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

2. 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

3. Surgical Outcome in Acromegaly
Experience of the neurosurgeon
Adenoma size
Invasiveness into adjacent structures
Pre-operative GH level

4. Remission of Acromegaly After Transsphenoidal Surgery
Microadenomas – %
Macroadenomas – % 10 20 30 40 50 60 70 80 90
100
Microadenoma (n=44)
Macroadenoma (n=44)
Remission Rate (%)
Shimon I. Neurosurgery. 2001;48:1239

5. Remission of Acromegaly After Transsphenoidal Surgery
Study
Patients
GH Criteria ng/mL
IGF-1
Micro-adenomas
Macro-adenomas
Ahmed 1990
139
Mean GH <2.5
91%
46%
Fahlbusch 1992
224
OGTT <2
72%
50%
Davis 1993
175
Basal/OGTT <2.5
60%
35%
Osman 1994 79
OGTT <2.5
84%
Sheaves 1996
100
61%
23%

6. Remission of Acromegaly After Transsphenoidal Surgery (cont’d)
Study
Patients
GH Criteria ng/mL
IGF-1
Micro-adenomas
Macro-adenomas
Swearingen 1998
162
OGTT <2
Normal-82%
91%
48%
Freda 1998
115
Basal/OGTT <2
Normal-87%
88%
53%
Lissett 1998 73
OGTT <2.5
59%
14%
Shimon 2001 98
Normal-72%
84%
64%
De P 2003 90
Mean GH <2.5 OGTT <1
Normal-68%
79%
56%

7. Remission of Acromegaly After Transsphenoidal Surgery According to Adenoma Size10 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)
Remission Rate (%)
Shimon I. Neurosurg. 2001;48:1239

8. 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

9. Current Clinical Practice?
Nadir GH <1 µg/L
Nadir GH >1 µg/L
IGF-1 Normal
No Treatment ?
IGF-1 Elevated
“Treat”
Treat

10. 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%)
108 treated patients
P<0.0001
Ayuk, et al (unpublished data).

11. Mortality in Acromegaly
1.0
GH <1 µg/L
0.8
NZ Population
GH <2 µg/L
0.6
Probability
GH <5 µg/L
0.4
GH >5 µg/L
0.2 5 10 15 20 25 30
Time (Years)
Holdaway IM,JCEM; 2004, 89:667

12. Factors Influencing Mortality in Acromegaly
1.0
IGF SD Score <2
0.8
NZ Population
0.6
Proportion Surviving
IGF SD Score >2
0.4
0.2 5 10 15 20 25 30
Time (Years)
Holdaway IM,JCEM; 2004, 89:667

13. Cox model predicted survival
Long-term Mortality After Transsphenoidal Surgery
1.0
Normal IGF-I
0.8
Elevated IGF-I
Cox model predicted survival
0.6
0.4
Patient in remission
Patient not in remission
0.2
0.0 5 10 15 20
Years after surgery
Swearingen, B. et al. J Clin Endocrinol Metab 1998;83:3419

14. Nadir GH levels after OGTT in postoperative patients with normal IGF-I
Freda PU, et al. 2004, JCEM; 89:495

15. 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 ( µg/L;group 2)
Longitudinal follow-up 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

16. 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

17. 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

18. 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

19. Available 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
Abe—Eur J Endocrinol 2001 90 57
French Acromegaly Registry— ENEA 2004
OCT/LAN 86
105
TOTAL:
Pre-operative SRIF 292
Untreated 339

20. French Acromegaly Registry– ENEA 2004, Sorrento; OCT/LAN (86), Untreated (105)
Surgical Remission Rate
Pre-treated Untreated
No. % No. %
All
Noninvasive
Remission rate improved in patients pre-treated for 4-6 months

21. Pre-surgical Treatment (292) Untreated (339) Summary of 6 Publications
Surgical Remission Rate
Pre-treated Untreated
No. % No. %
All
Noninvasive

22. Odds Ratio Plot (Fixed Effects)
Mantel-Haenszel chi-square = ; P =
French Registry
Abe & Ludecke
Biermasz NR
Kristof RA
Colao A
Stevenaert & Beckers

23. UK Primary Octreotide Study: Individual Growth Hormone Response (sc Oct, Oct-LAR)
Bevan JS et al. J Clin Endocrinol Metab. 2002;87:

24. Percentage of Original Size
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
Percentage of Original Size
Bevan J. et al., J Clin Endocrinol Metab. 2002; 87:

25. Tumor Shrinkage in Patients With Previously Untreated Acromegaly
Months of Therapy
T T T24
-10
-20
-30
-40
-50
-60
-70
(b)
Microadenomas
Macroadenomas
T T T24
Lanreotide SR
Octreotide LAR
Amato G. Clin Endocrinol. 2002;56:65

26. Effect of Octreotide on GH Levels in Acromegaly
Growth Hormone (µg/L)
Pre-treatment
During Treatment
% Normal
IGF-1: 30%
IGF-1: 63%
IGF-1: 75%
IGF-1: 86%
IGF-1: 83%
IGF-1: 53%
400
300
200
100 70 60 50 40 30 25 20 15 10 5
2.5
Newman et al. J Clin Endocrinol Metab. 1998;83:

27. Surgical Debulking Improves Hormonal Control of Acromegaly by SST analogs (OCT, LAN) (retrospective; 1-33 months, g/day)
Postoperative
washout
Baseline
Postoperative
washout
Baseline
SST
SST
Preoperative
sst
Preoperative
sst
Petrossians P, JCEM, 2005; 152:61

29. SSTR2 and SSTR5 expression in GH-secreting adenomas
(according to in vivo GH suppression by Octreotide)
Saveanu A, JCEM 2001; 86:140

30. BIM-23244, a bispecific (SSRR2 + SSTR5) analog
Saveanu A, JCEM 2001; 86:140

31. SST2 and D2DR expression in 11 GH-secreting tumors
Saveanu A, JCEM 2002; 87:5545

32. A Chimeric Somatostatin-Dopamine Molecule, BIM-23A387
OCT-responsive
OCT-partially responsive
Saveanu A, JCEM 2002; 87:5545

33. SOM-230, a somatostatin analog with broad spectrum binding affinity
Receptor subtype affinity (IC50, nM)
Compound SSTR1 SSTR SSTR SSTR4 SSTR5
SRIF
Octreotide
Lanreotide
SOM >

34. Effect of Infused OCT and SOM230 on IGF-1 Plasma Levels in Rats
Weckbecker G, Endocrinology, 2002; 143:4123

35. GH release in cultured GH-secreting adenomas
Incubated with SOM-230
Hofland LJ, JCEM 2004; 89:1577

36. PRL release in cultured mixed PRL/GH-secreting
Adenomas incubated with SOM-230
Hofland LJ, JCEM 2004; 89:1577

37. In vivo GH suppression 2-8 h
after SOM-230 injection
N = 8
N = 3
Van der Hoek J, JCEM 2004; 89:638

38. X X GHR Antagonist Action GH IGF-I Blocks GH effect
Normalizes IGF-I in 92% of patients
Pituitary
Tumor GH
B2036-PEG X
Liver X
IGF-I

39. IGF-I in 112 Patients with Acromegaly Treated with Pegvisomant or Placebo
10 mg
15 mg
20 mg
800
600
400
200 2 4 8 12
Time (weeks)
Serum IGF-I (ng/ml)
Trainer et al N Eng J Med :342;

40. Change in Serum GH in Patients With Acromegaly Treated With Daily Pegvisomant or Placebo2 4 8 12 5 10 15 20 25
placebo
10 mg
15 mg *
20 mg *
Time (weeks)
* P <0.001
vs. placebo
Serum GH
(ng/ml)
Trainer et al. NEJM. 2000:342;

41. Pegvisomant Impact on GH and IGF-I Levels
Dose mg
200 GH 20
150 15
100
Delta (%) 50
–25
IGF-I 15
–50 20
–75 2 4 8 12
Weeks
Trainer, PJ et al. N. Engl. J. Med. Apr 2000;342:

42. IGF-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)
Age (years)
van der Lely et al. Lancet. 2001;358:1754

43. Tumor Volume Changes in 92 Patients Receiving Daily Pegvisomant for >6 Months-3 -2 -1 1 2 3 4 6 12 18 24 30 36
Time (months)
Change in
Volume
(cm3)
No Radiation
Radiation
van der Lely et al. Lancet. 2001;358:1754

44. Acromegaly Cotreated with GHR Antagonist
and Octreotide
van der Lely, JCEM; 2001, 86:478

45. Cotreatment with Sandostatin-LAR and daily Pegvisomant (10/15 mg)
Jorgensen JO, JCEM, 2005; 90:5627

46. 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