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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 9 3104-3109
Copyright © 1998 by The Endocrine Society

Original Studies

Long-Acting Lanreotide Induces Clinical and Biochemical Remission of Acromegaly Caused by Disseminated Growth Hormone-Releasing Hormone-Secreting Carcinoid

Marlys R. Drange and Shlomo Melmed

Division of Endocrinology and Metabolism, Cedars-Sinai Research Institute, University of California School of Medicine, Los Angeles, California 90048

Address all correspondence and requests for reprints to: Shlomo Melmed, M.D., Division of Endocrinology and Metabolism, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, B-131, Los Angeles, California 90048. E-mail: melmed{at}cshs.org


   Abstract
Top
 Abstract
Introduction
 Case Report
 Materials and Methods
 Results
 Discussion
 References
 
Ectopic GHRH-secreting tumors, such as carcinoid, rarely cause acromegaly. As protracted exposure to high levels of GH is associated with considerable morbidity and mortality, these patients require early and effective medical therapy to control hormonal hypersecretion. We employed a prolonged release somatostatin analog, lanreotide, to treat a patient with disseminated GHRH-producing carcinoid. Before treatment, the patient had a biochemical profile characteristic of active acromegaly. Plasma GHRH levels were markedly elevated (200-fold), and urinary 5-hydroxyindolacetic acid (5-HIAA) levels were increased (4-fold). Magnetic resonance imaging revealed a large asymmetrical pituitary mass consistent with somatotroph hyperplasia. Somatostatin receptor scintigraphy revealed multiple bony and soft tissue lesions as well as striking pituitary uptake. Lanreotide (30 mg) was administered weekly by im injection for 12 weeks. Rapid and sustained symptomatic clinical improvement with diminished soft tissue swelling and hyperhidrosis was observed. GHRH levels decreased by 70%; glucose-suppressed GH and insulin-like growth factor I levels were reduced by 90% and 75%, respectively, to near normal values; urinary 5-HIAA levels normalized; and the pituitary mass remained unchanged. Unfortunately, the patient died due to complications of osteogenic sarcoma. In conclusion, prolonged release lanreotide induced clinical and biochemical remission in this patient with diffusely metastatic GHRH-producing carcinoid. This long-acting drug thus offers an effective, well tolerated, and convenient medical therapy for control of hormonal hypersecretion induced by excess GHRH.


   Introduction
Top
 Abstract
 Introduction
Case Report
 Materials and Methods
 Results
 Discussion
 References
 
ACROMEGALY, characterized by hypersecretion of GH, is generally caused by autonomous secretion of GH from a benign pituitary tumor resulting from clonal somatotroph expansion (1, 2). However, extrapituitary GHRH-producing tumors, such as carcinoid or pancreatic islet cell tumors, may rarely induce excessive GH secretion with resultant acromegaly (3, 4, 5, 6). Hypersomatotropism is associated with a reduced quality of life and increased mortality rate due to excess deaths from cardiac, respiratory, or malignant disease (7). The treatment of choice for acromegaly is surgical excision of the underlying tumor (8). Unfortunately, many GHRH-producing tumors are metastatic at the time of diagnosis and not amenable to surgical resection (6). Standard chemotherapy directed at GHRH-producing carcinoid tumors is generally unsuccessful at treating the activated GH axis (6, 9). Furthermore, resection or irradiation of the pituitary in an attempt to prevent excessive GH production is often ineffectual due to the inability to overcome the persistent stimulatory drive of ectopic GHRH (3, 10, 11). Thus, effective medical therapies for acromegaly due to ectopic GHRH production have been sought.

Octreotide, a long-acting somatostatin analog, with a 1.7-h circulating half-life (12), is accepted as a viable medical therapy for eutopic pituitary acromegaly (1, 8, 13). It has also been used in the past decade to manage ectopic acromegaly (11, 14, 15, 16, 17). Furthermore, somatostatin analog therapy may retard tumor progression in some patients with neuroendocrine tumors (14, 18, 19, 20). Administration of octreotide by continuous sc infusion has been shown to achieve superior and more sustained control of GH levels than intermittent repeated sc injections in pituitary-based acromegaly (21, 22, 23) and with GHRH-secreting carcinoid tumors (16, 17). Presumably, a somatostatin analog with a longer half-life would maintain a sustained drug concentration similar to a continuous infusion of octreotide. Indeed, a recently developed somatostatin formulation, lanreotide (BIM 23014), comprised of a cyclic octapeptide somatostatin analog encapsulated in microspheres, has a half-life of 4.5 days compared to 1.7 h for octreotide (24). Lanreotide was demonstrated to be as effective in controlling GH hypersecretion as multiple injections (25, 26) or a continuous infusion of octreotide (27) in patients with GH-secreting pituitary adenomas. Thus, this prolonged release formulation eliminates the need for multiple daily injections or infusion pump while maintaining the benefit of continuous infusion therapy.

We now report the first case in which prolonged release lanreotide was employed in the treatment of a patient with extrapituitary acromegaly caused by widely disseminated metastatic GHRH-producing carcinoid.


   Case Report
Top
 Abstract
 Introduction
 Case Report
Materials and Methods
 Results
 Discussion
 References
 
A 42-yr-old male engineer with history of metastatic carcinoid was referred for evaluation of acromegaly. A bronchial carcinoid tumor had been removed by right pneumonectomy in 1969. Carcinoid recurrence was demonstrated by bone biopsy in 1980. As a bone scan revealed diffuse metastases, he underwent local external beam irradiation. In 1983, he was unsuccessfully treated with a 12-month course of cyclophosphamide, methotrexate, and 5-fluorouracil followed by a brief trial of dacarbazine. By 1994, multiple liver lesions and a left pleural mass were observed in addition to diffuse skeletal metastatic deposits. Several pathological fractures were treated palliatively by radiotherapy, and he also underwent spinal decompression surgery in 1995 for lumbar involvement refractory to irradiation. At that time, acromegaly was considered, and a random GH value was reportedly elevated. However, the patient was lost to follow-up.

He presented in 1997 with a history of enlarging shoe size, soft tissue swelling of hands and feet, excessive perspiration, fatigue, difficulty chewing, decreased libido, secondary infertility, pretibial edema, asymptomatic hyperglycemia, and hypertension. At no time did the patient experience symptoms of carcinoid syndrome. He had typical acromegalic facial features and acral changes. Review of photographs revealed subtle acromegalic physical changes as early as 1980. Physical exam was also notable for mildly eunuchoidal body habitus, marked hepatomegaly, kyphoscoliosis, and the absence of visual field defects.

Endocrine evaluation (summarized in Table 1Go) showed elevated insulin-like growth factor I (IGF-I) and serum GH levels. Serum GH levels responded paradoxically to both oral glucose suppression and TRH stimulation tests. The subject’s plasma GHRH concentration was markedly elevated at 6.9 µg/L (normal, <0.05 µg/L). Urinary 5-hydroxyindolacetic acid (5-HIAA) levels were also increased. Serum PRL, LH, and FSH levels were mildly elevated. Magnetic resonance imaging of the pituitary (Fig. 1Go) revealed an asymmetrical pituitary mass measuring approximately 1 cm in height by 1.8 cm in the anteroposterior direction and 2 cm laterally. No discrete pituitary adenoma or hypothalamic defects were visualized. Bone scan revealed multiple calvarial and diffuse skeletal lesions.


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  		Table 1. Results of baseline diagnostic endocrine evaluation

 


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  		Figure 1. Magnetic resonance imaging. A coronal view with gadolinium obtained before initiation of treatment reveals a homogeneous intrasellar mass measuring 1 x 2 cm. A repeat scan obtained after 12 weeks of treatment with lanreotide showed no change in appearance of the mass.

 
Treatment with lanreotide was subsequently initiated. During the course of treatment, the patient was diagnosed with radiation-induced osteogenic sarcoma at the site of a previously treated pathological fracture. Although an aggressive chemotherapeutic regimen was instituted, the patient died due to osteogenic sarcoma complications. Autopsy was not performed.


   Materials and Methods
Top
 Abstract
 Introduction
 Case Report
 Materials and Methods
Results
 Discussion
 References
 
This clinical study was performed after obtaining approval by the institutional review board, informed consent from the patient, and FDA investigational new drug approval for compassionate use of an unapproved drug for individual treatment.

Medication

A prolonged release formulation of lanreotide (IPSTYL) was provided by the Henri Beaufour Institute (Milford, MA), the United States agent for Ipsen Biotech (Paris, France).

Treatment protocol and assessment

Before initiation of therapy with lanreotide, whole body somatostatin receptor scintigraphy was performed, and baseline biochemical evaluation was repeated. Initial injection was considered as a test dose with close observation for adverse reactions and frequently scheduled biochemical monitoring. Subsequently, the patient received 30 mg prolonged release lanreotide weekly by im injection in alternating hips.

Patient assessment included weekly self-reports of symptom relief and adverse effects. Physical examination was performed at injection weeks 1, 2, 4, 8, and 12. Laboratory monitoring was performed at scheduled intervals with decreasing frequency, i.e. every 2 h for the first 12 h after initial injection, at 24 h, then every 2 days for 1 week, then biweekly beginning in the second week after treatment initiation. After the initial test dose period, GH levels were measured before and 2 h after a 75-g oral glucose load. Specimens were all obtained before administration of the subsequent dose of lanreotide, as drug levels peak approximately 2 h after administration (24), and it was thought that this may affect the test results. Urinary 5-HIAA values were determined after a 3-day appropriate diet. A repeat magnetic resonance imaging scan of the pituitary was obtained after 12 weeks of treatment to assess the impact of therapy on the size of the intrasellar mass.

Assays

GHRH levels were measured as a single batch by commercial enzyme immunoassay at Nichols Institute (San Juan Capistrano, CA). Plasma samples for GHRH determinations were collected in treated tubes provided by Nichols Institute containing a proprietary cocktail of heparin and protease inhibitors and were stored at -70 C until all samples had been accumulated for measurement in the same assay. All other laboratory evaluations were performed by Endocrine Sciences (Calabasas Hills, CA).


   Results
Top
 Abstract
 Introduction
 Case Report
 Materials and Methods
 Results
Discussion
 References
 
Clinical course

Treatment with lanreotide by weekly injection resulted in rapid and sustained symptomatic improvement. The patient and his family reported an increase in energy and an improved sense of well-being. Diminution of perspiration, leg edema, and soft tissue swelling of the hands was noted by the subject and confirmed on physical exam. The drug was well tolerated with minimal adverse effects, including mild discomfort, ecchymosis, or transient sc swelling at the injection site.

Biochemical evaluation

The effect of lanreotide injection on plasma GHRH and serum GH levels in the 12-h period immediately after administration of the initial dose is shown in Fig. 2Go (inset). GHRH levels were elevated more than 200-fold above normal before treatment. Lanreotide attenuated peripheral GHRH levels by 50% within 4 h after administration, and this level of suppression was maintained for the remainder of the interdose period. In contrast, serum GH levels were suppressed 2–4 h after injection of the drug, then returned to baseline pretreatment values within 24 h.



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  		Figure 2. Effects of lanreotide treatment on plasma GHRH, serum GH and IGF-I, and urinary 5-HIAA levels. Inset, Acute effects of lanreotide (30 mg) on plasma GHRH ({blacksquare}) and serum GH (•) after initial im injection of lanreotide. Long term effects of lanreotide treatment (30 mg weekly) on plasma GHRH ({blacksquare}), serum GH 2 h after 75 g oral glucose ({square}), plasma IGF-I ({blacktriangleup}), and urinary 5-HIAA ({diamondsuit}) measured immediately before indicated injection (at lanreotide trough, 7 days after previous injection). Dashed lines represent the upper limit of the normal range. Arrows indicate lanreotide administration.

 
Figure 2Go depicts hormone levels measured at the end of an interdose period (7 days after the previous injection). Treatment with lanreotide resulted in suppression of GHRH concentrations by 70% when measured at the lanreotide trough, although values remained elevated above the normal range at that time point. Glucose-suppressed GH and IGF-I concentrations at the end of the interdose period were substantially reduced (90% and 75%, respectively). Furthermore, the paradoxical response of GH to glucose was attenuated. Urinary excretion of 5-HIAA normalized. Electrolytes, blood counts, and renal and liver function analyses remained within normal ranges (data not shown). Carbohydrate intolerance improved in the latter weeks of therapy based on normalization of 2-h postglucose values. However, the hemoglobin A1c value after more than 3 months of therapy did not reflect this change (8.4% pretreatment vs. 8.5%).

Imaging

Somatostatin receptor scintigraphy (Fig. 3Go) using indium 111-labeled octreotide demonstrated increased activity in multiple areas of the skull, bilateral humerus, femurs, and tibias. There was soft tissue activity in the neck, chest, and axilla. Notably, the pituitary gland appeared enlarged and exhibited intense scintigraphic activity (Fig. 4Go).



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  		Figure 3. Whole body somatostatin receptor scintigraphy. Indium-111-labeled octreotide was used for somatostatin receptor scintigraphy. Increased activity is present in bilateral humerus, femurs, and tibia. Multiple areas of the calvarium as well as areas in the soft tissue of the neck, chest, and axilla also exhibit increased activity.

 


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  		Figure 4. Somatostatin receptor scintigraphy: lateral view of head. The central area of intense activity (arrow) corresponds to the enlarged pituitary.

 
The size and appearance of the intrasellar mass after 12 weeks of treatment were unchanged compared to those in the initial pituitary magnetic resonance image (Fig. 1Go).


   Discussion
Top
 Abstract
 Introduction
 Case Report
 Materials and Methods
 Results
 Discussion
References
 
Ectopic GHRH-secreting tumors account for less than 1% of all cases of acromegaly (1). Approximately 50 cases have been reported in the literature to date (3, 4, 5, 6). Clinical presentation of ectopic acromegaly is indistinguishable from that of a GH-secreting pituitary adenoma, requiring demonstration of elevated plasma GHRH levels for diagnosis. Indeed, plasma GHRH levels are commonly elevated as much as 100- to 300-fold in patients with peripheral GHRH-secreting tumors compared with almost undetectable concentrations in patients with pituitary acromegaly or excess GHRH production by hypothalamic tumors (28). Moreover, patients with acromegaly, regardless of underlying etiology, exhibit the same sequelae of prolonged exposure to elevated GH and its target hormone, IGF-I. Early diagnosis and effective therapy are crucial to improve quality of life and normalize life expectancy.

Lanreotide has been successfully used to control symptoms of carcinoid syndrome (flushing and diarrhea) in patients with gastrointestinal carcinoid (29). It has also been used to manage acromegaly due to pituitary adenoma (25, 26, 27, 30, 31, 32). However, this drug has not yet been approved by the FDA for use in the United States and is currently under investigation for the treatment of pituitary acromegaly in multicenter trials. Thus, although the shorter acting octreotide has been used to control hormonal hypersecretion in patients with acromegaly due to GHRH-secreting extrapituitary tumors, this report represents the first case in which the long-acting analog, lanreotide, was employed for this purpose.

The presence of high numbers of high affinity somato-statin-binding sites on most endocrine tumors, including carcinoid (18, 33), can be exploited for diagnostic and therapeutic purposes in patients with ectopic acromegaly and is the basis of treating these tumors with somatostatin analogs. These analogs interrupt the pathophysiological process generated by autonomous GHRH secretion through inhibition of GH secretion from the anterior pituitary as well as suppression of tumoral elaboration of GHRH (15). Signal intensity on somatostatin receptor scintigraphy corresponds to the number of somatostatin-binding sites and has a good predictive value for determining the response to somatostatin analog therapy (20, 33, 34, 35). Also, this imaging modality is very sensitive (87–96%) in detecting small lesions (35), which makes it beneficial for localizing metastases or primary lesions not detected by conventional imaging techniques. In our patient, somatostatin receptor scintigraphy revealed the diffuse and extensive nature of the disease and predicted that lanreotide treatment would be effective.

Indeed, all biochemical markers of disease activity were significantly improved after 2 months of therapy. GHRH levels were substantially, but incompletely, suppressed, and GH and IGF-I were also suppressed. These findings are consistent with other reports of GHRH-secreting tumor-induced acromegaly effectively treated with octreotide (14, 15, 16, 17).

GHRH levels were suppressed 2 h after the initial injection and remained stably suppressed until the subsequent injection. This suggests that the marked, but transient, serum GH suppression that occurred in that time period represents direct lanreotide-induced inhibition of GH secretion at the pituitary level, rather than a secondary effect of diminished GHRH levels. Importantly, the time point at which GH was maximally suppressed corresponds to peak plasma lanreotide levels (24). However, the 30-mg depot dose used in this and previous clinical studies was designed to reduce serum GH levels in patients with acromegaly (presumably eutopic) for up to 2 weeks (24). These observations suggest that higher plasma lanreotide concentrations may be required in patients with ectopic acromegaly, particularly when the tumor burden is extensive, to achieve maximal direct inhibition of somatotroph secretion.

Despite the transient suppression of circulating GH after the initial lanreotide injection, continued treatment with lanreotide resulted in a progressive decline of GH and IGF-I levels to near-normal values, whereas GHRH levels declined at a slower rate and remained substantially elevated. This differential sensitivity between suppression of circulating GH vs. GHRH has been attributed to direct inhibition of GH secretion. Indeed, it has previously been suggested that direct inhibition of GH secretion is the predominant action of exogenous somatostatin and is more important for overall control of deleterious sequelae of acromegaly than is attenuation of GHRH hypersecretion in these patients (15, 17).

The carcinoid tumor burden in this patient may have been too great to achieve complete inhibition of peripheral GHRH secretion at the dose of lanreotide used. Alternatively, there is evidence that some GHRH secreted from ectopic tumors may have reduced bioactivity due to chemical modifications (5, 15). Indeed, immunohistochemical studies indicate that more than 25% of carcinoid tumors contain GHRH immunoreactivity, but clinical consequences are rarely associated with this (4). These observations suggest either that tumor-produced GHRH is secreted in insufficient quantities or with insufficient bioactivity to cause acromegaly. As high performance liquid chromatographic analysis was not performed, we cannot exclude the possibility that the partial suppression of GHRH by lanreotide observed in this patient was due to residual inactive GHRH metabolites.

An enlarged pituitary is often encountered in patients with ectopic GHRH-secreting tumors (1). Generally, this intrasellar mass represents somatotroph hyperplasia (3, 4, 36, 37); however, adenomatous transformation has occasionally been reported (1). Although, the patient had a pituitary mass visualized on magnetic resonance imaging, no discrete tumor was visualized. Histological examination is required for accurate differentiation of hyperplasia from adenoma. Interestingly, the subject’s pituitary mass exhibited very high signal intensity on somatostatin receptor scintigraphy. Lamberts et al. report a similar finding in a patient with somatotroph hyperplasia due to a GHRH-secreting pancreatic islet cell tumor (34). Moreover, octreotide therapy results in tumor shrinkage in up to 50% of patients with GH-secreting pituitary adenomas within the first 3 months of treatment (38). Given the predictive value of somatostatin receptor scintigraphy, one might have expected lanreotide administration to result in intrasellar mass regression. However, no appreciable tumor shrinkage was apparent despite substantial suppression of serum GH values. This finding is consistent with a previous report in which a hyperplastic pituitary mass failed to regress after 4 months of octreotide therapy (36) and in contrast to other studies employing octreotide, which demonstrated reduction of pituitary size (11, 14). These discrepant results most likely reflect differences in suppression of bioactive GHRH, as somatotroph hyperplasia may be maintained if suppression is inadequate. It is unclear if a longer duration of treatment or higher doses would have achieved more effective GHRH attenuation and resulted in pituitary shrinkage.

In conclusion, early diagnosis and effective treatment are critical to obviate the deleterious effects associated with acromegaly, even in patients whose primary underlying disorder is a slow growing neuroendocrine tumor. The prolonged release formulation of lanreotide successfully induced clinical and biochemical remission in this patient with acromegaly due to widely disseminated carcinoid. This drug thus offers an effective, well tolerated, and convenient medical therapy for control of hormonal hypersecretion induced by excess GHRH.

Received March 25, 1998.

Revised May 22, 1998.

Accepted May 29, 1998.


   References
Top
 Abstract
 Introduction
 Case Report
 Materials and Methods
 Results
 Discussion
 References
 

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Hormonal and Volumetric Long Term Control of a Growth Hormone-Releasing Hormone-Producing Carcinoid Tumor
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Comment on Long-Acting Lanreotide Inducing Clinical and Biochemical Remission of Acromegaly Caused by Disseminated GHRH Secreting Carcinoid
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