Four-Year Treatment with Octreotide-Long-Acting Repeatable in 110 Acromegalic Patients: Predictive Value of Short-Term Results?

Abstract

The effects of a very prolonged treatment with octreotide (OC)-long-acting repeatable (LAR) were retrospectively evaluated in 110 patients with acromegaly, showing a GH/IGF-I decrease of at least 20% vs. baseline after a short-term (6-month) OC-LAR challenge. OC-LAR was given (20 mg, im, every 28 d for 3 injections, then individually tailored) as adjuvant treatment (AT) in 59. The other 51 [primary treatment (PT)] were naive or previously treated by pharmacotherapy. IGF-I normalized in 83 patients [75%; from 770 +/- 26 (mean +/- SE) to 276 +/- 15 micro g/liter; P < 0.0001; median follow-up, 30 months; range, 18-54 months). A progressive increase in the rate of IGF-I normalization was observed. GH fell to less than 2.5 micro g/liter in 72% and to less than 1 micro g/liter in 27% (from 20.7 +/- 2.4 to 2.2 +/- 0.2 micro g/liter; P < 0.0001). PT and AT patients achieved similar final GH/IGF-I levels and rates of normalization. Patients attaining safe GH and normal IGF-I had GH levels below 5 micro g/liter after 3 months and IGF-I levels below 550 micro g/liter after 6 months. No tachyphylaxis was observed. The up-titration to 30 mg improved IGF-I suppression. Elderly patients had greater sensitivity. Tumor shrank in 46% of assessable patients, in 77% of PT patients, and in 91% of naive patients. The powerful suppression of GH/IGF-I levels without tachyphylaxis, the finding of progressive increase in the rate of IGF-I normalization and of superimposable effects in PT and AT patients, and the predictive value of short-term results support the role of PT of acromegaly with OC-LAR in at least some patients.

Somatostatin agonists for treatment of acromegaly

“…Several papers in recent years report the efficacy of primary pharmacotherapy in achieving biochemical disease control. Similar rates of patient control were achieved in the primary and adjuvant groups, with GH plasma levels ≤2.5 μg/L (64%) and/or normalization of IGF-1 (64%) Ayuk et al, 2002Ayuk et al, , 2004Bevan et al, 2002;Colao et al, 2001Colao et al, , 2006cCozzi et al, 2003Cozzi et al, , 2006. Even though de novo patients had higher pre-treatment GH or IGF-1 levels or both, than those already treated with surgery and/or radiotherapy, patients achieved the same ultimate level of biochemical control by the end of the study Cozzi et al, 2003).…”

“…Table 1 summarizes both primary and adjuvant pharmacotherapy results from studies lasting ≥6 months on >10 patients and shows 70% shrinkage with octreotide LAR, 26% with lanreotide SR 30 mg and 39% with lanreotide SR 60 mg. Recent studies of primary SRL pharmacotherapy suggest mean 79% tumor shrinkage with octreotide LAR Cozzi et al, 2003Cozzi et al, , 2006 and 50% with lanreotide 60 mg or 25% with lanreotide 30 mg Baldelli et al, 2000). Basal GH levels correlated positively with the degree of shrinkage which was >75% in 44% of patients in one study and >50% in 60% of patients in another .…”

“…If considering only GH levels <1 μg/L to be the cutoff for "normalizing" mortality, 33% of octreotide LAR Cozzi et al, 2003;Lancranjan and Atkinson, 1999;Lancranjan et al, 1996) and 25% of lanreotide SR Chanson et al, 2000a) treated patients achieved disease control, implying that ~50% of SRIF agonist treated GH-"controlled" patients may still be at higher risk for higher mortality rates. Prolonged treatment duration improves biochemical control as GH and IGF-1 plasma levels continue to decrease with time Colao et al, 2001;Cozzi et al, 2003Cozzi et al, ,2006Davies et al, 1998;Freda et al, 2005;Jallad et al, 2005;Ronchi et al, 2006). Primary pharmacotherapy is an optional treatment for selected patients (Ben-Shlomo and Melmed, 2003;Colao et al, 2006b).…”

“…a Frequencies are adopted from: octreotide LAR: http://www.rxlist.com according to manufacturer reports Cozzi et al, 2003;Davies et al, 1998;Flogstad et al, 1997;Jallad et al, 2005;Lancranjan and Atkinson, 1999;Lancranjan et al, 1996;Stewart et al, 1995); lanreotide autogel: Caron et al, 2002Caron et al, , 2006Lucas and Astorga, 2006); lanreotide SR: Attanasio et al, 2003;Caron et al, 1997;Chanson et al, 2000a,b;Giusti et al, 1996;Gutt et al, 2005;Lucas et al, 2003;Marek et al, 1994;Morange et al, 1994;Verhelst et al, 2000).…”

Antitumor effects of somatostatin

“…They reduce or normalize excessive growth hormone and insulin-like growth factor (IGF-1) levels associated with acromegaly (Ben-Sholmo and Melmed, 2003). In addition, somatostatin analog therapy is associated with tumor shrinkage in 37-82 % of patients receiving somatostatin analog as primary medical therapy (Bevan 2005;Melmed et al, 2005;Cozzi et al, 2003;Maiza et al, 2007). The efficacy of analogs on tumor growth is attributed to sst 2 and sst 5 whose expression predominates in growth hormone-secreting adenomas (Jaquet et al, 2000).…”