Does Preoperative Somatostatin Analog Treatment Improve Surgical Cure Rates in Acromegaly? A New Look at an Old Question

Abstract

Acromegaly is caused in most cases by chronic GH hypersecretion from a pituitary adenoma. Typically, acromegaly has an insidious onset, with patients often suffering from unrecognized signs and symptoms for up to a decade before diagnosis (1). Apart from the characteristic physical changes to the face and extremities, patients with acromegaly are at increased risk for cardiac disease and colorectal cancer (2–4). Retrospective cohort studies show that chronic GH hypersecretion increases mortality, which can be returned to normal with effective control of GH and IGF-I (5, 6). Surgery, usually via the transsphenoidal route, is first-line therapy for acromegaly in suitable and willing patients. The surgical cure rate is 70–85% for noninvasive microadenomas and enclosed (noninvasive) macroadenomas, and for large macroadenomas and invasive tumors, the cure rate is lower (20–50%); the overall cure rate is in the region of 55–65% (7). The expertise of the surgeon is a crucial element in the outcome of acromegaly, with dedicated pituitary neurosurgeons having better results (8). Somatostatin analogs (SSAs) are the main medical treatment for acromegaly, and some centers have more than 20-yr experience with these compounds. In general, SSAs are used as an adjuvant therapy in patients whose symptoms and hormone abnormalities are not completely controlled by surgery. Primary therapy with a SSA is increasing in popularity, particularly among elderly or infirm subjects, or among those unwilling to undergo surgery. Adjuvant SSA therapy normalizes GH and IGF-I in 49–56% and 48–66% of patients, respectively (9). Primary SSA treatment controls GH and IGF-I in approximately 50 and 60% of patients, respectively. SSAs are also associated with tumor shrinkage in acromegaly, with approximately 37% of patients showing some decrease in tumor size during primary medical therapy (10), and 21% of those receiving adjuvant SSA treatment (11). This tumor shrinkage does not appear to be due to tumoricidal or strong pro-apoptotic effects but, rather, to a complex pattern of morphological alterations within the tumor that include decreases in secretory granule number and capacity and fibrosis (12, 13). Apart from tumor size/invasiveness and surgical expertise, few other factors influence improved cure rates in acromegaly. One factor that has been studied repeatedly is the preoperative use of SSAs to try to improve the subsequent surgical cure rate. The combination of improved hormone secretion, decreased symptoms/signs, and tumor shrinkage led to the preoperative use of SSAs in some centers as early as the 1980s (14, 15). In a large series, we compared postoperative biochemical outcome in 48 patients who were pretreated with octreotide compared with 104 patients who did not receive SSAs (16). Tumor shrinkage occurred in 56.5% of pretreated patients with marked shrinkage ( 25%) being seen with longer duration of SSA therapy. Disease control occurred at a significantly higher rate in pretreated patients with microadenomas or enclosed (noninvasive) macroadenomas as compared with nonpretreated patients. Overall, adenomatous tissue was soft and easy to remove among the pretreated group. Many other groups have examined the issue of pretreatment since these early studies. Whereas some large series support the value of treating with a SSA before surgery, other groups have demonstrated no clear value, although symptomatic improvement, tumor shrinkage, and morphological changes have been validated (17–19). The discrepancies among the studies have led to uncertainty regarding whether pretreatment of surgical candidates leads to improved control of acromegaly. As such, none of the previously mentioned studies was ideally designed, nor does any provide definitive data. An ideal study should be a prospective randomized controlled trial that includes a large number and variety of patients with acromegaly in both treatment arms. In addition, patients should be evaluated preop-