Acromegaly therapeutic outcomes - PowerPoint Presentation

Slide1

Acromegaly therapeutic outcomes(Supplementary)

Dr

Maryam

Dehghani

Slide2

What is the value of somatostatin receptor scintigraphy to predict the effect of somatostatin

analog

therapy on pituitary adenomas?

Slide3

2014

Slide4

Slide5

2019 European Society of Endocrinology

Slide6

Octreotide remains 40 years after its development a drug, which is used in treatment of acromegaly & GEP-NETs

.

Very little innovation that

competes with this drug

occurred

over this period

.

This review

discusses several

aspects of 40 years of clinical use of octreotide, including the

application of radiolabeled forms of

the peptide

Slide7

In vivo visualization of SST2 receptors

The presence of a

high density of SST2 receptors on human

NETs

,

as

demonstrated

by

in

vitro

auto radiography

using

125I-Tyr3-octreotide:Suggested : feasibility

to visualize such tumors

in

vivo

after administration

of

Tyr3-octreotide

coupled to

123I

Slide8

In vivo visualization of SST2 receptors

[

123I-Tyr3]octreotide scanning

revealed:

The localization

of the primary tumors

& their metastases in

38 of 42

patients with carcinoids, islet cell tumors

,

paragangliomas

.

The

surgically removed tumors of a number of these patients were subsequently investigated

in

vitro

while

also

,preoperative

hormonal studies

with octreotide,

had been carried out.

There

was a

close

parallel relationship

between:

Presence

of SST2

on

these tumors

in

vitro

Hormonal

response

pre-operatively

In

vivo

visualization

of these

tumors

Slide9

In vivo visualization of SST2 receptors

Because of logistical

&

practical drawbacks of

123I

, an

alternative

:

Created

by coupling

a spacer

(DTPA) to octreotide

, resulting in a compound which

efficiently binds to

111Indium

DTPA

= diethylene

triamine

penta

acetic

acid

Slide10

Recently , introduction of PET imaging with

68Ga-labeled somatostatin analogs

has been developed; this new compound allows an even greater spatial resolution

than 111In-DTPA-octreotide

Slide11

Clinical Applications of Somatostatin

Analogues

Somatostatin analogues labeled with a radioactive

tracer, have been

used as external imaging agents for a wide range of disorders

, including:

indium-111

-

labeled

& gallium-68-labeled

somatostatin analogues,

octreotate

,

DOTATATE, …The

majority of

GEP-NETs , bronchopulmonary NETs,

pheo

, MTC,

many pituitary tumors

,

can

be visualized by

external imaging

techniques, using these agents by either scintigraphy or PET.

2020

Slide12

THE JOURNAL OF NUCLEAR MEDICINE • September 2017

Slide13

There is now evidence for a

shift from radiolabeled

sstr agonists

to

antagonists

Slide14

14

Slide15

Type 1

This

tumor type be identified as a concave MRI shape

Tumor

extension occurs mainly to

sphenoid

sinus

than

suprasellar

extension

These

tumors

are more

accessible

for

debulking

and likely explain why only

one surgical

procedure was needed in most of these

pts

2015 JCEM

Slide16

Tumour volume

Reducing

size & preventing

growth

are clinically

goals

, for acromegaly

macroadenomas

,

larger tumors is independently : poor clinical outcomes.

Tumor response to

SRL

(significant reduction) :

volume

reduction cut-off 20–25%

(LQ)

For

routine measurements :

Reduction

a

single

dimension (

diameter), rather volume(Simpler to measure & sufficient to assess meaningful mass change (DR) )

T2-weighted MRI hypointensity

at diagnosis :

predicts tumor shrinkage in SRL

tx

(MQ

), marker

of tumor responsiveness (DR).

16

Slide17

Citation:

Giustina

A,

Mazziotti

G,

Torri

V,

Spinello

M,

Floriani

I, et al. (2012) Meta-Analysis on the Effects of Octreotide on Tumor Mass in Acromegaly.

PLoS

Editor: Raul M.

Luque

, University of Cordoba, Spain

Received December 23, 2011; Accepted April 9, 2012; Published May 4,

2012

Slide18

Slide19

Discordant IGF1 & GH postop as well as

in treated

with SRLs (

MQ

) :

1-result of discrepancies

in assays

used (MQ)

2-

biological

factor:

sex

, glucose metabolism

&

GH receptor polymorphism

(VLQ)

OGTT

in pts treated with an

SRL

is

not likely

to be clinically useful

(

As clinical importance of such a finding remains to be established )

19

Biochemical outcomes

Slide20

Williams2020:

Slide21

Personalized medicine in the treatment of acromegaly (

2018 European Society of Endocrinology)

Slide22

Biochemical response to fg-SRL

is evaluated

by <<

randomly

measuring GH

&

IGF-I

>>

three

patterns of

patient response

:

1-

Controlled pts

or full responders

( 30% )

■ GH

below 1 g/L & normal

age matched

IGFI

2 -

Partial

responders

(45-50)

■ reduction of GH

and/or IGFI ≥

50%

from baseline but

without normalization

3-

Resistant

pts

or poor responders

(20-25% )

■

GH &

IGFI reduction of <50% from baseline

■

tumors that present a reduction of less than 20% ■ increase in tumor size during treatment

Slide23

predictors of responsiveness :

*

Dense

GH granulation

:

greater

responsiveness

to first-generation SRL

(

LQ)

Sparsely :

more invasive

, MRI : T2-

hyperintensity

.

*

T2-

hyperintense

:

less respond

to SRL

(LQ).

,, hyperintense

&

isointense

: higher

IGF1

,,Hypointense

:

smaller

&

less invasive

*

IHC

to assess

SST2 & SST5

: might be useful for individualizing treatment decisions (VLQ). ,,Sparsely : less SST2 & more SST5

,

resistant

to SRLsThese markers not approved & still remain investigational23

Slide24

Williams 2020 : *Most

important

determinant

*

of

SRL responsiveness :

SST2

expression

Immunopositive

for SST2

: more respond

to octreotide and

lanreotide

higher

SST2 to SST5

ratio

: improved outcomes

.

Tumors

lacking SST5

immunoreactivity

are

resistant to pasireotide, while those immunoreactive for SST5 had superior biochemical responses

Negative predictors of SRL therapeutic responses :Age, treatment duration, frequency of drug administration, total daily dose, tumor size, degree of tumor GH granularity, pretreatment GH & IGF1

24

Slide25

Slide26

The aim : SSTR2a protein expression & gsp status, relation to clinical effect of octreotide

.

Reduced

expression of

SSTR2

has

been suggested as an explanation for the

poor response

to

octreotide

Slide27

An acute octreotide test was performedChange in IGF-1 after 6 mo

preop

erative octreotide treatment was recordedAll

underwent

TSS

The

adenoma

SSTR2a expression

was

examined

by

IHC

& Western blot analysis, and gsp

status determined

.

Slide28

IHC of

SSTR2a in a somatotroph

pituitary

adenoma:

grade

1

adenoma

less than

25%

of

cells positive

grade

2

between

25

% and 75%

of

cells

positively

stained

grade

3 more than 75% positively stained cells.

Western blot analysis :SSTR2a (upper

panel), the band

at about

78

kDa

β-actin

(lower panel), the

band at

about 42

kDa

.

Slide29

An acute somatostatin test was performed in 62 of

pts

, always prior to medical treatment with a somatostatin analogue.

During the test, 1–3

measurements of

basal

GH were

performed, and 2–3 analyses between 2

and 4

h

following SQ

injection of octreotide.

The percentage reduction

in GH

was calculated for each patient.

Slide30

SSTR2a expression patternThere were no

differences

between the groups for clinical variables such as

tumour

size

or

preop

GH or IGF-1

levels

(

data not shown

)

Slide31

Percentage GH reduction after octreotide inj, in IHC SSTR2a grade1, 2,3 adenomas

Not

preoptreated

with

octreotid

SSTR2a protein expression &

acute response

to octreotide

The acute response to octreotide was significantly different

between groups (

P =

0·004).

GH reduction in group 3 adenomas was significantly more.

Slide32

SSTR2a protein expression & long-term response to octreotide

Clinical data on

long-term

effect

available

in

20

of

pts

treated with octreotide prior to

TSS

Percentage

reduction in

IGF-1 after 6

mo

(range

3– 9

mo

)

was

used

Six pts had a grade 1 adenoma, five had a grade 2 adenoma and nine patients had a grade 3

Slide33

long-term effect of octreotide on IGF-1 reduction.

There were significant differences between

groups

(P = 0·012):

Grade

3 adenomas

: better

long-term response

to octreotide than

group

1 (

P =

0·025)

,

2 (

P =

0·014) adenomas

Slide34

Acute octreotide response & preop long-term octreotide response

:

were better in adenomas

containing a large proportion

of cells

that

stained positively for SSTR2a

by IHC

.

The

gsp

oncogene was detected in 43%

of adenomas but

did not correlate to octreotide response.However

, the SSTR2a protein level assessed by

Western blot did

not

correlate

with

octreotide

response.

The

clinical effect of octreotide correlates

with the proportion of cells positive for SSTR2a in IHC, rather than adenoma SSTR2a protein level.

There may be a down-regulation of SSTR2a during octreotide treatment.

Slide35

Diagnosis

an

accompanying elevated IGF1

(age & gender- matched)

GH nadir during a

75

- g glucose load

:

Ultrasensitive assays : less than

0.4

μg

/L

Or

Standard assays : less than

1

μg

/L

In acromegaly:

Oral

glucose fails to suppress GH

35

GH

may

increase, remain unchanged, or fall modestly in approximately 1/3 of

patients

NEJM 2006

Slide36

Unlike those of GH, serum IGF-1 do not fluctuate hourly according to food intake, exercise, or

sleep

IGF-I correlate with mean 24-hour

basal GH

measured

every 10

to 20 minutes

.

In

normal subjects,

IGF-1 are:

Highest

during puberty

, decline gradually thereafter values are

significantly

lower in adults older than

60

years

than in younger subjects.

Females

have higher

levels

than do malespregnancy may also be associated with elevated IGF-1

Serum GH should be measured in equivocal or elevated

age- and

sex adjusted

IGF-1

values.

Slide37

Serum GH fluctuate widely, from less than 0.5 ng/mL (with ultrasensitive assays)

during most

of day to as high as 20 or 30

ng/mL

at night

or

after

vigorous exercise

.

Random

serum GH

may

be elevated in

:uncontrolled DM,

liver disease,

malnutrition

Several factors determine measured GH values, including:

Age, gender, BMI, type of assay employed.

Spontaneous

GH secretion is attenuated by 50% to 70% in

65

years or

moreGH correlate inversely with BMIlean subjects exhibit higher GH values, as do female . So

dynamic tests have been proposed to confirm pituitary GH hypersecretion.

GH

Slide38

J Clin Endocrinol Metab. April 2008

2008

Slide39

Study procedures

Subjects were asked to

skip the administration of their current medication (i.e

.

antihypertensive)

at the morning of

test.

After an

overnight fast

, a

baseline

blood sample was obtained for

the determination

of blood glucose, GH, IGF-I

.

Subjects

then

ingested 75

g

glucose.

Subjects rested in

semi recumbent

position until the end of test, andadditional blood samples for GH and glucose measurements were collected at 30, 60, 90, 120, and 180 min.

Slide40

Slide41

When there is discrepancy between GH and IGF-I values: Multiple GH

sampling

(three to five times over 2 h) is helpful (MQ)

During follow-up after neurosurgery or radiotherapy:

GH during

OGTT

&

IGF-I

(HQ)

For

pts

receiving medical

tx

SRLor

dopamine

agonist:

IGF-I

&

random

GH

are sufficient In fact, an OGTT may not be helpful for monitoring response, in any medical tx

(MQ)GH receptor antagonist:

Only

IGF-I

(

HQ)

Oral estrogens

reduce

IGF-I (interpreted

with

caution)

(MQ

)

Slide42

THANK YOU …

Slide43

J

Clin

Endocrinol

Metab

, Volume 95, Issue 7, 1 July 2010, Pages 3141–3148,