acromegal
TRANSCRIPT
ACROMEGALY
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 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
(%
)
Remission of Acromegaly After Transsphenoidal Surgery
Study Patients GH Criteria ng/mL IGF-1 Micro-
adenomasMacro-
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 Mean GH
<2.5 61% 23%
Remission of Acromegaly After Transsphenoidal Surgery (cont’d)
Study Patients GH Criteria ng/mL IGF-1 Micro-
adenomasMacro-
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 Basal/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
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
(%)
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 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
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0.0001108 treated patientsAyuk, et al (unpublished data).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 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
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
• 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
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 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 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)
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
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)
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
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.
Per
cen
tag
e o
f O
rig
ina
l Siz
e
Tumor 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
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 µg/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
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 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
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