ACROMEGALY

Ilan Shimon, MD
Rabin Medical Center, Petach-Tiqva

Objectives of Treatment for Acromegaly

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

Surgical Outcome in Acromegaly

Experience of the neurosurgeon

Adenoma size Invasiveness into adjacent structures

Pre-operative GH level

Remission of Acromegaly After Transsphenoidal Surgery

Microadenomas 70-90 % Macroadenomas 40-60 %
100 90 80 70 60 50 40 30 20 10 0

Remission Rate (%)

Microadenoma (n=44)

Macroadenoma (n=44)
Shimon I. Neurosurgery. 2001;48:1239

Remission of Acromegaly After Transsphenoidal Surgery

Study Ahmed 1990 Fahlbusch 1992 Davis 1993 Osman 1994 Sheaves 1996 Patients GH Criteria ng/mL Mean GH <2.5 OGTT <2 Basal/OGTT <2.5 OGTT <2.5 Mean GH <2.5 IGF-1 Microadenomas 91% Macroadenomas 46%

139

224

72%

50%

175

60%

35%

79

84%

100

61%

23%

Remission of Acromegaly After Transsphenoidal Surgery (contd)

Study Swearingen 1998 Freda 1998 Patients GH Criteria ng/mL OGTT <2 Basal/OGTT <2 OGTT <2.5 Basal/OGTT <2 Mean GH <2.5 OGTT <1 Normal72% Normal68% IGF-1 Normal82% Normal87% Microadenomas 91% Macroadenomas 48%

162

115

88%

53%

Lissett 1998 Shimon 2001

73

59%

14%

98

84%

64%

De P 2003

90

79%

56%

Remission of Acromegaly After Transsphenoidal Surgery According to Adenoma Size

100
90 80 70 60 50 40 30 20

Remission Rate (%)

10
0

3-6 (n=16)

7-10 (n=26)

11-20 (n=26)

>20 (n=10)

Adenoma Size (mm)

Shimon I. Neurosurg. 2001;48:1239

Acromegaly
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?

Nadir GH <1 g/L

Nadir GH >1 g/L

IGF-1 Normal

No Treatment Treat

IGF-1 Elevated

Treat

Association Between Serum IGF-I and Nadir GH Concentrations Across an OGTT

Nadir GH <1 g/L Nadir GH >1 g/L

IGF-1 Normal

52 (58%)

37 (42%)

IGF-1 Elevated

34 (13%)

226 (87%)
P<0.0001

108 treated patients

Ayuk, et al (unpublished data).

Mortality in Acromegaly
1.0

GH <1 g/L
0.8

Probability

0.6

NZ Population GH <2 g/L

0.4

GH <5 g/L GH >5 g/L

0.2

0 0 5 10 15 20 25 30

Time (Years)
Holdaway IM,JCEM; 2004, 89:667

Factors Influencing Mortality in Acromegaly

1.0

IGF SD Score <2 Proportion Surviving

0.8

NZ Population
0.6

0.4

IGF SD Score >2

0.2

0 0 5 10 15 20 25 30

Time (Years)
Holdaway IM,JCEM; 2004, 89:667

Long-term Mortality After Transsphenoidal Surgery

1.0 Normal IGF-I 0.8
Cox model 0.6 predicted survival

Elevated IGF-I

0.4 0.2 0.0 0 5 10 15 20 Patient in remission Patient not in remission

Years after surgery

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

110 post-operative patients with acromegaly
76 remission (normal IGF-1)
50 normal GH nadir (<0.14 g/L; group 1) 26 abnormal GH nadir (0.3+0.05 g/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

Conclusions
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

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

Six studies with treated/untreated patients before pituitary surgery
Five studies used subcutaneous OCT OCT dose was usually started at 300 g/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 Studies

Study StevenaertMetabolism 1996 ColaoJCEM 1997 KristofActa Neurochir 1999 BiermaszJCEM 1999 AbeEur J Endocrinol 2001 French Acromegaly Registry ENEA 2004 OCT 64 22 11 19 90 OCT/LAN 86 Untreated 108 37 13 19 57 105

TOTAL: Pre-operative SRIF 292 Untreated 339

French Acromegaly Registry ENEA 2004, Sorrento; OCT/LAN (86), Untreated (105)
Surgical Remission Rate
Pre-treated Untreated

No.
All Noninvasive 86 40

%
55 67

No.
105 54

%
51 65

Remission rate improved in patients pre-treated for 4-6 months

Pre-surgical Treatment (292) Untreated (339) Summary of 6 Publications

Surgical Remission Rate
Pre-treated Untreated

No.
All Noninvasive 292 166

%
63.4 83.7

No.
339 169

%
54.5 74

Odds Ratio Plot (Fixed Effects)

Mantel-Haenszel chi-square = 0.7341; P = 0.3916
Odds ratio meta-analysis plot [f ixed effects]

stratum 1

French Registry Abe & Ludecke Biermasz NR Kristof RA Colao A Stevenaert & Beckers

1.14 (0.62, 2.10)

stratum 2

0.65 (0.28, 1.48)

stratum 3

0.61 (0.12, 2.98)

stratum 4

0.53 (0.07, 3.79)

stratum 5

2.84 (0.83, 9.77)

stratum 6

5.74 (1.42, 32.93)

stratum 7

0.98 (0.29, 3.10)

com bined [fixed] 0.01 0.1 0.2 0.5 1 2 5 10

1.18 (0.84, 1.66) 100

odds ratio (95% confidence interval)

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
Percentage of Original Size

120%

100%
80% 60% 40% 20% 0%
Baseline 12 Weeks 24 Weeks 48 Weeks
Bevan J. et al., J Clin Endocrinol Metab. 2002; 87:4554-4563.

Tumor Shrinkage in Patients With Previously Untreated Acromegaly

(a)
0 -10 -20 -30 -40 -50 -60 -70 Macroadenomas Microadenomas

(b)
0 -10 -20 -30 -40 -50 -60 -70

Shrinkage (%)

Shrinkage (%)

Lanreotide SR

Octreotide LAR

T0

T12 Months of Therapy

T24

T0

T12 Months of Therapy

T24

Amato G. Clin Endocrinol. 2002;56:65

Effect of Octreotide on GH Levels in Acromegaly

400 300 200 100 70 60 50 40 30 25 20 15 10 5 2.5

Growth Hormone (g/L)

Pre-treatment During Treatment

% Normal % Normal IGF-1: 30% IGF-1: 53%

% Normal IGF-1: 63%

% Normal % Normal % Normal IGF-1: 75% IGF-1: 86% IGF-1: 83%

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)

Baseline Preoperative Postoperative

sst washout

SST

Baseline

Postoperative SST Preoperative washout sst

Petrossians P, JCEM, 2005; 152:61

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

Saveanu A, JCEM 2001; 86:140

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

Saveanu A, JCEM 2001; 86:140

SST2 and D2DR expression in 11 GH-secreting tumors

Saveanu A, JCEM 2002; 87:5545

A Chimeric Somatostatin-Dopamine Molecule, BIM-23A387

OCT-responsive

OCT-partially responsive

Saveanu A, JCEM 2002; 87:5545

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

Receptor subtype affinity (IC50, nM)

Compound

SSTR1

SSTR2

SSTR3

SSTR4

SSTR5

SRIF-14

2.26

0.23

1.43

1.77

0.88

Octreotide
Lanreotide

1140
2330

0.56
0.75

34
107

7030
2100

7
5.2

SOM-230

9.3

1.5

>100

0.16

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 adenomas Incubated 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

GH
Blocks GH effect

B2036-PEG

X
Liver

Normalizes IGF-I in 92% of patients

X
IGF-I

IGF-I in 112 Patients with Acromegaly Treated with Pegvisomant or Placebo

800

Serum IGF-I (ng/ml)

600

placebo

10 mg 400

15 mg 20 mg
200

4 8 Time (weeks)

12

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

Change in Serum GH in Patients With Acromegaly Treated With Daily Pegvisomant or Placebo
25 20 20 mg * 15 mg * * P <0.001 vs. placebo

Serum 15 GH (ng/ml)
10 5

10 mg
placebo

12
Trainer et al. NEJM. 2000:342;1171-1177

Time (weeks)

Pegvisomant Impact on GH and IGF-I Levels

200 150 Delta (%) 100 50 0 25 0 Dose mg

GH

20 15

50 IGF-I
75 2 4 Weeks
Trainer, PJ et al. N. Engl. J. Med. Apr 2000;342:1171-7.

15
20 8 12

IGF-1 at Baseline and After 12 Months of Pegvisomant

2500 2000

Serum IGF-1 (ng/mL) 1500

1000

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

500

16-24

25-39 40-54 Age (years)

55+

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

Tumor Volume Changes in 92 Patients Receiving Daily Pegvisomant for >6 Months
4 3 No Radiation Radiation

Change in Volume (cm3)

2 1 0 -1 -2 -3 0 6 12 18 24 30 36 Time (months)
van der Lely et al. Lancet. 2001;358:1754

Acromegaly Cotreated with GHR Antagonist and Octreotide

van der Lely, JCEM; 2001, 86:478

Cotreatment with Sandostatin-LAR and 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