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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1093
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 3 1856-1863
Copyright © 2005 by The Endocrine Society

CLINICAL REVIEW

The Antitumoral Effects of Somatostatin Analog Therapy in Acromegaly

John S. Bevan

Department of Endocrinology, Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, Scotland, United Kingdom

Address all correspondence and requests for reprints to: Dr. J. S. Bevan, M.D., F.R.C.P., Department of Endocrinology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, Scotland, United Kingdom. E-mail: j.s.bevan{at}arh.grampian.scot.nhs.uk.


   Abstract
Top
 Abstract
Introduction
 Somatostatin Analogs
 Antigrowth Effects of sst...
 Effects of Somatostatin Analogs...
 Predictors of Tumor Shrinkage...
 Magnitude of Tumor Shrinkage...
 Summary
 References
 
Somatostatin analogs are the mainstay of medical therapy for acromegaly. Suppression of GH hypersecretion, lowering of IGF-I production, and control of symptoms are established benefits of therapy. In addition, clinically significant tumor shrinkage has been seen in a number of studies, particularly in patients undergoing primary medical therapy. This review summarizes current knowledge of the effects of somatostatin analogs on tumor size and cellular morphology and examines the available data on predictors of tumor shrinkage.


   Introduction
Top
 Abstract
 Introduction
Somatostatin Analogs
 Antigrowth Effects of sst...
 Effects of Somatostatin Analogs...
 Predictors of Tumor Shrinkage...
 Magnitude of Tumor Shrinkage...
 Summary
 References
 
SOMATOSTATIN IS SECRETED by hypothalamic neurons and enters the hypophyseal portal circulation, in which it acts to regulate pituitary hormone secretion (1). Its primary effect is to inhibit the secretion of GH and TSH (2, 3, 4, 5, 6, 7, 8); however, it can also inhibit prolactin and ACTH secretion under some circumstances (4, 6, 7, 8). The effects of somatostatin are mediated by somatostatin receptors (ssts), of which there are five different subtypes (9, 10, 11, 12). sst2 and sst5 are the subtypes primarily involved in the control of GH secretion, although sst1 may also have a role (9, 10). In addition to the expression of ssts in normal pituitary, ssts are also expressed in GH-secreting pituitary tumors (13, 14, 15, 16). sst2 and sst5 are the predominantly expressed subtypes, whereas sst4 is infrequently expressed (13). sst expression is variable both within GH-secreting tumors and between different GH-secreting tumors (17).


   Somatostatin Analogs
Top
 Abstract
 Introduction
 Somatostatin Analogs
Antigrowth Effects of sst...
 Effects of Somatostatin Analogs...
 Predictors of Tumor Shrinkage...
 Magnitude of Tumor Shrinkage...
 Summary
 References
 
Somatostatin analogs are compounds that bind to one or more ssts and are known also as sst ligands (SRLs) (17, 18, 19, 20, 21, 22, 23). The first commercially available SRL was octreotide formulated for sc administration (Novartis, Cambridge, MA) (20, 21). This compound has highest affinity for sst2 and sst5, but the affinity to sst2 is about 10 times greater than to sst5 (22). The sc formulation of the drug is administered with multiple daily injections (two to four) and is the shortest acting of the available somatostatin analog formulations (21). The GH-suppressive effect lasts at most 5 h after injection, and because of this, GH levels tend to rise between doses given every 8 h (21). A medium-acting SRL formulation, lanreotide SR, is available in Europe (17, 24). Among the subtypes, lanreotide has highest affinities for sst2 and sst5, with affinity to sst2 approximately 10 times greater than sst5 (22). This formulation is longer acting than the sc version of octreotide because the drug is encapsulated in microspheres that provide prolonged release over 10–14 d after im administration (23). Lanreotide SR is provided in a 30-mg dose only, and the pharmacological effect is manipulated by changing the dosing interval among every 7, 10, or 14 d (17, 23).

Octreotide is also available in a long-acting formulation, octreotide LAR (23, 24). As with lanreotide SR, the active compound, octreotide, is encapsulated in microspheres of a biodegradable polymer. After an im injection, drug levels begin to rise over 7–14 d and plateau for 20–30 d (24). Dosing every 4 wk is typical, but dosing intervals beyond 4 wk may be possible in some patients, particularly those with lower GH and IGF-I levels (25). The pharmacological effect of the drug can be manipulated by varying the dose from 10 to 30 mg with a fixed dosing interval of 28 d. Another long-acting SRL formulation, lanreotide Autogel (Ipsen Limited, Slough, UK), has recently become available in many European countries (26). Like octreotide LAR, lanreotide Autogel also has a monthly administration schedule. The active drug in lanreotide Autogel is the same as in lanreotide SR and as such also has affinity to sst2 more than sst5 (26). The drug naturally congeals into a slow-release aqueous gel that can be given deep sc once monthly. The pharmacological effect can be manipulated by varying the dose from 60, 90, or 120 mg with a fixed monthly administration schedule (26).


   Antigrowth Effects of sst Activation
Top
 Abstract
 Introduction
 Somatostatin Analogs
 Antigrowth Effects of sst...
Effects of Somatostatin Analogs...
 Predictors of Tumor Shrinkage...
 Magnitude of Tumor Shrinkage...
 Summary
 References
 
Native somatostatin has been shown to inhibit the proliferation of both normal and tumorous cells (11, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40). The antiproliferative action is mediated through the ssts by a variety of mechanisms. These depend on the receptor subtype and the target tissue and include cell cycle arrest and the induction of apoptosis. Activation of sst1, -2, -4, and -5 all appear able to induce cell cycle arrest, whereas sst3, and possibly sst2, induce apoptosis (11, 28, 29, 30, 35, 36). Indirect effects of somatostatin on growth factor production may also be involved (37, 38, 39, 40). IGF-I, a key local modulator of growth, is reduced by somatostatin via its effects on GH secretion. Finally, angiogenesis appears to be inhibited by somatostatin, although the underlying mechanisms are unclear (27, 32). Direct inhibition of endothelial cell growth has been demonstrated in several cellular models, whereas an indirect effect via suppression of vascular endothelial growth factor is also possible (27).

The effects of sst activation on tumor cytochemistry and morphology have been studied in vitro in patients with GH-secreting pituitary adenomas. Losa et al. (41) compared immunocytochemical findings in 39 GH-secreting adenomas from patients who were pretreated with an analog of somatostatin, octreotide, to a control group of 39 untreated acromegalic patients. This study showed that the Ki-67 staining index was lower in the octreotide-pretreated subjects. Ki-67 is a nuclear protein expressed only in cycling cells, so a lower Ki-67 index is reflective of a suppressive effect on cell cycling. Apoptosis did not appear significantly altered by octreotide pretreatment. This study supports the earlier findings of Thapar et al. (42) with respect to the antiproliferative effects of octreotide. These investigators compared growth fractions for pituitary tumors as assessed by the cell cycle-specific marker Ki-67 in 16 subjects who had received octreotide therapy before surgical resection, as compared with a control group that went to surgery without any form of pretreatment. This study showed that octreotide pretreatment significantly suppressed the growth fraction and increased the proportion of cells in G1 and M phases. Taken together, these articles suggest that a reduction in cell cycling, rather than an increase in apoptotic rate, is the basis for the antiproliferative action.

The effects of octreotide on cell cycling do not appear to be associated with significant morphological changes. Ezzat et al. (43) examined 86 GH-secreting adenomas, 43 of which were from patients treated before resection with octreotide. Necrotic changes were not noted. Acidophilia and interstitial fibrosis occurred with greater frequency in the octreotide-treated group. There was a slight downward trend of cell and cytoplasmic size in all treated tumors and no statistically significant change in the size of nuclei, secretory granules, or lysosomes. A lack of uniformity in morphological response was noted. The investigators concluded that no striking morphological alterations were consistently associated with octreotide treatment. This is different from the effects seen when prolactinomas are treated with a dopamine agonist. Studies in this setting have noted marked reductions in cellular, cytoplasmic, and nuclear volume as well as marked perivascular and interstitial fibrosis and effects on the endoplasmic reticulum and Golgi (44).


   Effects of Somatostatin Analogs on Tumor Size
Top
 Abstract
 Introduction
 Somatostatin Analogs
 Antigrowth Effects of sst...
 Effects of Somatostatin Analogs...
Predictors of Tumor Shrinkage...
 Magnitude of Tumor Shrinkage...
 Summary
 References
 
Many studies with SRLs do not report on changes in tumor size as an outcome of therapy. Those that do use a variety of methodologies to define tumor shrinkage, with some using absolute or percentage changes in diameter, whereas others use absolute or percentage changes in volume. Most define a 10–25% reduction in tumor volume as significant tumor shrinkage. In addition, measurements from magnetic resource imaging and computed tomography images are difficult to standardize and suffer from observer subjectivity, particularly with irregularly shaped tumors. Furthermore, computed tomography and magnetic resource imaging performed before 1990 had inferior resolution, compared with modern imaging. These challenges make it difficult to compare results among studies. Ideally, future studies will minimize some of these problems by following the practice established in more recent trials, in which blinded radiological assessment in a centralized reading facility was employed (45). For the purposes of this review, the standards for tumor shrinkage established within each paper reviewed were used to determine the number of patients that showed tumor shrinkage from that report.

Tumor shrinkage as an outcome of therapy has been assessed most frequently for the short-acting SRL, octreotide (45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66). Twenty-two studies were identified in which tumor size was measured as an end point for octreotide sc therapy (Table 1Go). These studies included 478 patients with pituitary imaging performed before and after variable doses of octreotide sc for variable lengths of time. The definition of tumor shrinkage differed across studies. Overall, 217 of 478 patients (45%) had a reduction in tumor size. For primary medical therapy patients (defined as patients without prior surgery or radiation, although some patients may have been treated with bromocriptine), 110 of 217 (51%) had tumor shrinkage. For adjunctive therapy patients (defined as those with prior surgery and/or radiation) 22 of 82 (27%) experienced tumor shrinkage. In studies in which primary and adjunctive therapy patients were not considered separately, 85 of 179 (47%) had tumor shrinkage.


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  		TABLE 1. Tumor shrinkage rates with the short-acting SRL, octreotide SC

 
A number of studies has now examined tumor shrinkage as an outcome of therapy with the medium-length SRL formulation, lanreotide SR (67, 68, 69, 70, 71, 72, 73, 74). Eight studies were identified in which tumor size was measured as an end point for lanreotide SR therapy (Table 2Go). These studies included 263 patients who had pituitary imaging performed before and after variable doses of lanreotide SR for variable lengths of time. Again, tumor shrinkage was variably defined. Overall, 62 of 263 patients (24%) had a decrease in tumor size. For primary therapy patients (defined as patients without prior surgery or radiation therapy, although some had prior octreotide sc or octreotide LAR therapy), 40 of 130 (31%) had tumor shrinkage. However, the ability to interpret these data is limited by the fact that two of the studies looked at the effects of lanreotide after only a short washout from octreotide (69, 71), and another had a treatment period of only 1–3 months (73). Eight of 87 adjunctive therapy patients (9%) experienced tumor shrinkage, with most of these data coming from one study in which the washout period before lanreotide therapy was short (69). In mixed groups in which results were not broken down between primary and adjunctive therapy patients, 14 of 46 (30%) had tumor shrinkage. In one study in this group, patients were preselected for sensitivity to a somatostatin analog, which could have artificially increased the response rate (70).


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  		TABLE 2. Tumor shrinkage rates with lanreotide SR

 
Seven studies were found in which changes in tumor size were measured as an end point for the long-acting SRL formulation, octreotide LAR (Table 3Go) (24, 25, 45, 67, 75, 76, 77). These studies included 180 patients (101 primary and 79 adjunctive) who had pituitary imaging performed before and after variable doses of octreotide LAR for variable lengths of time. Tumor shrinkage was defined differently across the studies. In at least two of the studies, patients were preselected for responsiveness to octreotide, which could artificially increase the response rate (25, 76). Overall, 103 of 180 patients (57%) had a decrease in tumor size. For primary therapy patients (defined as patients without prior surgery or radiation, although some may have been treated with bromocriptine, octreotide sc, or lanreotide SR), 81 of 101 patients (80%) had tumor shrinkage. Again, pretreatment in some studies makes interpretation of results difficult. For adjunctive therapy patients, 22 of 79 patients (28%) experienced tumor shrinkage. For the other long-acting SRL formulation, lanreotide Autogel, no studies evaluating the effects of this product on tumor size have been published as of April 2004.


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  		TABLE 3. Tumor shrinkage rates with octreotide LAR

 
The above data can be combined to look at all somatostatin analogs, regardless of the active compound or type of formulation (Fig. 1Go) (24, 25, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77). These studies included 921 patients who had pituitary imaging performed before and after variable doses of an SRL for variable lengths of time. Overall, 382 of 920 patients (42%) had a decrease in tumor size. For primary therapy patients (patients without prior surgery or radiation therapy but some with previous drug therapy), 231 of 448 patients (52%) had tumor shrinkage. This contrasts with the data in adjunctive therapy patients, in which 52 of 248 patients (21%) experienced tumor shrinkage. In mixed groups, in which the data were not separated for primary and adjuvant therapy patients, 99 of 225 patients (44%) had tumor shrinkage.



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  		FIG. 1. Tumor shrinkage with SRL therapy.

 
In many patients with acromegaly, simply preventing further tumor growth, and thus future mass complications, is a useful treatment outcome. It is therefore helpful to look at the percentage of patients who experienced no further tumor growth during SRL therapy. In the 36 studies reviewed here, only three reported patients with continued tumor growth. Abe and Lüdecke (46) found that six of 90 patients treated with octreotide sc for 4–6 months showed tumor growth. All six were invasive tumors, and maximum tumor diameter increased by a mean of 6.8 mm (range, 3–17); notably, none of these patients had shown any fall in GH/IGF-I with octreotide treatment. Lucas et al. (73) found an increase of greater than 20% in tumor volume in 13 of 73 patients treated per protocol with lanreotide SR for 1–3 months. However, the majority of patients in this study were treated for only 1 month, so the apparent increases in tumor size may have been due to difficulties with accurate tumor measurement. The paper contains no data on the GH and IGF-I responses in this subgroup of patients. Attanasio et al. (68) described one patient who experienced asymptomatic tumor growth after lanreotide SR for 6 months, despite hormonal normalization. The tumor enlargement appeared to be due to cystic expansion. Overall, of the 921 patients surveyed in the 36 studies reviewed here, only 20 experienced further tumor enlargement, suggesting that more than 97% of patients have control of tumor growth on SRL therapy, at least for treatment periods of up to 3 yr. This is a much higher percentage of patients than will experience biochemical control, suggesting that mechanisms other than those involved in controlling hormonal hypersecretion could be operative in controlling tumor growth.


   Predictors of Tumor Shrinkage with SRL Therapy
Top
 Abstract
 Introduction
 Somatostatin Analogs
 Antigrowth Effects of sst...
 Effects of Somatostatin Analogs...
 Predictors of Tumor Shrinkage...
Magnitude of Tumor Shrinkage...
 Summary
 References
 
Patient status regarding prior therapy appears to be a predictor of whether tumor shrinkage will be observed (25, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 78). Tumor shrinkage rates appear to be higher in patients who have not undergone previous surgery or radiation. Across different types of SRL therapy, 229 of 440 of primary therapy patients (52%) showed tumor shrinkage, whereas 49 of 244 of adjuvant therapy patients (20%) experienced tumor shrinkage. These lower shrinkage rates are likely to be caused by changes in tumor anatomy, i.e. scarring and fibrosis, rather than changes in tumor biology or responsiveness to medication.

Tumor size is another factor that may impact whether tumor shrinkage is observed with SRL therapy. However, studies have differed regarding the effect of pretreatment tumor size on susceptibility to shrinkage. Bevan et al. (45) found that 71% of microadenomas shrank by more than 60%, whereas only 35% of macroadenomas shrank to the same degree. However, Ezzat et al. (52) found that macroadenomas were twice as likely to shrink as microadenomas. Amato et al. (67) also found that tumor shrinkage was greater in macroadenomas than microadenomas, as did Cozzi et al. (25). Plöckinger et al. (60) found that pretreatment tumor volume correlated positively with shrinkage. However, both Lucas et al. (73) and Lundin et al. (57) found that initial tumor size did not predict the amount of tumor shrinkage. Overall, these results suggest that both macroadenomas and microadenomas can shrink in response to SRL therapy.

Biochemical response is another factor that has been examined as a predictor of whether SRL therapy will induce tumor shrinkage. Some studies suggest that a biochemical response predicts tumor shrinkage. Abe and Lüdecke (46) found that continued tumor growth on octreotide occurred only in patients with no biochemical response. Arosio et al. (47) found that if GH level was reduced by more than 50%, the tumor shrinkage rate was 58%, but in those in which GH was reduced less than 50%, the tumor shrinkage rate was only 29%. However, these results did not attain statistical significance. Ezzat et al. (52) found that tumor shrinkage occurred only in patients with GH and IGF-I reductions, whereas Lucas et al. (73) found that a positive biochemical response to lanreotide predicted tumor shrinkage. Verhelst et al. (74) found a larger decrease in IGF-I in patients with tumor shrinkage than in those without tumor shrinkage. These studies contrast with a number of other studies that show no relationship between biochemical response and tumor shrinkage. Two papers by Cozzi et al. (25, 72), one with lanreotide SR and the other with octreotide LAR, found that GH/IGF-I suppression did not correlate with tumor shrinkage. Bevan et al. also found no significant relationship between the amount of tumor regression and GH suppression (45). Lundin et al. (57) found that GH suppression did not correlate with tumor shrinkage, as did others (60, 64, 67, 75).

The effect of SRL dosage on tumor shrinkage has also been examined. Ezzat et al. (52) found a possible dose-response effect on tumor shrinkage for octreotide sc. Nineteen percent of patients on octreotide sc 100 µg three times a day (TID) had tumor shrinkage, whereas 37% had tumor shrinkage on 250 µg TID. However, Cozzi et al. (25) found no relationship between tumor shrinkage and the dose of octreotide LAR. Finally, Plöckinger et al. (60) studied the relationship between sst scintigraphy done with 111 indium-pentetreotide and tumor shrinkage. This study found that increased pituitary uptake of 111 indium-pentetreotide did not predict tumor shrinkage.


   Magnitude of Tumor Shrinkage with SRL Therapy
Top
 Abstract
 Introduction
 Somatostatin Analogs
 Antigrowth Effects of sst...
 Effects of Somatostatin Analogs...
 Predictors of Tumor Shrinkage...
 Magnitude of Tumor Shrinkage...
Summary
 References
 
The amount of tumor shrinkage is determined most easily from the studies of de novo patients given primary SRL therapy, and data from the principal studies are shown in Table 4Go. Mean tumor volume reduction was approximately 50%, but there was a wide range of responses. The effect of SRL therapy on pressure effects such as chiasmal compression has not been studied systematically, and, indeed, many of the studies of primary medical therapy specifically excluded patients with chiasmal compression. It is well known that visual field defects may be permanent after previous surgery and/or radiotherapy, and Colao et al. (75) reported four of 21 previously surgically treated patients with visual field defects did not improve during octreotide LAR. By contrast, Amato et al. (67) reported improvement in the visual fields in all three patients with abnormalities in their study of primary SRL therapy.


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  		TABLE 4. Magnitude of tumor shrinkage in de novo patients given primary SRL therapy

 

   Summary
Top
 Abstract
 Introduction
 Somatostatin Analogs
 Antigrowth Effects of sst...
 Effects of Somatostatin Analogs...
 Predictors of Tumor Shrinkage...
 Magnitude of Tumor Shrinkage...
 Summary
References
 
In summary, somatostatin analog therapy is associated with tumor shrinkage in a significant proportion of patients with acromegaly. For all patients reviewed here (921 in 36 reports), regardless of whether they received prior therapy or the type of SRL received, 42% showed tumor shrinkage. For patients receiving a SRL as primary medical therapy, the number was even higher, with 52% of patients showing tumor shrinkage vs. 21% for adjuvant therapy patients. The fact that many primary therapy patients had been pretreated with another medical therapy may mean that the degree of tumor shrinkage was underestimated in some studies. The finding that primary therapy patients experienced greater tumor shrinkage than adjuvant therapy patients was consistent across all the studies reviewed; an average tumor volume reduction of 50% was observed. Other variables, including pretreatment tumor size, biochemical response to therapy, and positive sst scintigraphy, were less consistent in predicting tumor shrinkage. Fewer than 3% of patients were shown to have tumor enlargement during SRL therapy. The control of tumor growth in nearly all patients, with a substantial proportion showing tumor shrinkage, is an important consideration in selecting a SRL as medical therapy for acromegaly.


   Footnotes
 
J.S.B. has received research funding, lecture honoraria, and consulting fees from Novartis, Ipsen and Pfizer during the past 5 yr.

First Published Online December 21, 2004

Abbreviations: SRL, sst ligand; sst, somatostatin receptor; TID, three times a day.

Received June 14, 2004.

Accepted December 7, 2004.


   References
Top
 Abstract
 Introduction
 Somatostatin Analogs
 Antigrowth Effects of sst...
 Effects of Somatostatin Analogs...
 Predictors of Tumor Shrinkage...
 Magnitude of Tumor Shrinkage...
 Summary
 References
 

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