acromegaly ilan shimon, md rabin medical center, petach-tiqva
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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
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
(%
)
Remission of Acromegaly After Transsphenoidal Surgery
Remission of Acromegaly After Transsphenoidal Surgery
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)
Saveanu A, JCEM 2001; 86:140
BIM-23244, a bispecific (SSRR2 + SSTR5) analog
Saveanu A, JCEM 2002; 87:5545
SST2 and D2DR expression in 11 GH-secreting tumors
A Chimeric Somatostatin-Dopamine Molecule, BIM-23A387
Saveanu A, JCEM 2002; 87:5545
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
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