that

local

therapy

has

the

capability

to

destroy

tumor

cells

and

to

cure

the

hosts

An

animal

model

using

transplanted

tumors

has

predictive

value

for

the

therapeutic

effect

in

human

cancer

if

the

model

tumor

comprises

more

than

of

the

body

weight

of

the

host

and

if

this

tumor

is

metastasized

-LSB-

-RSB-

Eight

models

mentioned

in

Table

fulfil

these

requirements

viz.

the

models

marked

in

column

with

So

the

positive

therapeutic

results

obtained

with

these

models

predict

that

local

therapy

can

be

therapeutically

effective

in

human

patients

with

metastatic

cancer

Conclusion

In

models

with

transplanted

tumors

in

laboratory

animals

there

is

overwhelming

evidence

showing

the

therapeutic

effect

of

local

application

of

free

This

therapy

is

effective

against

a

broad

range

of

tumors

In

addition

the

magnitude

of

the

therapeutic

data

-LRB-

for

instance

-LSB-

-RSB-

-RRB-

suggests

that

this

form

of

therapy

can

also

induce

objective

therapeutic

responses

in

human

cancer

patients

N.B.

Not

every

transplanted

tumor

or

tumor

type

is

sensitive

to

local

application

For

instance

transplanted

lymphoma

or

lymphoma

are

not

sensitive

in

our

hands

-LRB-

Table

-RRB-

Local

tumor

treatment

in

veterinary

patients

-LRB-

Table

-RRB-

Subject

Positive

results

in

veterinary

patients

with

spontaneous

cancer

are

an

important

intermediate

between

experiments

with

transplanted

cancer

in

laboratory

animals

and

clinical

application

in

human

cancer

cases

If

therapeutic

effects

are

positive

in

well-performed

well-interpreted

experiments

with

transplanted

cancer

in

laboratory

animals

as

well

as

in

spontaneous

cancer

in

veterinary

patients

then

one

can

be

almost

certain

that

such

a

therapy

will

also

be

effective

in

human

cancer

patients

Table

effect

of

local

application

veterinary

cancer

patientsType

of

cancerHostTherapeutic

effectReferencesBovine

ocular

squamous

cell

carcinomaCattle

-LSB-

-RSB-

Vulval

papilloma

and

carcinoma

complexCattle

-LSB-

-RSB-

SarcoidsHorses

-LSB-

-RSB-

FibrosarcomaDogs

-LSB-

-RSB-

This

Table

summarizes

to

our

knowledge

all

published

studies

on

local

application

of

free

in

veterinary

cancer

patients

Detectable

effect

Many

CR

cases

Data

Table

summarizes

all

published

studies

that

we

know

on

local

application

in

veterinary

cancer

patients

Bovine

Ocular

Squamous

Cell

Carcinoma

-LRB-

BOSCC

-RRB-

BOSCC

originates

in

the

cornea

the

third

eyelid

-LRB-

membrana

nictitans

-RRB-

the

lower

or

the

upper

eyelid

Ultimately

the

tumor

covers

the

whole

eye

It

also

metastasizes

to

the

draining

lymph

nodes

This

tumor

occurs

frequently

in

tropical

countries

with

intense

solar

radiation

particularly

at

high

altitudes

BOSCC

is

for

various

reasons

a

very

useful

veterinary

tumor

model

The

tumor

is

readily

visible

and

can

be

directly

treated

with

peritumoral

or

intratumoral

injection

in

field

studies

In

The

Netherlands

BOSCC

is

a

very

rare

disease

So

our

first

tests

of

sensitivity

of

BOSCC

were

performed

in

only

five

cows

with

BOSCC

-LSB-

-RSB-

The

results

showed

that

BOSCC

can

be

sensitive

to

local

therapy

In

Zimbabwe

about

of

the

cows

are

affected

by

BOSCC

This

allows

large-scale

studies

-LSB-

-RSB-

Added

to

this

BOSCC

causes

an

enormous

economical

burden

In

our

most

extensive

study

in

Zimbabwe

-LSB-

-RSB-

we

treated

BOSCC

cases

with

tumor

areas

ranging

from

to

Peritumoral

injections

of

various

doses

of

were

applied

during

days

Nine

months

after

treatment

the

daily

doses

of

U

had

induced

complete

tumor

regression

in

and

of

the

animals

respectively

In

the

control

animals

the

tumors

had

completely

regressed

in

only

of

the

cases

After

months

the

comparable

figures

were

and

respectively

and

there

had

been

no

change

in

the

control

group

The

tumors

on

the

third

eyelid

and

limbus

were

the

most

responsive

-LSB-

-RSB-

Similar

results

were

obtained

in

other

studies

-LSB-

-RSB-

Even

large

BOSCC

tumors

of

up

to

mm

can

regress

completely

by

local

therapy

-LSB-

-RSB-

Bovine

Vulval

Papilloma

and

Carcinoma

Complex

-LRB-

BVPCC

-RRB-

BVPCC

is

a

common

disease

in

Bos

taurus

breeds

of

cattle

kept

at

high

altitude

with

high

levels

of

solar

radiation

in

Africa

-LSB-

-RSB-

It

also

occurs

in

other

countries

and

continents

with

similar

high

levels

of

solar

radiation

Burdin

-LSB-

-RSB-

originally

described

the

pathogenesis

of

this

neoplasm

Hill

et

al.

-LSB-

-RSB-

adapted

this

description

to

develop

a

useful

system

for

clinical

staging

of

the

tumors

In

Zimbabwe

BVPCC

occurs

in

about

of

the

cattle

It

causes

much

animal

suffering

In

addition

BVPCC

usually

proceeds

to

a

more

advanced

stage

So

BVPCC

forms

a

real

economical

burden

for

the

farmer

and

on

a

national

scale

Twenty

three

papillomas

and

carcinomas

of

the

bovine

vulva

were

treated

with

local

therapy

Sixteen

partial

remissions

and

three

complete

remissions

add

to

a

tumor

reduction

in

of

the

treated

cows

-LSB-

Stewart

et

al.

to

be

published

-RSB-

Remissions

were

striking

in

papillomas

with

a

massive

lymphocytic

infiltrate

in

particular

in

those

epithelial

areas

that

showed

marked

dysplasia

or

-LRB-

pre

-RRB-

malignant

changes

Sarcoids

Sarcoids

are

fibro-epithelial

skin

tumors

of

horses

donkeys

and

mules

Infiltrative

growth

is

prominent

but

they

seldom

metastasize

After

surgical

removal

they

usually

recur

Sarcoids

were

treated

by

intratumoral

injections

for

or

days

There

were

and

objective

responses

respectively

after

months

-LSB-

-RSB-

Fibrosarcomas

in

dogs

Tumors

often

occur

in

cats

and

dogs

as

owners

care

for

pets

even

into

advanced

age

as

members

of

the

family

Like

ageing

humans

they

show

a

large

variety

of

tumors

in

their

later

years

Preliminary

data

demonstrated

that

fibrosarcomas

in

dogs

are

sensitive

to

local

therapy

-LSB-

-RSB-

Conclusion

Local

therapy

can

be

effective

against

spontaneous

veterinary

tumors

Local

application

has

an

enormous

economical

impact

as

BOSCC

as

well

as

BVPCC

occur

in

about

of

cattle

in

Zimbabwe

and

probably

also

in

other

tropical

countries

Local

treatment

of

BOSCC

leads

to

CR

in

the

majority

of

the

cases

and

led

to

tumor

reduction

in

the

majority

of

BVPCC

cases

For

ethical

reasons

specific

immunity

can

not

be

tested

in

veterinary

patients

However

specificity

and

systemic

effects

have

been

shown

in

mice

-LSB-

-RSB-

and

rabbits

-LSB-

-RSB-

with

transplanted

tumors

Effective

local

treatment

greatly

improves

the

quality

of

life

by

reducing

suffering

These

therapeutic

effects

in

veterinary

cancer

patients

make

a

strong

case

for

the

development

and

acceptance

of

local

therapy

with

free

in

human

cancer

patients

Results

of

local

tumor

treatment

in

human

cancer

patients

-LRB-

Table

-RRB-

Subject

The

final

step

in

the

experimental

chain

is

the

local

application

of

free

to

human

cancer

Many

research

groups

have

pioneered

in

this

field

We

now

summarize

and

discuss

the

results

Table

effect

of

local

application

on

human

cancer

patientsType

of

cancerNumber

of

patientsCRPRSDPDReferencesBasal

cell

-LSB-

-RSB-

Bladder

-LSB-

-RSB-

Bladder

-LSB-

-RSB-

Bladder

-LSB-

-RSB-

Bladder

-LSB-

-RSB-

Bladder

-LSB-

-RSB-

Gastro-intestinal

-LSB-

-RSB-

Hepatocellular

-LSB-

-RSB-

Lung

cancer

pleural

-LSB-

-RSB-

-LSB-

-RSB-

-LSB-

-RSB-

-LSB-

-RSB-

-LSB-

-RSB-

-LSB-

-RSB-

-LSB-

-RSB-

Ovarian

-LSB-

-RSB-

Ovarian

-LSB-

-RSB-

Neoplastic

-LSB-

-RSB-

Total

Percentage

-LRB-

-RRB-

CR

complete

regression

PR

partial

regression

SD

stable

disease

PD

progressive

disease

Data

Basal

cell

carcinoma

Kaplan

et

al.

-LSB-

-RSB-

treated

basal

carcinoma

of

the

skin

A

total

of

tumors

were

treated

in

eight

patients

Overall

response

rates

were

complete

response

in

of

treated

tumors

partial

response

in

out

of

treated

tumors

stable

disease

with

no

improvement

in

one

tumor

site

Bladder

carcinoma

Pizza

et

al.

-LSB-

-RSB-

obtained

tumor

regressions

after

intralesional

injections

of

in

bladder

cancer

Repeated

injections

of

under

cystoscopic

control

resulted

in

complete

regression

of

the

tumor

in

three

out

of

six

patients

and

in

partial

regression

of

another

three

patients

Huland

and

Huland

-LSB-

-RSB-

obtained

histologically

confirmed

complete

remission

lasting

more

than

months

in

one

out

of

five

patients

with

urinary

bladder

carcinoma

after

continuous

perfusion

of

the

bladder

for

days

Gomella

et

al.

-LSB-

-RSB-

treated

patients

with

superficial

bladder

carcinoma

Patients

were

treated

first

with

transurethral

resection

leaving

a

marker

lesion

followed

by

intravesical

instillation

There

were

three

complete

responses

one

lasting

more

than

months

Ferlazzo

et

al.

-LSB-

-RSB-

treated

superficial

bladder

cancer

cases

with

intravesical

infusions

of

This

gave

similar

clinical

results

as

obtained

by

vesical

instillation

with

BCG

after

transurethral

resection

Den

Otter

et

al.

-LSB-

-RSB-

treated

patients

with

recurrent

bladder

carcinoma

stage

grades

to

with

incomplete

transurethral

resection

leaving

a

marker

tumor

of

cm

Two

days

after

resection

was

instilled

for

h.

Patients

were

asked

to

turn

over

regularly

in

order

to

ensure

maximal

exposure

of

to

the

bladder

wall

This

procedure

was

repeated

on

five

consecutive

days

Two

months

later

the

effect

was

measured

by

cystoscopy

examination

In

eight

out

of

ten

patients

the

marker

tumor

had

regressed

completely

Four

patients

were

still

tumor

free

after

to

months

In

one

patient

with

a

history

of

bladder

cancer

requiring

cystoscopies

the

marker

had

only

partially

regressed

after

months

After

removal

of

the

remainder

of

the

marker

this

patient

was

tumor

free

during

the

follow-up

of

months

Also

a

patient

with

an

years

history

of

recurrent

bladder

cancer

remained

tumor

free

during

the

whole

follow-up

period

-LSB-

-RSB-

The

finding

that

these

patients

remained

tumor

free

for

months

suggests

that

these

patients

were

-LRB-

locally

-RRB-

immune

to

the

tumor

after

tumor

regression

Grasso

et

al.

-LSB-

-RSB-

treated

patients

with

transitional

bladder

carcinoma

with

intravesical

instillations

of

for

h

during

days

After

months

of

the

lesions

had

disappeared

or

were

clearly

reduced

This

result

seems

to

contrast

with

the

findings

by

Den

Otter

et

al.

-LSB-

-RSB-

The

different

treatment

protocols

may

be

essential

Den

Otter

et

al.

started

with

an

incomplete

TUR

followed

by

instillations

whereas

Grasso

et

al.

did

not

perform

a

TUR

before

instillation

TUR

causes

tumor

cell

damage

which

may

induce

tumor

immunity

Interestingly

Grasso

et

al.

obtained

relapses

after

a

median

follow-up

of

months

this

contrasted

to

the

restrospective

analysis

in

which

the

historical

recurrence

rate

per

year

was

Gastrointestinal

tumors

Shirai

et

al.

-LSB-

-RSB-

treated

five

patients

with

hepatocellular

carcinoma

with

intratumoral

injections

In

two

patients

and

tumor

regression

was

observed

Krastev

et

al.

-LSB-

-RSB-

treated

patients

with

different

forms

of

stage

III

and

IV

gastrointestinal

malignancies

-LRB-

primary

or

metastatic

-RRB-

for

whom

no

further

treatment

options

were

available

With

locoregionally

applied

a

modest

but

clinically

worthwhile

improvement

was

obtained

in

six

out

of

patients

remarkably

these

six

all

belonged

to

the

group

of

seven

patients

that

were

treated

with

intratumoral

Melanoma

Radny

et

al.

-LSB-

-RSB-

treated

patients

with

skin

and

soft-tissue

melanoma

metastases

with

intralesional

injection

of

A

total

of

patients

with

AJCC

stage

III

or

IV

melanoma

and

single

or

multiple

skin

and

soft-tissue

metastases

were

included

was

administered

intralesionally

into

all

cutaneous

and

soft-tissue

metastases

accessible

from

the

skin

times

weekly

over

weeks

Response

evaluation

was

confined

to

the

intralesionally

treated

tumors

CR

of

the

treated

metastases

was

achieved

in

patients

the

longest

remission

lasting

months

to

date

In

five

patients

a

PR

was

achieved

and

in

a

further

three

PD

-LRB-

one

patient

was

not

assessable

-RRB-

A

total

of

metastases

were

treated

There

was

CR

in

-LRB-

-RRB-

and

PR

in

-LRB-

-RRB-

The

therapy

was

generally

well

tolerated

the

observed

adverse

events

were

mainly

of

grade

severity

Pfohler

and

coworkers

-LSB-

-RSB-

treated

two

patients

with

multiple

cutaneous

metastases

of

malignant

melanoma

with

intra

and

perilesional

application

of

and

achieved

complete

regression

of

these

metastases

Mesothelioma

Goey

et

al.

-LSB-

-RSB-

treated

patients

with

pleural

mesothelioma

stage

I-IIA

with

continuous

daily

intrapleural

infusion

of

PR

occurred

in

four

out

of

evaluable

patients

with

a

median

time

to

progression

of

months

-LRB-

range

-RRB-

SD

occurred

in

seven

patients

with

a

median

time

to

progression

of

months

-LRB-

range

-RRB-

There

were

no

CRs

The

median

overall

survival

time

was

months

-LRB-

range

-RRB-

Astoul

et

al.

-LSB-

-RSB-

treated

patients

with

malignant

pleural

mesothelioma

The

response

rate

was

evaluated

days

after

treatment

There

were

one

CR

PR

three

SD

and

seven

PD

The

median

survival

time

of

responders

differed

significantly

from

that

of

the

non-responders

-LRB-

versus

months

-RRB-

Castagneto

et

al.

-LSB-

-RSB-

treated

consecutive

patients

with

unresectable

malignant

pleural

mesothelioma

with

pleural

effusion

with

intrapleural

instillation

of

In

of

the

patients

there

was

no

further

or

minimal

asymptomatic

pleural

fluid

collection

Median

overall

survival

was

months

whereas

the

expected

survival

range

of

patients

with

involvement

of

the

visceral

pleura

is

months

Krastev

et

al.

-LSB-

-RSB-

treated

a

patient

with

a

large

abdominal

mesothelioma

with

intratumoral

injections

and

instillation

in

the

peritoneal

cavity

The

tumor

regressed

completely

the

patient

was

cured

and

is

still

healthy

and

working

years

after

publication

Neoplastic

effusions

Masotti

et

al.

-LSB-

-RSB-

treated

neoplastic

pleural

effusions

in

patients

with

non-small

cell

lung

cancer

with

intrapleural

administration

of

CR

was

obtained

in

seven

patients

and

PR

in

six

patients

Lissoni

et

al.

-LSB-

-RSB-

treated

patients

with

neoplastic

effusions

from

a

variety

of

solid

tumors

There

were

four

CR

and

six

PR

with

a

median

duration

of

months

Castagneto

et

al.

-LSB-

-RSB-

treated

pleural

effusions

of

mesothelioma

as

described

in

the

previous

section

Ovarian

carcinoma

Edwards

et

al.

-LSB-

-RSB-

treated

patients

with

ovarian

carcinoma

with

infusions

of

Eligibility

criteria

included

six

or

more

courses

of

prior

platinum-based

chemotherapy

and

laparotomy-confirmed

persistent

or

recurrent

ovarian

cancer

Among

assessable

patients

there

were

six

laparotomy-confirmed

CRs

and

three

PRs

The

median

survival

time

of

the

cohort

was

months

and

the

overall

survival

probability

was

For

the

nine

patients

who

demonstrated

responses

the

median

survival

time

had

not

been

reached

at

the

time

of

publication

-LRB-

range

to

months

-RRB-

Taylor

et

al.

-LSB-

-RSB-

treated

patients

with

advanced

ovarian

cancer

with

intraperitoneal

Nine

out

of

patients

showed

an

objective

response

Renal

cell

carcinoma

-LRB-

lung

metastases

-RRB-

Huland

et

al.

-LSB-

-RSB-

introduced

inhalation

therapy

for

lung

metastases

of

renal

cell

carcinoma

Progressive

pulmonary

metastases

responded

dramatically

in

of

the

patients

for

a

median

of

months

and

were

stabilized

in

of

patients

for

a

median

of

months

The

overall

median

response

duration

was

months

Median

survival

was

months

expected

survival

according

to

risk

analysis

was

months

-LSB-

-RSB-

The

PortugeseSpanish

Inhaled

Group

-LSB-

-RSB-

studied

the

effect

of

inhaled

on

pulmonary

metastases

of

renal

cell

carcinomas

They

found

Objective

Responses

-LRB-

OR

-RRB-

a

median

progression

free

survival

of

months

and

an

overall

survival

of

months

Quantification

of

therapeutic

data

Therapeutic

data

of

Table

were

further

analyzed

regarding

CR

PR

SD

and

PD

This

analysis

was

possible

in

cancer

patients

treated

with

locally

applied

There

were

CR

PR

SD

and

PD

These

data

may

be

too

optimistic

as

positive

results

are

published

more

frequently

than

negative

results

Toxic

effect

of

local

application

Table

shows

the

toxic

effect

of

local

application

to

cancer

patients

There

were

papers

with

an

abstract

mentioning

toxic

side

effects

In

papers

there

were

no

or

minor

side

effects

one

paper

-LSB-

-RSB-

reports

some

side

effects

and

three

papers

-LSB-

-RSB-

mention

more

serious

side

effects

The

latter

papers

have

in

common

that

very

high

doses

-LRB-

see

Table

-RRB-

were

used

for

intrapleural

intraperitoneal

or

subcutaneous

administration

In

essence

these

massive

doses

act

in

a

pseudo-systemic

manner

Much

of

these

massive

doses

of

will

be

absorbed

and

as

a

consequence

will

give

generalized

effects

similar

to

systemic

treatment

Hence

toxicity

mentioned

in

the

latter

three

papers

form

the

exception

to

the

rule

that

local

application

causes

no

or

minimal

side

effects

In

reference

-LSB-

-RSB-

side

effects

are

due

to

the

very

high

daily

doses

of

IU

as

this

was

a

Phase

I-IIA

study

with

escalating

doses

of

In

this

case

treatment

may

give

systemic

toxicity

complications

In

paper

-LSB-

-RSB-

patients

were

treated

with

repeated

intrapleural

instillations

with

IU

twice

weekly

for

weeks

in

addition

in

non-progressing

patients

IU

were

administered

s.c.

thrice

weekly

for

up

to

months

Obviously

such

high

intrapleural

doses

are

readily

resorbed

and

reach

the

general

circulation

Hence

the

toxicity

-LRB-

grade

fever

and

grade

cardiac

toxicity

-RRB-

in

patients

is

not

surprising

In

paper

-LSB-

-RSB-

dose-limiting

toxicity

was

seen

in

patients

treated

with

infusions

with

the

maximum

tolerated

dose

obviously

there

was

toxicity

per

definition

Table

effects

of

local

application

on

human

cancer

patientsReference

Toxic

side

effects

-LSB-

-RSB-

Local

pain

swelling

erythema

in

one

patient

fluelike

symptoms

-LSB-

-RSB-

No

early

or

late

adverse

clinical

side

effects

-LSB-

-RSB-

No

evidence

of

side

effects

-LSB-

-RSB-

Toxicity

from

given

intravesically

was

minimal

One

patient

malaise

for

h

after

each

treatment

Two

patients

developed

asymptomatic

lower

urinary

tract

infections

-LSB-

-RSB-

patients

had

hematuria

after

the

end

of

treatment

one

patient

had

fever

-LRB-

grade

I

-RRB-

and

seven

patients

had

hypotension

-LRB-

grade

I-II

-RRB-

-LSB-

-RSB-

No

toxic

effects

-LSB-

-RSB-

Negligible

adverse

effects

-LSB-

-RSB-

Abstract

did

not

contain

toxicity

data

-LSB-

-RSB-

Treatment

of

pleural

effusions

of

lung

cancer

was

well

tolerated

-LSB-

-RSB-

Side

effects

of

treatment

were

minimal

-LSB-

-RSB-

Therapy

was

generally

well

tolerated

the

observed

adverse

events

were

mainly

of

grade

severity

-LSB-

-RSB-

Intrapleural

administration

of

was

associated

with

acceptable

toxicity

Dose

limiting

toxicity

was

observed

at

IU

daily

and

consisted

of

catheter

infection

fever

and

flue-like

symptoms

-LSB-

-RSB-

Intrapleural

administration

of

was

well

tolerated

-LSB-

-RSB-

Patients

with

malignant

pleural

mesothelioma

received

intrapleurally

U

twice

weekly

for

weeks

In

non

progressing

patients

U

were

subcutaneously

administered

thrice

weekly

for

up

to

months

Toxicity

-LRB-

WHO

criteria

-RRB-

with

intrapleural

consisted

of

grade

fever

in

patients

and

cardiac

toxicity

-LRB-

failure

-RRB-

grade

in

one

patient

-LSB-

-RSB-

Abstract

did

not

contain

toxicity

data

-LSB-

-RSB-

Significant

locoregional

dose-limiting

toxicity

was

seen

with

day

infusionsb

-LRB-

including

bowel

perforation

-RRB-

with

as

the

maximum

tolerated

dose

but

catheter

infection

was

the

only

significant

complication

seen

with

hrs

infusions

-LSB-

-RSB-

Abstract

did

not

contain

cytotoxicity

data

-LSB-

-RSB-

No

important

toxicity

in

patients

with

neoplastic

effusions

after

intracavitary

administration

of

-LSB-

-RSB-

aInhaled

most

common

toxicities

were

cough

-LRB-

of

cycles

-RRB-

and

fatigue

-LRB-

-RRB-

Grade

or

toxicities

-LSB-

-RSB-

aLocoregional

perfusion

of

the

bladder

with

is

safe

-LSB-

-RSB-

patients

Toxicity

associated

with

exclusive

inhalation

of

was

local

and

consisted

mainly

of

cough

-LSB-

-RSB-

aIntravesical

instillation

No

evidence

of

toxicity

-LSB-

-RSB-

aRegionally

administered

was

well

tolerated

in

patients

with

advanced

squamous

cell

carcinoma

of

the

head

and

neckToxicity

as

described

in

the

abstracts

of

the

papers

mentioned

in

Table

data

from

Abstracts

that

did

not

contain

information

for

Table

continuous

day

infusions

followed

by

intervals

Dose

response

Figure

shows

the

total

applied

doses

of

and

the

percentage

of

objective

responses

Results

suggest

that

-LRB-

a

-RRB-

good

therapeutic

results

can

be

obtained

with

low

doses

of

-LRB-

to

IU

-RRB-

-LRB-

b

-RRB-

that

there

is

no

dose-response

effect

in

the

range

of

total

dose

of

up

to

IU

Of

course

in

this

figure

there

are

only

a

few

data

for

different

tumors

treated

slightly

different

by

different

groups

More

detailed

analysis

with

homogeneous

groups

of

mice

with

transplanted

lymphoma

in

mice

showed

a

dose

response

effect

in

the

dose

range

of

IU

given

on

five

consecutive

days

-LSB-

-RSB-

It

is

not

surprising

that

this

was

not

reproduced

with

the

very

heterogeneous

data

in

Fig.

Nevertheless

these

data

of

Fig.

are

remarkable

as

total

doses

of

IU

of

can

result

in

objective

responses

We

have

analysed

whether

high

and

low

percentages

of

objective

responses

are

obtained

with

sensitive

and

non-sensitive

tumor

types

respectively

This

seems

not

to

be

the

case

as

bladder

carcinoma

mesothelioma

and

ovarian

carcinoma

were

reported

as

sensitive

-LRB-

OR

-RRB-

as

well

as

non-sensitive

-LRB-

OR

-RRB-

-LRB-

Table

Fig.

-RRB-

Another

hypothesis

is

offered

by

the

work

of

Jacobs

et

al.

-LSB-

-RSB-

He

found

that

intratumoral

application

is

more

effective

than

peritumoral

application

We

therefore

further

analyzed

whether

the

different

therapeutic

effects

can

be

ascribed

to

differences

in

the

localization

of

application

Also

this

was

not

the

case

Another

possibility

is

that

intratumoral

application

leads

to

more

intratumoral

edema

formation/leakage

causing

hemodynamic

stagnation

and

additional

tumor

necrosis

This

may

stimulate

the

antitumor

response

and

consequently

lead

to

superior

therapeutic

effects

Obviously

this

hypothesis

is

difficult

to

study

in

human

cancer

patients

for

logistical

and

ethical

reasons

A

more

simple

explanation

of

the

absence

of

a

dose-response

effect

is

that

different

tumors

have

different

sensitivity

for

local

therapy

e.g.

due

to

different

tumor

associated

antigenicity

Those

that

are

well-responsive

can

be

cured

by

lower

doses

those

that

are

less

responsive

are

-LRB-

automatically

-RRB-

treated

with

higher

doses

Hence

it

is

impossible

to

evaluate

dose-response

effects

using

different

tumors

Fig.

Objective

response

versus

total

applied

dose

of

The

data

are

derived

from

the

abstracts

of

the

papers

mentioned

in

Table

Conclusions

Local

therapy

can

be

effective

against

a

variety

of

human

tumors

In

some

studies

results

suggest

that

metastases

are

cured

and

that

-LRB-

systemic

-RRB-

immunity

is

obtained

-LSB-

-RSB-

There

is

no

obvious

dose

response

with

regard

to

therapeutic

effects

Good

therapeutic

effects

can

be

obtained

with

total

doses

of

to

IU

these

doses

cause

no

or

negligible

toxic

effects

High

total

doses

of

IU

and

higher

may

exert

toxic

side

effects

as

are

described

in

systemic

treatment

Combined

therapy

modalities

-LRB-

Table

-RRB-

Subject

Combination

of

various

therapeutic

modalities

like

surgery

irradiation

chemotherapy

hormone

therapy

etc.

are

standard

in

tumor

treatment

For

this

reason

several

groups

have

also

used

local

therapy

with

free

combined

with

other

treatment

modalities

Table

of

local

therapy

with

other

therapeutic

modalitiesTherapyTumorHostTherapeutic

effectReferencesSurgery

FibrosarcomaDogCR

for

months

vs

no

CRa

-LSB-

-RSB-

Radiotherapy

vs.

disease

free

survival

P

a

-LSB-

-RSB-

Nasopharyngeal

carcinoma

vs

disease

free

survival

a

-LSB-

-RSB-

Cytokine

leukemiaMouse

Synergistic

effect

with

survival

-LSB-

-RSB-

ChemotherapyCyclophosphamideMelanoma

vs

curesa

-LSB-

-RSB-

Cis-platinumTerato

vs

cures

survival

at

ca

vs

ca

daysa

-LSB-

-RSB-

adenocarcinomaMouseSynergistic

effect

with

long

term

survivors

-LSB-

-RSB-

inhibition

of

tumor

residuab

-LSB-

-RSB-

CR

PR

vs

CR

PRc

-LSB-

-RSB-

ImiquinodMelanoma

metastasesMan

OR

-LSB-

-RSB-

aComparison

of

therapeutic

effect

of

combined

therapy

and

therapy

without

residua

left

after

ifosfamide

treatmentcCis-platinum/IL

vs

only

Data

Surgery

Ziekman

-LSB-

-RSB-

described

cases

of

incomplete

surgical

removal

of

a

tumor

in

veterinary

patients

followed

by

intra-operative

local

application

This

led

to

complete

tumor

regression

for

instance

in

dogs

with

fibrosarcomas

instillation

in

the

bladder

to

treat

bladder

tumors

seems

only

effective

after

a

preceeding

TUR

-LRB-

see

above

-RRB-

Radiotherapy

Everse

et

al.

-LSB-

-RSB-

treated

mice

with

s.c.

growing

tumors

with

radiotherapy

combined

with

therapy

The

combined

therapy

was

more

effective

than

radiotherapy

or

therapy

alone

Similar

results

were

obtained

by

Jűrgenliemk-Schulz

et

al.

-LSB-

-RSB-

Early

nasopharyngeal

carcinoma

is

not

clinically

apparent

and

hence

these

tumors

are

often

diagnosed

in

an

advanced

stage

The

standard

treatment

is

irradiation

often

complemented

with

chemotherapy

In

The

Netherlands

usually

WHO

type

nasopharynx

carcinoma

occurs

Type

is

very

therapy

resistant

That

is

only

about

of

the

patients

treated

with

irradiation

have

a

years

tumor

free

survival

-LSB-

-RSB-

In

this

study

tumors

of

patients

were

irradiated

daily

for

weeks

In

weeks

and

the

tumors

were

-LRB-

transnasally

-RRB-

injected

with

low

doses

of

from

Monday

through

Friday

The

years

tumor

free

survival

was

-LSB-

-RSB-

Cytokine

therapy

Belardelli

et

al.

-LSB-

-RSB-

described

that

combined

treatment

with

beta

and

produced

a

synergistic

antitumor

effect

of

mice

injected

with

highly

metastasized

Friend

Leukemia

Cells

survived

T

cells

appeared

to

be

essential

for

therapy

Chemotherapy

Enk

et

al.

-LSB-

-RSB-

treated

melanoma

patients

with

pulmonary

metastases

with

dacarbazine

and

concurrent

inhalation

of

The

patients

condition

previously

had

progressed

on

chemotherapy

predominantly

on

dacarbazine

based

regimens

Five

of

the

patients

experienced

a

complete

pulmonary

remission

Eight

patients

achieved

a

partial

pulmonary

remission

and

five

patients

experienced

stabilization

of

the

disease

Four

of

the

five

patients

with

a

complete

response

and

seven

of

the

eight

patients

with

a

partial

response

were

previously

treated

with

dacarbazine

and

progressed

The

complete

responses

all

persisted

during

a

follow-up

of

months

whereas

patients

with

partial

responses

or

stable

disease

progressed

when

was

discontinued

Silagi

et

al.

-LSB-

-RSB-

found

synergism

between

cyclophosphamide

and

in

the

treatment

of

mice

with

sarcoma

or

melanoma

Bernsen

et

al.

-LSB-

-RSB-

treated

mice

bearing

Murine

Ovarian

Teratocarcinoma

-LRB-

MOT

-RRB-

with

cis-platinum

and

The

effect

of

the

combined

treatment

was

greater

than

either

therapies

alone

Similarly

in

horses

with

sarcoids

-LRB-

a

characteristic

equine

fibro-epithelial

tumor

of

the

skin

-RRB-

the

therapeutic

effect

of

cis-platin

and

local

was

greater

than

the

therapeutic

effect

of

either

therapies

alone

-LSB-

-RSB-

Indrova

et

al.

-LSB-

-RSB-

studied

mice

with

associated

tumors

Peritumoral

administration

could

substantially

inhibit

growth

of

tumor

residua

after

chemotherapy

with

cyclophosphamide

or

ifosfamide

derivatives

Cabanes

et

al.

-LSB-

-RSB-

treated

mice

bearing

pulmonary

adenocarcinoma

with

a

combination

of

liposomal

doxorubicin

and

free

Both

the

tumor

and

the

application

were

i.v.

or

both

were

i.p.

There

were

synergistic

effects

with

long-term

survivors

Green

et

al.

-LSB-

-RSB-

treated

melanoma

cases

with

multiple

cutaneous

and/or

subcutaneous

metastases

Metastases

were

treated

with

imiquinod

daily

for

weeks

before

the

introduction

of

intralesional

This

was

injected

up

to

three

times

a

week

lesions

in

a

total

of

patients

were

treated

A

clinical

response

was

seen

in

of

the

lesions

with

being

CR

Furthermore

patients

with

clinically

responding

cutaneous

lesions

experienced

a

marked

slowing

of

the

appearance

of

new

lesions

No

cutaneous

lesions

that

responded

reappeared

on

cessation

of

the

treatment

Imiquimod

alone

is

often

sufficient

to

elicit

a

response

in

purely

cutaneous

lesions

The

addition

of

intralesional

however

greatly

increased

the

response

rate

in

subcutaneous

lesions

and

in

otherwise

refractory

cutaneous

melanomas

Conclusion

Combined

therapy

of

locally

applied

and

surgery

radiotherapy

or

chemotherapy

may

lead

to

a

synergistic

therapeutic

effect

The

durable

complete

responses

of

melanoma

metastases

in

the

lung

after

combined

chemotherapy

and

suggested

that

the

metastases

were

eradicated

-LSB-

-RSB-

Mechanism

of

tumor

regression

due

to

local

application

Original

hypothesis

on

the

mechanism

of

in

tumor

destruction

The

original

hypothesis

about

the

function

of

systemically

applied

in

cancer

therapy

was

that

induced

Leucocyte

Activated

Killer

cells

-LRB-

LAK

cells

-LSB-

-RSB-

LAK

cells

were

thought

to

invade

the

tumor

and

to

kill

tumor

cells.The

following

data

are

incompatible

with

the

cytotoxic

LAK-cell

hypothesis

or

any

kind

of

cytotoxic

cell

hypothesis

Hardly

any

intravenously

injected

LAK-cell

reaches

the

tumor

-LSB-

-RSB-

In

the

lymphoma

model

it

is

impossible

to

induce

cytotoxic

LAK

cells

-LSB-

-RSB-

Yet

therapy

is

very

effective

in

this

model.No

general

correlation

was

established

between

in

vitro

sensitivity

to

the

cytolytic

activity

of

LAK

cells

and

the

antitumor

effects

observed

in

vivo

-LSB-

-RSB-

Various

types

of

leucocytes

may

dominate

the

tumor

infiltrate

after

application

macrophages

T

cells

NK

cells

NKT

cells

plasma

cells

neutrophilic

eosinophilic

cells

etc.

-LSB-

-RSB-

The

assumption

that

all

these

different

types

of

cytotoxic

cells

are

directly

induced

by

in

different

tumors

is

too

complex

to

be

true

In

contrast

should

induce

a

similar

mechanism

against

a

wide

range

of

-LRB-

sensitive

-RRB-

cancers.In

addition

when

lymphoma

is

growing

both

i.p.

and

s.c.

and

if

is

injected

i.p.

at

day

after

tumor

transplantation

then

in

about

of

the

cases

the

s.c.

tumor

regresses

completely

at

about

day

this

in

spite

of

the

tumor

containing

only

leucocytes

-LSB-

-RSB-

Furthermore

effector/target

cell

ratios

of

cytotoxic

T-cells

are

usually

very

low

-LRB-

in

the

order

of

-RRB-

It

is

very

unlikely

that

such

a

huge

tumor

is

rejected

by

these

few

leukocytes

So

cytotoxic

cells

are

not

the

major

cause

of

tumor

regression

in

this

experiment

-LSB-

-RSB-

As

this

hypothesis

was

at

least

at

some

points

wanting

to

explain

the

mechanism

of

the

antitumor

activity

of

we

started

to

study

the

histopathology

of

induced

tumor

regression

as

study

of

the

histopathology

of

the

induced

reaction

would

be

essential

induced

histopathology

in

normal

tissue

-LSB-

-RSB-

The

study

of

the

histopathological

events

during

tumor

regression

proved

to

be

extremely

difficult

The

breakthrough

came

by

serendipity

Professor

Hennink

and

his

group

at

the

Faculty

of

Pharmacy

Utrecht

University

are

developing

slow

release

systems

-LRB-

microspheres

-RRB-

among

others

for

To

study

the

biocompatibility

of

these

microspheres

we

injected

microspheres

loaded

with

subcutaneous

in

rats

-LSB-

-RSB-

We

discovered

that

the

microspheres

could

be

stained

with

PAS

and

thus

these

stained

microspheres

marked

the

release

site

This

possibility

of

a

precise

localisation

of

was

a

great

tool

to

further

analyse

the

function

of

the

released

In

a

series

of

sections

obtained

during

the

induced

process

we

could

trace

a

sequence

of

reactions

First

a

localized

edema

developed

related

to

swelling

of

the

endothelial

lining

of

the

capillaries

After

days

necrosis

of

the

connective

tissue

was

observed

in

the

center

of

this

edematous

area

About

a

week

later

there

were

three

zones

around

this

necrotic

area

Near

the

necrotic

border

was

a

zone

of

mixed

inflammatory

cells

The

second

zone

was

a

large

area

of

edematous

connective

tissue

The

outer

zone

showed

angiogenesis

a

massive

proliferation

of

macrophages

around

the

newly

formed

blood

vessels

and

also

an

influx

of

lymphocytes

About

week

later

these

macrophages

invaded

the

necrotic

material

showing

features

of

phagocytosis

Finally

also

plasma

cells

and

occasionally

eosinophils

appeared

in

the

peri-necrotic

inflammatory

area

The

plasma

cells

indicate

the

induction

of

an

immune

reaction

In

short

two

main

phases

could

be

ascertained

in

this

process

an

almost

immediate

marked

edema

due

to

leakage

of

the

local

blood

vessels

a

later

and

more

complex

reaction

consisting

of

the

induction

of

angiogenesis

a

macrophage

reaction

migration

of

the

infiltrate

into

the

seminecrotic

tissue

and

finally

clearance

of

tissue

in

combination

with

granulomatous

processes.Next

we

again

studied

the

histopathology

of

the

mechanism

of

tumor

regression

induced

by

free

Of

course

the

histopathological

events

after

injection

of

in

or

around

a

tumor

are

far

more

complex

than

the

histopathological

events

after

subcutaneous

injection

of

loaded

microspheres

in

normal

tissue

in

rats

But

the

events

after

injection

of

at

the

site

of

tumors

were

similar

to

those

after

injection

of

loaded

microspheres

in

normal

tissue

It

is

remarkable

however

that

induced

tumor

regression

may

be

fast

requiring

only

some

days

or

slow

requiring

several

months

or

intermediate

These

differences

can

be

related

to

histopathological

differences

of

the

tumor

tissues

Before

we

describe

these

differences

we

have

to

pay

attention

to

some

hemodynamic

features

in

tumors

Some

hemodynamic

features

in

tumors

In

tumors

the

interstitial

fluid

pressure

is

higher

in

the

center

of

the

tumor

mass

than

in

surrounding

tissue

due

to

vessel

leakage

-LSB-

-RSB-

The

increased

vascular

leakage

in

tumors

is

explained

as

follows

The

tumor

vessels

usually

lack

a

continuous

basal

membrane

-LSB-

-RSB-

Endothelial

injury

in

ischemic

tissue

-LSB-

-RSB-

Tumors

have

poor

homeostatic

control

of

the

circulation

due

to

lack

of

smooth

muscle

and

lack

of

innervation

-LSB-

-RSB-

This

vascular

leakage

causes

increase

of

interstitial

pressure

This

pressure

will

cause

vascular

compression

particularly

of

the

post-capillary

venules

This

leads

to

stagnation

of

the

blood

flow

and

vascular

distension

of

the

prestenotic

vessels

and

sometimes

thrombosis

in

smaller

blood

vessels

Stagnation

of

blood

causes

necrosis

in

particular

in

the

tumor

center

A

peripheral

rim

of

vital

tumor

tissue

often

survives

as

it

is

just

outside

the

area

of

deficient

blood

circulation

Local

application

into/near

the

tumor

appeared

to

induce

additional

edema

in

and

around

the

tumor

just

as

in

normal

tissue

Increased

edema

exerts

extra

pressure

that

causes

further

stagnation

of

the

blood

flow

and

of

the

lymph

drainage

Obviously

this

leads

to

tumor

necrosis

and

thrombosis

within

only

a

few

days

This

early

edema

is

illustrated

with

photographs

-LSB-

-RSB-

Fast

tumor

regression

of

well-vascularized

tumors

-LRB-

Fig.

-RRB-

-LSB-

-RSB-

It

is

remarkable

that

induced

tumor

regression

is

very

quick

in

the

case

of

-LRB-

very

-RRB-

fast

growing

tumors

like

lymphoma

and

mastocytoma

-LSB-

-RSB-

Similarly

relatively

fast

growing

cases

of

mammary

carcinoma

-LSB-

-RSB-

or

BOSCC

are

more

responsive

to

than

slower

growing

BOSCC

-LSB-

-RSB-

In

fast

growing

tumors

the

intratumoral

vascular

tree

is

relatively

poorly

developed

and

also

the

endothelial

lining

of

the

microvessels

is

abnormal

Local

application

will

further

stimulate

vascular

leakage

So

we

assume

that

much

fluid

will

leak

from

the

tumor

vessels

leading

to

edema

microthrombosis

and

extensive

hemorrhages

in

the

tumor

It

is

noteworthy

that

soon

after

injection

the

tumor

becomes

firmer

indicating

swelling

of

the

tumor

mass

by

edema

This

leads

to

extensive

necrosis

Fig.

of

tumor

regression

caused

by

local

application

of

cancer

Of

course

this

large

necrotic

tumor

mass

will

induce

an

acute

clearance

reaction

to

remove

this

necrotic

debris

which

causes

an

early

reduction

in

size

of

the

tumor

mass

This

induces

a

marked

immune

reaction

It

is

also

noteworthy

that

this

tumor

necrosis

is

accompanied

by

marked

angiogenesis

Adjacent

to

many

of

the

newly

formed

smaller

blood

vessels

there

is

a

cuff

of

proliferating

macrophages

which

ultimately

move

into

the

necrotic

debris

As

different

tumors

differ

in

tumor

associated

antigen

make-up

they

will

induce

also

different

types

of

immune

reactions

dominated

by

macrophages

T

cells

plasma

cells

or

eosinophilic

cells

This

phenomenon

can

be

observed

in

biopsies

taken

late

at

the

margin

of

the

disappearing

tumor

As

a

result

of

the

increased

tumor

immunity

isolated

tumor

strands

may

be

enveloped

by

granulomatous

inflammatory

tissue

destroying

tumor

cells

Specific

antitumor

immunity

induced

by

has

been

described

by

Maas

et

al.

-LSB-

-RSB-

After

an

animal

is

cured

a

second

implant

of

the

same

tumor

is

rejected

-LSB-

-RSB-

Our

present

hypothesis

-LRB-

Fig.

-RRB-

seems

now

most

straightforward

to

explain

the

fast

tumor

regression

induced

by

in

fast

growing

tumors

The

primary

function

of

locally

applied

is

the

induction

of

vascular

leakage

This

leads

to

an

acute

massive

tumor

necrosis

and

clearance

of

necrotic

tumor

material

As

a

consequence

of

massive

liberation

of

antigenic

tumor

material

an

immune

reaction

develops

The

different

types

of

dominant

cytotoxic

cells

-LRB-

CTL

eosinophils

macrophages

etc.

-RRB-

depend

on

the

character

of

the

tumor-associated

antigens

released

in

the

necrotic

tumor

debris

According

to

this

view

maximal

therapeutic

results

will

be

obtained

with

maximal

edema

formation

within

the

tumor

In

line

with

this

view

is

the

finding

that

is

more

effective

when

injected

directly

into

the

tumor

than

when

injected

peritumorally

-LSB-

-RSB-

It

is

interesting

that

it

was

originally

thought

that

killed

tumor

cells

through

induction

of

cytotoxic

LAK

cells

and

that

the

vascular

leakage

seemed

a

nasty

side

effect

-LSB-

-RSB-

According

to

our

present

views

it

is

just

the

other

way

round

vascular

leakage

causing

edema

is

the

primary

effect

of

the

development

of

systemic

immunity

-LSB-

-RSB-

seems

the

secondary

effect

An

intriguing

point

was

for

many

years

that

in

the

model

local

therapy

is

not

effective

days

after

tumor

cell

transplantation

whereas

it

can

be

effective

after

days

until

about

days

before

the

expected

death

-LSB-

-RSB-

Similarly

Maekawa

et

al.

-LSB-

-RSB-

found

that

local

therapy

was

only

effective

when

therapy

was

given

seven

or

more

days

after

transplantation

of

myeloma

This

can

be

explained

by

the

observation

that

these

days

are

required

for

developing

a

corona

of

angiogenesis

around

the

tumor

this

is

essential

for

an

effective

local

therapy

Slow

tumor

regression

of

less

vascularized

tumors

A

number

of

tumors

show

a

slow

induced

regression

Examples

are

BOSCC

-LSB-

-RSB-

and

sarcoids

in

the

skin

of

horses

-LSB-

-RSB-

This

regression

pattern

more

closely

follows

the

histological

changes

as

observed

in

the

model

in

which

the

microspheres

were

deposited

in

normal

subcutaneous

tissue

-LSB-

-RSB-

Also

in

these

slowly

growing

tumors

edema

will

be

induced

in

the

tumor

but

this

is

more

focal

at

the

site

of

the

injection

and

does

not

involve

the

entire

tumor

Also

the

necrotic

focus

develops

slower

and

the

necrosis

is

less

hemorrhagic

In

these

tumors

the

complete

development

of

the

induced

response

takes

at

least

some

weeks

So

the

tumor

immunity

will

develop

slower

and

consequently

tumor

regression

will

be

slower

Moreover

in

BOSCC

the

tumor

contains

only

about

of

tumor

cells

the

other

is

stroma

When

a

the

tumor

is

reduced

in

size

by

then

usually

hardly

any

or

no

tumor

cell

is

present

anymore

the

remaining

is

stroma

After

killing

of

the

tumor

cells

the

final

regression

of

the

stroma

requires

several

additional

months

Of

course

both

processes

-LRB-

edema

and

leukocyte

infiltration

after

neoangiogenesis

-RRB-

are

always

present

as

a

result

of

local

application

But

in

fast-regression

models

edema

is

more

prevailing

in

slow-regression

models

leukocyte

and

particularly

macrophage

infiltration

dominate

Solid

subcutaneous

tumors

expand

by

infiltrating

the

surrounding

tissue

These

tumor

strands

are

the

first

targets

of

macrophages

as

the

tumor

strands

are

in

close

proximity

to

surrounding

tumor

stroma

and

are

progressively

destroyed

-LSB-

-RSB-

So

the

body

of

the

tumor

and

the

infiltrating

tumor

strands

are

destroyed

in

two

different

ways

namely

by

edema

due

to

vascular

leakage

and

a

granulomatous

antitumor

response

originating

in

the

tumor

surrounding

stroma

respectively

Obviously

may

stimulate

the

existing

inflammation

as

often

present

in

tumors

and

hence

attracts

more

macrophages

and

inflammatory

cells

and

as

a

consequence

intensifies

the

already

existing

cellular

response

to

the

tumor

Usually

there

is

in

the

perivascular

zones

a

marked

increase

of

varied

types

of

inflammatory

cells

The

reduction

of

the

tumor

can

be

accelerated

by

using

in

combination

with

a

tumor

necrosis

inducing

agent

as

is

demonstrated

by

local

cis-platin

treatment

of

mice

with

MOT

tumors

-LSB-

-RSB-

and

sarcoids

in

horses

-LSB-

-RSB-

Everse

et

al.

-LSB-

-RSB-

showed

that

irradiation

stimulated

the

therapeutic

effect

of

therapy

in

mice

We

assume

that

the

necrotic

material

is

phagocytosed

thus

boosting

an

immune

reaction

A

remarkable

finding

is

that

injected

into

the

primary

tumor

can

induce

regression

not

only

of

the

primary

tumor

but

also

the

metastasis

in

the

draining

lymph

node

-LSB-

-RSB-

However

after

surgical

removal

of

the

primary

tumor

can

not

induce

regression

of

the

lymph

node

metastasis

-LSB-

-RSB-

We

assume

that

this

depends

on

the

differences

between

the

histological

structure

of

the

primary

tumors

Usually

in

primary

tumors

there

is

extensive

vascularization

and

leucocyte

infiltration

and

the

tumor

is

in

close

contact

with

the

surrounding

stroma

In

contrast

early

tumors

in

lymphatic

tissue

often

have

a

scanty

vascularization

and

are

situated

within

the

lymph

nodes

without

a

direct

stroma

contact

Tumor

tolerance

and

local

In

the

previous

sections

histopathological

techniques

were

used

to

study

the

mechanism

of

induced

tumor

regression

In

this

section

we

will

also

pay

some

attention

to

immunological

data

Besides

stimulating

immune

responses

may

also

inhibit

immune

responses

This

is

clear

as

deficiency

of

leads

to

autoimmunity

-LSB-

-RSB-

inhibits

the

immune

response

by

stimulation

of

T

regulatory

cells

-LRB-

Treg

-RRB-

These

cells

suppress

immune

reactivity

including

antitumor

immune

responses

-LSB-

-RSB-

The

presence

of

antigen

-LSB-

-RSB-

and

are

important

in

the

maintenance

of

regulatory

T

lymphocytes

Depletion

of

Treg

is

important

for

tumor

rejection

-LSB-

-RSB-

Depletion

of

Treg

with

antibody

stimulates

tumor

rejection

-LSB-

-RSB-

Because

of

this

tolerance

inducing

role

of

through

Treg

some

authors

have

suggested

to

use

for

cancer

immunotherapy

is

a

cytokine

that

is

functionally

closely

related

to

but

it

does

not

induce

tolerance

-LSB-

-RSB-

In

the

first

animal

studies

for

anti-cancer

therapy

were

performed

with

Although

therapy

still

lacks

therapeutic

successes

in

human

clinic

some

authors

still

suggest

that

should

replace

for

immunotherapy

of

cancer

-LSB-

-RSB-

Importantly

and

in

contrast

to

is

capable

of

breaking

tolerance

-LSB-

-RSB-

This

may

be

crucial

for

effective

anti-cancer

immunotherapy

This

reversal

of

tolerance

is

mediated

through

the

activation

of

immature

dendritic

cells

-LSB-

-RSB-

Activation

of

intratumoral

dendritic

cells

and

reversal

of

tolerance

exerted

through

local

regulatory

T

lymphocytes

could

be

the

link

between

local

effects

of

intratumoral

therapy

and

systemic

immunity

Stimulation

of

systemic

immunity

by

local

therapy

is

also

suggested

by

clinical

data

on

cytokines

in

treated

human

patients

Pro-inflammatory

cytokines

-LRB-

IFN-gamma

-RRB-

are

more

increased

after

local

therapy

than

anti-inflammatory

cytokines

In

contrast

anti-inflammatory

cytokines

-LRB-

-RRB-

are

increased

after

systemic

therapy

-LSB-

-RSB-

These

data

highlight

mechanistic

differences

between

local

and

systemic

therapy

The

discussion

above

may

lead

to

the

question

whether

the

specific

immune

system

is

involved

in

induced

tumor

rejection

Pleiotropic

effects

of

high

local

concentrations

of

could

lead

to

aspecific

activation

of

T

cells

activation

of

NK

cells

and

the

generation

of

LAK

cells

Nevertheless

the

immune

system

must

be

involved

as

local

treatment

causes

systemic

immunity

that

resides

in

lymphocytes

or

and

lymphocytes

-LSB-

-RSB-

Conclusions

Local

application

seems

to

induce

severe

vascular

leakage

in

well-vascularized

and

fast

growing

tumors

This

leakage

in

fast

growing

tumors

induces

a

massive

hemorrhagic

necrosis

which

results

in

early

clearance

of

the

tumor

tissue

In

less-vascular

tumor

tissue

the

edema

formation

is

more

limited

Neoangiogenesis

allows

the

arrival

of

especially

macrophages

that

move

to

the

tumor

site

This

leads

to

tumor

cell

killing

and

a

specific

immune

reaction

resulting

in

tumor

regression

The

character

of

this

immune

reaction

probably

depends

on

the

different

types

of

tumor-associated

antigens

present

in

the

seminecrotic

tumor

debris

According

to

our

views

the

primary

effects

of

local

application

to

a

tumor

are

the

vascular

phenomena

followed

by

a

host

of

complex

histological

events

clearing

the

tumor

necrosis

The

immune

reactivity

seems

to

be

a

secondary

and

presumably

an

indirect

effect

Of

course

this

is

an

analysis

at

the

histopathological

level

The

whole

process

is

far

more

complicated

as

immune

regulatory

events

including

cells

and

cytokines

are

involved

Characteristics

of

local

therapy

Local

treatment

of

cancer

often

cures

also

the

metastases

-LSB-

-RSB-

This

systemic

effect

is

probably

the

result

of

induced

systemic

immunity

-LSB-

-RSB-

Local

therapy

can

cure

large

local

tumors

-LSB-

-RSB-

and

even

large

metastasized

tumor

burdens

-LSB-

-RSB-

Local

therapy

is

effective

against

a

large

variety

of

spontaneous

carcinomas

melanoma

fibrosarcoma

equine

sarcoid

mesothelioma

lung

metastases

of

renal

cell

carcinoma

and

melanoma

-LRB-

references

see

Tables

-RRB-

Of

course

local

application

is

no

panacea

for

all

tumors

and

all

types

of

cancer

all

the

time

Intratumoral

application

is

more

effective

than

peritumoral

-LRB-

juxtatumoral

-RRB-

application

-LSB-

-RSB-

or

application

at

a

more

distant

site

-LSB-

-RSB-

A

single

application

may

be

sufficient

-LSB-

-RSB-

This

can

be

advantageous

during

surgery

when

a

tumor

can

not

be

excised

completely

Local

therapy

is

particularly

effective

in

fast

growing

tumors

-LSB-

-RSB-

Most

of

the

tumors

that

well

respond

to

local

treatment

are

those

with

an

already

-LRB-

pre

-RRB-

existing

peritumoral

leukocytic

infiltrate

Local

treatment

of

the

primary

tumor

may

result

in

regression

of

both

the

primary

tumor

and

a

metastasis

in

the

draining

regional

lymph

nodes

-LSB-

-RSB-

induced

tumor

regression

can

be

fast

-LSB-

-RSB-

but

it

is

often

a

slow

process

requiring

months

-LSB-

-RSB-

The

fast

tumor

regression

is

often

observed

in

fast

growing

highly

vascularized

tumors

in

which

causes

vascular

leakage

leading

to

edema

and

intravascular

thrombosis

followed

by

necrosis

This

is

also

a

consequence

of

the

often

abnormal

endothelial

lining

of

the

intratumoral

vascular

tree

Slow

tumor

regression

is

often

observed

in

poorly

vascularized

tumors

with

prominent

macrophage

infiltration

after

induced

neovascularization

and

an

activation

of

the

existing

round

cell

infiltrate

Prior

induction

of

tumor

necrosis

and

local

inflammation

may

accelerate

the

effect

of

Local

therapy

can

exert

a

synergistic

therapeutic

effect

with

surgery

radiotherapy

and

chemotherapy

-LRB-

references

see

Table

-RRB-

Thus

local

treatment

can

be

a

valuable

addition

to

the

standard

oncotherapy

Local

has

minor

side

effects

and

is

generally

well

tolerated

-LRB-

references

see

Table

-RRB-

It

can

usually

be

applied

without

difficulty

It

does

not

require

complex

technical

procedures

Local

does

not

hamper

or

interfere

with

the

standard

oncotherapy

The

local

therapy

findings

suggest

to

revisit

our

views

on

the

relation

between

local

and

systemic

oncotherapy

at

least

as

far

as

therapy

concerns

Systemic

chemotherapy/hormone

therapy

and

later

immunotherapy

were

initially

particularly

reserved

for

patients

in

which

adequate

tumor

treatment

by

surgery

and

radiotherapy

was

not

possible

In

most

of

these

cases

the

tumor

was

inoperable

or

disseminated

and

often

the

patient

was

in

the

terminal

phase

of

the

disease

Now

with

modern

therapeutic

regimes

the

indications

of

systemic

treatment

have

been

extended

whereas

local

tumor

treatment

is

becoming

rare

Data

described

in

this

paper

show

that

cancer

treatment

with

local

application

can

lead

to

cure

of

metastases

We

stress

that

there

are

good

reasons

to

consider

tumor

treatment

also

in

early

cancer

Surgical

treatment

remains

the

golden

standard

in

malignant

tumors

Local

therapy

may

be

considered

in

local

tumors

if

these

tumors

can

not

be

resected

completely

Occasionally

a

previously

inoperable

lesion

might

become

fit

for

surgical

interventions

due

to

the

reduction

of

the

tumor

size

In

some

cases

local

application

may

be

considered

as

an

adjunct

to

the

standard

treatment

particularly

if

recurrences

are

expected

An

example

of

the

latter

is

local

treatment

in

TUR-treated

bladder

tumors

Local

therapy

may

also

be

used

as

an

adjunct

to

treat

a

primary

tumor

showing

metastases

In

advanced

tumor

cases

local

treatment

of

the

primary

tumor

may

induce

a

specific

immune

response

and

might

also

contribute

to

cure

or

decrease

tumor

size

and

sometimes

also

may

have

a

positive

effect

on

the

metastases

does

not

interfere

with

the

standard

oncotherapy

and

might

be

an

useful

adjunct

to

diminish

suffering

and

expand

lifespan

Dose

at

the

tumor

site

Only

about

of

the

systemically

applied

dose

reaches

the

tumor

In

other

words

the

same

dose

injected

locally

results

at

the

site

of

the

tumor

in

a

times

higher

concentration

than

a

systemically

applied

dose

Reduced

side

effects

An

advantage

of

local

treatment

is

furthermore

that

side

effects

both

local

and

systemic

are

modest

if

present

at

all

since

the

required

local

dose

is

only

a

fraction

of

the

dose

required

in

systemic

treatment

No

immunologic

overflow

feed-back

Systemic

therapy

causes

immuno

suppression

as

indicated

by

systemic

production

This

is

probably

the

body

's

reaction

to

a

generally

activated

immune

system

-LRB-

cytokine

storm

-RRB-

Local

avoids

this

down-regulating

feedback

and

leads

to

systemic

increase

of

pro-inflammatory

cytokines

like

IFN-gamma

and

Reduced

costs

of

locally

applied

low

doses

Systemic

chemotherapy

and

immunotherapy

in

cows

and

horses

is

no

option

Cattle

and

horses

are

so

large

that

systemic

oncotherapy

is

out

of

order

e.g.

required

doses

of

would

be

very

large

and

hence

far

too

expensive

in

animal

husbandry

This

problem

can

be

circumvented

by

local

therapy

The

results

in

cattle

and

horses

show

that

local

therapy

in

these

large

animals

is

feasible

readily

to

apply

economic

and

therapeutically

effective

Local

application

doses

and

duration

of

the

treatment

The

number

of

injections

required

for

optimal

treatment

is

still

a

point

of

debate

A

single

injection

containing

up

to

million

U

is

sufficient

in

the

model

-LSB-

-RSB-

whereas

doses

of

only

U

were

required

in

case

daily

injections

on

five

consecutive

days

were

given

-LSB-

-RSB-

However

Kusnierczyk

et

al.

-LSB-

-RSB-

cured

mice

with

s.c.

solid

colon

carcinoma

with

multiple

treatments

whereas

no

cure

was

obtained

by

a

single

injection

Treating

spontaneous

BOSCC

with

a

single

dose

of

million

U

-LSB-

-RSB-

gave

comparable

results

as

daily

injection

of

the

same

dose

on

ten

consecutive

working

days

-LSB-

-RSB-

For

logistic

reasons

most

clinicians

-LRB-

both

in

human

and

in

veterinary

medicine

-RRB-

strongly

prefer

to

apply

one

single

dose

instead

of

daily

injections

over

five

or

ten

consecutive

working

days

A

single

large

dose

can

also

be

appropriate

for

tumor

treatment

during

surgery

when

the

tumor

mass

can

not

completely

be

removed

But

such

a

single

dose

should

be

much

higher

-LRB-

about

IU

-RRB-

than

doses

on

five

or

ten

consecutive

working

days

-LRB-

ca

IU

per

day

in

mice

-RRB-

Very

different

doses

time

schedules

and

routes

of

application

were

used

In

a

human

patient

we

might

consider

U

as

low

dose

-LRB-

-RRB-

U

as

intermediate

dose

and

U

high

dose

for

local

application

But

a

systemically

applied

dose

is

far

more

toxic

than

the

same

dose

after

local

application

In

addition

the

same

dose

given

i.p.

in

a

mouse

can

be

regarded

to

be

high

whereas

this

dose

is

low

when

it

is

given

intravenously

in

a

human

patient

A

systemically

applied

dose

of

U

is

intermediate

But

if

this

dose

is

given

daily

for

days

then

it

is

a

large

total

dose

Nowadays

we

usually

treat

cancer

with

a

single

local

injection

of

U

This

dose

is

based

on

data

obtained

in

mice

cattle

and

dogs

-LSB-

-RSB-

It

may

be

astounding

that

in

local

treatment

the

same

dose

is

effective

in

a

mouse

as

well

as

in

cattle

In

fact

similar

local

processes

have

to

be

induced

in

these

different

species

In

systemic

application

however

the

dose

required

by

a

cow

has

to

be

about

fold

of

that

used

in

mice

We

preferably

inject

inside

the

tumor

This

leads

to

better

therapeutic

results

than

peritumoral

application

-LSB-

-RSB-

Website

Our

website

on

local

therapy

is

available

at

We

provide

information

targeted

on

medical

professionals

Readers

are

invited

to

co-operation

Please

reach

us

at

w.denotter@uu.nl

immunotherapy
boscc
sarcoids
nasopharyngeal carcinoma
bladder carcinoma