ACROMEGALY Ilan Shimon, MD Rabin Medical Center, Petach-Tiqva

ACROMEGALYACROMEGALY

Ilan Shimon, MD

Rabin Medical Center,

Petach-Tiqva

• Control and reverse symptoms and signs

• Suppress GH and IGF-1 to control morbidity and mortality

• Decrease pituitary tumor size

• Control tumor mass effects

• Preserve normal pituitary hormone secretion

Objectives of Treatment for Acromegaly

Surgical Outcome in AcromegalySurgical Outcome in Acromegaly

• Experience of the neurosurgeon

• Adenoma size

• Invasiveness into adjacent structures

• Pre-operative GH level

Remission of Acromegaly After Transsphenoidal Surgery


Shimon I. Neurosurgery. 2001;48:1239

Microadenomas – 70-90 %

Macroadenomas – 40-60 %

0

10

20

30

40

50

60

70

80

90

100

Microadenoma (n=44) Macroadenoma (n=44)

Re

mis

sio

n R

ate

(%

)



Study PatientsGH Criteria

ng/mLIGF-1

Micro-adenomas

Macro-adenomas

Ahmed 1990

139Mean GH

<2.591% 46%

Fahlbusch 1992

224 OGTT <2 72% 50%

Davis 1993

175Basal/OGTT

<2.560% 35%

Osman 1994

79OGTT <2.5

84%

Sheaves 1996

100Mean GH

<2.561% 23%

Remission of Acromegaly After Transsphenoidal Surgery (cont’d)Remission of Acromegaly After

Transsphenoidal Surgery (cont’d)

Study PatientsGH Criteria

ng/mLIGF-1

Micro-adenomas

Macro-adenomas

Swearingen 1998

162 OGTT <2Normal-

82%91% 48%

Freda 1998 115Basal/OGTT

<2Normal-

87%88% 53%

Lissett 1998 73OGTT <2.5

59% 14%

Shimon 2001

98Basal/OGTT

<2Normal-

72%84% 64%

De P 2003 90Mean GH

<2.5OGTT <1

Normal-68%

79% 56%

Remission of Acromegaly After Transsphenoidal Surgery According

to Adenoma Size

Remission of Acromegaly After Transsphenoidal Surgery According

to Adenoma Size

Shimon I. Neurosurg. 2001;48:1239

0

10

20

30

40

50

60

70

80

90

100

3-6 (n=16) 7-10 (n=26) 11-20 (n=26) >20 (n=10)

Adenoma Size (mm)

Rem

issi

on R

ate

(%)

AcromegalyAcromegaly

• Definition of surgical cure

• Pre-operative medical treatment

• Primary medical treatment

• Improved remission by medical therapy after surgical debulking

• Multi-recepotor SRIF analogs

• GH receptor antagonist

• Combination therapy

Current Clinical Practice?Current Clinical Practice?

Nadir GH<1 µg/L

Nadir GH>1 µg/L

IGF-1 Normal No Treatment ?

IGF-1 Elevated “Treat” Treat

Association Between Serum IGF-I and Nadir GH

Concentrations Across an OGTT

Association Between Serum IGF-I and Nadir GH

Concentrations Across an OGTT

Nadir GH<1 µg/L

Nadir GH>1 µg/L

IGF-1 Normal 52 (58%) 37 (42%)

IGF-1 Elevated 34 (13%) 226 (87%)

P<0.0001108 treated patientsAyuk, et al (unpublished data).

Mortality in AcromegalyMortality in AcromegalyP

roba

bilit

y

GH <1 µg/L

1.0

GH <2 µg/L

GH <5 µg/L

GH >5 µg/L

NZ Population

0.8

0.6

0.4

0.2

00 5 10 15 20 25 30

Time (Years)

Holdaway IM,JCEM; 2004, 89:667

Factors Influencing Mortality in Acromegaly

Factors Influencing Mortality in Acromegaly

Holdaway IM,JCEM; 2004, 89:667

Pro

port

ion

Sur

vivi

ng

Time (Years)

IGF SD Score <2

NZ Population

IGF SD Score >2

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25 30

Cox model predicted survival

Long-term Mortality After Transsphenoidal Surgery

Years after surgery

Normal IGF-I

Elevated IGF-I0.8

0.4

0.2

1.0

0.6

Patient in remission

Patient not in remission

0 5 10 15 20

0.0

Swearingen, B. et al. J Clin Endocrinol Metab 1998;83:3419

Nadir GH levels after OGTT in postoperative patients with normal IGF-I

Freda PU, et al. 2004, JCEM; 89:495

Post-operative Follow-Up With Normal IGF-1 Values

Post-operative Follow-Up With Normal IGF-1 Values

• 110 post-operative patients with acromegaly

– 76 remission (normal IGF-1)

• 50 normal GH nadir (<0.14 µg/L; group 1)

• 26 abnormal GH nadir (0.3+0.05 µg/L;group 2)

• Longitudinal follow-up 1-6.5 years

– IGF-1 Group 1 normal in all

– IGF-1 Group 2 elevated in 5

• Conclusion: persistent abnormal GH suppression is associated with increased risk of recurrence

Freda PU, et al. 2004, JCEM; 89:495

ConclusionsConclusions

• Evaluate normal ranges of GH and IGF-1 assays (“know your assay”)

• Patients with evidence of hypersecretion of GH should be considered for treatment irrespective of IGF-1 value

• Patients with elevated IGF-1 should be considered for treatment irrespective of GH value

• Treatment of co-morbidities may be even more important and may influence the decision to treat

Pre-operative Treatment With Somatostatin Analogs—

Clinical Studies

Pre-operative Treatment With Somatostatin Analogs—

Clinical Studies

• Only few studies with small number of patients

• No randomized placebo-controlled studies

• Most studies with short-acting analogs

• No consistency in pre-operative dosage and treatment interval

Pre-operative Treatment With Somatostatin Analogs

Pre-operative Treatment With Somatostatin Analogs

• Six studies with treated/untreated patients before pituitary surgery

• Five studies used subcutaneous OCT

• OCT dose was usually started at 300 µg/day, and individually increased

• Pre-operative medical therapy was maintained for 1-39 months before surgery, usually for 3-6 months

• The criteria for post-operative remission not similar

Available Comparative StudiesAvailable Comparative Studies

Study OCT Untreated

Stevenaert—Metabolism 1996 64 108

Colao—JCEM 1997 22 37

Kristof—Acta Neurochir 1999 11 13

Biermasz—JCEM 1999 19 19

Abe—Eur J Endocrinol 2001 90 57

French Acromegaly Registry—ENEA 2004

OCT/LAN 86 105

TOTAL: Pre-operative SRIF 292Untreated 339

French Acromegaly Registry–ENEA 2004, Sorrento;

OCT/LAN (86), Untreated (105)

French Acromegaly Registry–ENEA 2004, Sorrento;

OCT/LAN (86), Untreated (105)

Surgical Remission Rate

Pre-treated Untreated

No. % No. %

All 86 55 105 51

Noninvasive 40 67 54 65

Remission rate improved in patientspre-treated for 4-6 months

Pre-surgical Treatment (292)Untreated (339)

Summary of 6 Publications

Pre-surgical Treatment (292)Untreated (339)

Summary of 6 Publications

Surgical Remission Rate

Pre-treated Untreated

No. % No. %

All 292 63.4 339 54.5

Noninvasive 166 83.7 169 74

Odds Ratio Plot (Fixed Effects)

Odds Ratio Plot (Fixed Effects)

Mantel-Haenszel chi-square = 0.7341; P = 0.3916

Odds ratio meta-analysis plot [fixed effects]

0.01 0.1 0.2 0.5 1 2 5 10 100

stratum 7 0.98 (0.29, 3.10)

stratum 6 5.74 (1.42, 32.93)

stratum 5 2.84 (0.83, 9.77)

stratum 4 0.53 (0.07, 3.79)

stratum 3 0.61 (0.12, 2.98)

stratum 2 0.65 (0.28, 1.48)

stratum 1 1.14 (0.62, 2.10)

combined [fixed] 1.18 (0.84, 1.66)

odds ratio (95% confidence interval)

French Registry

Abe & Ludecke

Biermasz NR

Kristof RA

Colao A

Stevenaert & Beckers

UK Primary Octreotide Study:Individual Growth

Hormone Response

(sc Oct, Oct-LAR)

Bevan JS et al. J Clin Endocrinol Metab. 2002;87:4554-4563.

Tumor Changes After Primary OCT Therapy Expressed as a Percentage of the Pre-treatment

Volume in 20 Macroadenomas

Tumor Changes After Primary OCT Therapy Expressed as a Percentage of the Pre-treatment

Volume in 20 Macroadenomas

0%

20%

40%

60%

80%

100%

120%

Baseline 12 Weeks 24 Weeks 48 Weeks

Bevan J. et al., J Clin Endocrinol Metab. 2002; 87:4554-4563.

Pe

rce

nta

ge

of

Ori

gin

al S

ize

Tumor Shrinkage in Patients With Previously Untreated AcromegalyTumor Shrinkage in Patients With Previously Untreated Acromegaly

Amato G. Clin Endocrinol. 2002;56:65

(a)

Shr

inka

ge (

%)

Months of Therapy

T0 T12 T24

0

-10

-20

-30

-40

-50

-60

-70S

hrin

kage

(%

)

0

-10

-20

-30

-40

-50

-60

-70

(b)

Microadenomas

Macroadenomas

T0 T12 T24

Lanreotide SR

Octreotide LAR

Months of Therapy

Effect of Octreotide on GH Levels in Acromegaly

Effect of Octreotide on GH Levels in Acromegaly

Gro

wth

Ho

rmo

ne

(µg

/L)

Pre-treatment

During Treatment

% Normal

IGF-1: 30%

% Normal

IGF-1: 63%

% Normal

IGF-1: 75%

% Normal

IGF-1: 86%

% Normal

IGF-1: 83%

% Normal

IGF-1: 53%

400

300200100

7060

5040

30

25201510

52.5

Newman et al. J Clin Endocrinol Metab. 1998;83:3034-3040.

Surgical Debulking Improves Hormonal Control of Acromegaly by SST analogs (OCT, LAN)

(retrospective; 1-33 months, 300-1500 g/day)

Surgical Debulking Improves Hormonal Control of Acromegaly by SST analogs (OCT, LAN)

(retrospective; 1-33 months, 300-1500 g/day)

Baseline BaselinePreoperativesst

Preoperativesst

Postoperativewashout

Postoperativewashout

SST SST

Petrossians P, JCEM, 2005; 152:61

Saveanu A, JCEM 2001; 86:140

SSTR2 and SSTR5 expression in GH-secreting adenomas(according to in vivo GH suppression by Octreotide)


BIM-23244, a bispecific (SSRR2 + SSTR5) analog


SST2 and D2DR expression in 11 GH-secreting tumors

A Chimeric Somatostatin-Dopamine Molecule, BIM-23A387


OCT-responsive OCT-partially responsive

SOM-230, a somatostatin analog with broad spectrum binding affinity

Compound SSTR1 SSTR2 SSTR3 SSTR4 SSTR5

SRIF-14 2.26 0.23 1.43 1.77 0.88

Octreotide 1140 0.56 34 7030 7

Lanreotide 2330 0.75 107 2100 5.2

SOM-230 9.3 1 1.5 >100 0.16

Receptor subtype affinity (IC50, nM)

Effect of Infused OCT and SOM230 on IGF-1 Plasma Levels in Rats

Weckbecker G, Endocrinology, 2002; 143:4123

GH release in cultured GH-secreting adenomasIncubated with SOM-230

Hofland LJ, JCEM 2004; 89:1577

PRL release in cultured mixed PRL/GH-secreting Adenomas incubated with SOM-230

Hofland LJ, JCEM 2004; 89:1577

In vivo GH suppression 2-8 h after SOM-230 injection

N = 8

N = 3

Van der Hoek J, JCEM 2004; 89:638

GHR Antagonist Action

Pituitary Tumor

Liver

GH

IGF-I

B2036-PEG

X

X

• Blocks GH effect

• Normalizes IGF-I in 92% of patients

IGF-I in 112 Patients with AcromegalyTreated with Pegvisomant or Placebo

Trainer et al N Eng J Med. 2000:342;1171-1177

placebo

10 mg

15 mg

20 mg

800

600

400

200

0 2 4 8 12Time (weeks)

Ser

um

IG

F-I

(n

g/m

l)

Change in Serum GH in Patients With Acromegaly Treated With Daily

Pegvisomant or Placebo

Change in Serum GH in Patients With Acromegaly Treated With Daily

Pegvisomant or Placebo

0 2 4 8 12

5

10

15

20

25

placebo

10 mg

15 mg *20 mg *

Time (weeks)

* P <0.001vs. placebo

SerumGH

(ng/ml)

Trainer et al. NEJM. 2000:342;1171-1177

Pegvisomant Impact on GH and IGF-I Levels

Trainer, PJ et al. N. Engl. J. Med. Apr 2000;342:1171-7.

2 4 8 12

15

15

–75

–50

–25

0

Del

ta (

%)

GH

IGF-I

20

20

50

100

150

200

0

Weeks

Dose mg

IGF-1 at Baseline and After 12 Months of PegvisomantIGF-1 at Baseline and After 12 Months of Pegvisomant

Serum IGF-1 (ng/mL)

500

1000

1500

2000

2500

55+16-24 25-39 40-54

97% normalization of IGF-1 (n=90)

van der Lely et al. Lancet. 2001;358:1754

Age (years)

Tumor Volume Changes in 92 Patients Receiving Daily Pegvisomant

for >6 Months

Tumor Volume Changes in 92 Patients Receiving Daily Pegvisomant

for >6 Months

van der Lely et al. Lancet. 2001;358:1754

-3

-2

-1

0

1

2

3

4

0 6 12 18 24 30 36

Time (months)

Change in

Volume (cm3)

No RadiationRadiation

van der Lely, JCEM; 2001, 86:478

Acromegaly Cotreated with GHR Antagonist

and Octreotide

Cotreatment with Sandostatin-LARand daily Pegvisomant (10/15 mg)

Jorgensen JO, JCEM, 2005; 90:5627

IGF-1 before and after 6 weeks of combined treatment SSTR (LAR/Autogel) analog monthly + Pegvisomant

(up to 80 mg) weekly

Feenstra J et al, Lancet 2005, 365:1644

Documents

ACROMEGALY Ilan Shimon, MD Rabin Medical Center, Petach-Tiqva