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 % 10 20 30 40 50 60 70 80 90 100 Microadenoma (n=44) Macroadenoma (n=44) Remission Rate (%) Shimon I. Neurosurgery. 2001;48:1239

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%

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%

Remission of Acromegaly After Transsphenoidal Surgery According to Adenoma Size 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) Remission Rate (%) 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 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%) 108 treated patients P<0.0001 Ayuk, et al (unpublished data).

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

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

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

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 Abe—Eur J Endocrinol 2001 90 57 French Acromegaly Registry— ENEA 2004 OCT/LAN 86 105 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. % No. % All 86 55 105 51 Noninvasive 40 67 54 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. % 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 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.

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; 87:4554-4563.

Tumor Shrinkage in Patients With Previously Untreated Acromegaly Months of Therapy T0 T12 T24 -10 -20 -30 -40 -50 -60 -70 (b) Microadenomas Macroadenomas T0 T12 T24 Lanreotide SR Octreotide LAR Amato G. Clin Endocrinol. 2002;56:65

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;83:3034-3040.

Surgical Debulking Improves Hormonal Control of Acromegaly by SST analogs (OCT, LAN) (retrospective; 1-33 months, 300-1500 g/day) Postoperative washout Baseline Postoperative washout Baseline SST SST Preoperative sst Preoperative 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 1140 0.56 34 7030 7 Lanreotide 2330 0.75 107 2100 5.2 SOM-230 9.3 1 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

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

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. 2000:342;1171-1177

Change in Serum GH in Patients With Acromegaly Treated With Daily Pegvisomant or Placebo 2 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;1171-1177

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;342:1171-7.

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

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

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