Somatostatin Analogues in the Treatment of Gastroenteropancreatic Neuroendocrine Tumors

REVIEW SOMATOSTATIN ANALOGUES IN GEPNETS

Somatostatin Analogues in the Treatment of Gastroenteropancreatic Neuroendocrine Tumors THIERRY DELAUNOIT, MD; JOSEPH RUBIN, MD; FLORENCE NECZYPORENKO, MD; CHARLES ERLICHMAN, MD; AND TIMOTHY J. HOBDAY, MD Gastroenteropancreatic neuroendocrine tumors constitute a heterogeneous group of neoplasms that are often associated with typical symptoms due to excessive and uncontrolled release of diverse hormones. Because these tumors are usually slow growing, surgery is the cornerstone of treatment. However, these rare tumors can present with rapid progression that requires aggressive systemic therapy or diffuse metastatic disease not amenable to surgical palliation. For most patients, medical approaches are necessary at some point in the course of their disease, especially since most tumors are at an advanced stage at the time of diagnosis. Most gastroenteropancreatic neuroendocrine tumors express high levels of somatostatin receptors, which are bound by somatostatin or its synthetic analogues. These agents, alone or combined with other therapies, such as interferon or radioisotopes, are therefore used frequently to control hormone-related symptoms and, for some patients, the growth of the disease itself. This article reviews the evidence for the use of somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine tumors based on a MEDLINE search of literature published from January 1970 to July 2003.

Mayo Clin Proc. 2005;80(4):502-506 GEPNET = gastroenteropancreatic neuroendocrine tumor; PR = partial response; SST = somatostatin; SSTR = SST receptor

G

astroenteropancreatic neuroendocrine tumors (GEPNETs), including gastrointestinal carcinoid tumors and pancreatic islet cell carcinomas, are rare malignancies derived from neuroendocrine cells scattered along the gastrointestinal system. GEPNETs are often characterized by the production of hormones and bioactive substances. They are generally slowly progressive and may present with typical clinical symptoms related to excessive and uncontrolled release of diverse hormones. Production of serotonin may cause flushing and diarrhea, as in the classic carcinoid syndrome. Catecholaminergic and neuroglycopenic symptoms, such as fatigue, weakness, tremulousness, and hunger, may result from excess insulin. Production of adrenocorticotropic hormone or cortisol may cause the myriad symptoms of steroid hormone excess. HypergasFrom the Department of Oncology (T.D., J.R., C.E., T.J.H.) and Molecular Medicine Program (F.N.), Mayo Clinic College of Medicine, Rochester, Minn. Drs Delaunoit and Neczyporenko are now with the Institut Jules Bordet, Brussels, Belgium. Dr Delaunoit has been supported by Amis de l’Institut Bordet and a grant from Yvonne and Thomas Rucquois. Individual reprints of this article are not available. Address correspondence to Timothy J. Hobday, MD, Department of Oncology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). © 2005 Mayo Foundation for Medical Education and Research

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trinemia may cause diarrhea and fulminant peptic ulcer disease, whereas glucagon production may result in diabetes mellitus and necrolytic migratory erythema. Some patients may have excessive production of multiple hormones.1,2 Treatment of such a heterogeneous group of tumors and symptoms represents a challenge for the physician. The choice of treatment for GEPNETs depends primarily on the pathologic differentiation and stage at diagnosis but also on the presence of symptoms related to hormonal secretion. Often, these tumors are slow growing and sometimes can be managed with clinical observation only. However, they can display accelerated progression, requiring a much more aggressive strategy. Surgery remains the only curative approach to GEPNETs. However, these malignant tumors are generally diagnosed at an advanced stage when cure cannot be achieved. To date, several approaches have been used to control tumor growth in advanced disease, whether due to bulky disease or hormonal secretions, and to improve quality of life in symptomatic patients. Surgery should always be considered an option, even in advanced cases, to control symptoms related to tumor bulk and/or excessive hormone production. Somatostatin (SST) analogues are important agents in the medical treatment of GEPNETs. They not only can reduce secretion of hormones and hence control hormone-related symptoms but also are capable of controlling disease progression. This article reviews the evidence for the use of SST analogues in the treatment of GEPNETs based on a MEDLINE search of literature published from January 1970 to July 2003. Primary search terms included carcinoid tumor, islet cell carcinoma, neuroendocrine tumor, octreotide, and interferon. SST AND ITS ANALOGUES Somatostatin is a natural small cyclic peptide hormone synthesized as part of a large prohormone molecule that is enzymatically cleaved into its active form. Somatostatin is secreted at multiple sites throughout the human body, including the digestive system.3 Its activity is mediated through 5 specific SST receptors (SSTRs) (SSTR-1 to SSTR-5) located on the membrane of the target cells. Somatostatin receptor 3 mediates apoptosis in endocrine cells, whereas inhibition of cell proliferation is mediated by activation of SSTR-1, SSTR-2, and SSTR-5, inducing antimitotic effects

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SOMATOSTATIN ANALOGUES IN GEPNETS

TABLE 1. Somatostatin Analogues in the Treatment of Gastroenteropancreatic Neuroendocrine Tumors Somatostatin analogue Octreotide Long-acting octreotide Lanreotide Prolonged-release lanreotide

Administration

Dosage

Subcutaneous Intramuscular Subcutaneous

100-300 µg every 8 h 20-30 mg every 28 d 750-3000 µg every 8 h

Intramuscular

30 mg every 14 d

in most cell types.4-7 Expression of SSTR-2 and SSTR-5 is particularly high in GEPNETs. Both SSTR-2 and SSTR-5 are found in approximately 90% and 80% of tumors, respectively, making these tumors potentially sensitive to hormonal treatment that targets these receptors.8,9 The presence of SSTR in malignant GEPNETs appears to correlate with response to SST analogues, as shown by Kvols et al.10 They performed autoradiography using 125I-Tyr3-SMS 201-995, a tyrosine-substituted analogue of octreotide, in 8 patients with GEPNETs. All were strongly positive for SSTR and showed symptomatic improvement along with a decrease in secretion of at least 1 hormone when treated with octreotide.10 Because of extremely rapid blood clearance and postinfusion hormonal hypersecretion rebound, native SST is no longer used in the treatment of GEPNETs and has been replaced by synthetic analogues. The available SST analogues, octreotide and lanreotide (Table 1), have been shown to have a strong affinity for SSTR-2 and SSTR-5 and demonstrate, in vitro and in vivo, antisecretory and antiproliferative effects but no postadministration hypersecretion rebound.8,10 Both octreotide and lanreotide have a longer duration of action compared with SST and can be administered subcutaneously or intramuscularly every 8 hours. Prolonged-release formulations now allow drug ad-

ministration every 2 to 4 weeks. Both octreotide and lanreotide have been shown to be efficacious in managing symptoms and tumor progression compared with standard doses of short-acting SST analogues.11,12 Only octreotide is available in the United States. During the past 30 years, several studies have been performed to assess the tolerability and efficacy of different types and doses of SST analogues in GEPNETs, including pancreatic neuroendocrine tumors and carcinoid tumors.7,11,13-31 The results of these studies are summarized in Table 2. All studies have assessed treatment by radiological objective response, hormonal response, or both. In most of the trials performed to date, symptomatic improvement has also been evaluated. No major difference has been observed among the various agents and modes of administration. In general, SST analogues are safe, easy to use, and generally well tolerated, with most patients experiencing at most mild adverse effects. Flatulence, diarrhea, and abdominal pain are seen in less than 10% of patients. Steatorrhea, nausea, vomiting, hyperglycemia or hypoglycemia, leg cramps, blurred vision, night sweats, or pain at injection site is experienced less often. With long-term use of SST analogues, cholelithiasis has been reported in 20% or more of patients. Treatment discontinuation related to adverse effects is rare. Objective tumor responses occur in 5% to 15% of patients and appear to be more frequent in those with carcinoid tumors. Stable disease is observed in approximately 40% of treated patients. Biological response and symptomatic improvement are seen in a large proportion of patients (Tables 2 and 3), with a median duration of response between 6 and 17 months. On the basis of these studies, SST analogues appear to be useful in the management of symptomatic disease related to either hormonal secretion or tumor burden.

TABLE 2. Octreotide Studies in Gastroenteropancreatic Neuroendocrine Tumors* Reference

No. of patients

Arnold et al, 1996 Maton et al,20 1989 Kvols et al,23 1987 Ruszniewski et al,22 1993 Eriksson et al,28 1990 Eriksson & Oberg,27 1993 di Bartolomeo et al,15 1996 Saltz et al,13 1994 Ricci et al,31 2000

52 107 22 4 14 19 58 34 15

14

Shojamanesh et al,26 2002

15

Tomassetti et al,25 1998

16

Rubin et al,11 1999

Response (%)

26 vs 22/20/25

Agent

Dosage

OR

SD

Octreotide Octreotide Octreotide Octreotide Octreotide Octreotide Octreotide Octreotide Long-acting octreotide Long-acting octreotide Long-acting octreotide Octreotide vs long-acting octreotide

200 µg 3 times daily Various doses 150-500 µg 3 times daily 200 µg twice daily 100 µg twice to 3 times daily 100 µg twice daily 500-1000 µg 3 times daily 250 µg 3 times daily 20 mg/mo

0 7.5 NR NR 28.6 NR 3 0 7

20-30 mg/mo 20 mg/mo 300-900 µg/d (total dose) vs 10/20/30 mg/mo

BR

SR

36.5 39 NR NR 21.4 31.6 46.5 50 40

74 79.4 68.2 75 28.6 31.6 77

NR 67.3 100 100 NR NR 73

6

47

NR

NR

0

87.5

81

100

NR

NR

41

71†

NR

82

58 vs 67/71/62

*BR = biochemical response; NR = not reported; OR = objective response; SD = stable disease; SR = symptomatic response. †Combined end point. Mayo Clin Proc.

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TABLE 3. Lanreotide Studies in Gastroenteropancreatic Neuroendocrine Tumors* Response (%)

No. of patients

Reference Eriksson et al, 1997 Imam et al,7 1997 Faiss et al,24 1999 Ricci et al,29 2000

19 8 30 25

Scherubl et al,21 1994

18

Tomassetti et al,25 1998

18

Ruszniewski et al,30 1996

39

Wymenga et al,17 1999

55

16

Agent Lanreotide Lanreotide Lanreotide Prolonged-release lanreotide Prolonged-release lanreotide Prolonged-release lanreotide Prolonged-release lanreotide Prolonged-release lanreotide

Dosage

OR

SD

BR

SR

4 mg 3 times daily 4 mg 3 times daily 5 mg 3 times daily 30 mg every 14 d

5 0 6.7 8

70 87.5 37 40

58 62.5 NR 42

NR 100 NR 65

30 mg every 10-14 d

NR

39

NR

30 mg every 10 d

0

77.7

NR

30 mg every 14 d

0

NR

18

30 mg every 14 d

6

81

38

86/42/50, F/D/A 100 39/30, F/D 42

*A = abdominal pain; BR = biochemical response; D = diarrhea; F = flushing; NR = not reported; OR = objective response; SD = stable disease; SR = symptomatic response.

Several authors have suggested a dose-dependent antiproliferative effect of octreotide or lanreotide on GEPNET growth. Imam et al7 evaluated apoptotic effects of octreotide on neuroendocrine tumors using BON-1, a human serotonin-secreting pancreatic endocrine tumor cell line xenografted into nude mice. They showed a 3-fold increase in apoptotic cells in mice receiving treatment with highdose octreotide (600 mg/kg daily) compared with a placebo group (P<.001). Standard doses of octreotide (100-1500 µg/d) or lanreotide (30 mg every 14 days) seemed slightly less effective than high doses of both drugs. In parallel to their preclinical study, Imam et al also studied apoptosis of tissue samples in 8 patients with neuroendocrine tumors treated with high doses of lanreotide (12 mg/d) and 8 patients treated with interferon (4 patients), standard-dose SST analogues (3 patients), or both (1 patient). The percentage of apoptotic cells was correlated with clinical outcome. After 6 and 12 months of treatment, 5 patients treated with high-dose lanreotide showed a biochemical response, 4 of whom also showed an increase in apoptotic index. No objective response was seen. None of the 8 patients treated in the other cohort showed any increase in apoptotic cells.7 Of 19 patients with progressive GEPNETs treated with high-dose lanreotide (12 mg/d), Eriksson et al16 reported 1 patient with partial response (PR) and 12 with stable disease. Induction of apoptosis, determined by posttreatment tumor biopsies, was observed in patients with biochemical and radiological responses as well as those with stable disease. This induction of apoptosis suggests potential activation of SSTR-3, which mediates apoptosis, when high doses of SST analogues are used. Faiss et al24 reported an overall response rate of 6.7% and 11 patients with stable disease in a trial that used a high dose of lanreotide (15 mg/d) in 30 patients with advanced and progressive GEPNETs. The clinical outcomes in these small phase 2 studies are not clearly superior to those 504

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observed in the literature with regular doses. On the basis of these observations, further studies are needed to assess the exact role of high doses of SST analogues and the SST/ SSTR-3 pathway in induction of apoptosis and control of growth in GEPNETs. Currently, no convincing evidence exists to support the use of SST analogues at high doses. The tumor growth rate before treatment seems to have a significant predictive value for tumor response to SST analogues. Aparicio et al32 showed 76% disease stabilization in a group defined as having slowly progressing disease compared with only 33% in patients classified as having rapidly progressing disease. More recently, another study, which included 15 patients with gastrinomas, showed that none of the patients responding to therapy belonged to the group defined as having rapidly progressing disease.26 Therefore, tumor growth rate before treatment must be taken into account when SST analogues are considered as therapy for disease progression. Some authors have suggested that there is incomplete cross-resistance between the SST analogues lanreotide and octreotide. Ricci et al31 studied 15 patients previously treated with long-acting lanreotide and showed that 1 and 6 patients experienced radiological PR and stable disease, respectively, when treated with long-acting octreotide. The same group administered long-acting lanreotide to 5 patients previously treated with subcutaneous octreotide.29 Objective, symptomatic, and biochemical responses were observed in 1, 2, and 1 patients, respectively. These results, although interesting, were achieved in small numbers of patients and therefore allow no firm conclusions. Few data are available regarding any benefit of SST analogues on survival of patients with GEPNETs. To date, no prospective randomized trial has been performed in patients with GEPNETs treated with SST analogues compared with observation. Additional studies are necessary to determine any convincing effect of SST analogues on survival.

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SOMATOSTATIN ANALOGUES IN GEPNETS

SST ANALOGUES IN COMBINATION WITH INTERFERON ALFA Somatostatin analogues and interferon alfa, used as single agents, are safe and have some activity for progressive GEPNETs. Combination therapies have been evaluated in clinical trials. Adding interferon alfa (3 × 106 IU 3 times a week) to the regimen of patients previously treated with octreotide alone was shown to produce biochemical responses in 77% of the patients enrolled in the study of Tiensuu Janson et al33 without objective tumor response. Frank et al34 described their experience with interferon alfa, 5 × 106 IU twice a week, in 21 patients with progressive GEPNETs, 16 of whom were previously treated with octreotide. They observed 1 patient with a complete response and 13 with stable disease, 11 of whom were previously treated with octreotide. Biochemical response, with more than 50% reduction of hormone secretion, was achieved in 69% of patients. More recently, Fjallskog et al35 published their results in 16 patients with progressive pancreatic neuroendocrine tumors treated with various doses of interferon alfa (3-5 × 106 IU 3-7 d/wk, titrated to toxicity); 3 had PR and 11 had stable disease. Median duration of response was 23 months, whereas it was 13 months for stable disease. Interestingly, all patients previously treated with SST analogues experienced stable disease, whereas 1 and 5 patients previously treated with interferon alfa monotherapy had PR and stable disease, respectively. Biochemical responses were observed in 10 patients, with a median duration of 22 months. In contrast to these studies, Faiss et al36 showed, in a prospective, randomized, multicenter trial, that the combination of lanreotide and interferon alfa (5 × 106 IU 3 times a week) had no higher antiproliferative effect than that of monotherapy with lanreotide or interferon alfa in 80 therapynaive patients with progressive and metastatic GEPNETs. However, hormone-related symptoms were significantly better controlled with the combination. The toxic effects reported in these studies were described as moderate and were predominantly related to interferon alfa (fever, anorexia, depression, confusion, arthralgia, and pain at injection site). Two patients experienced grade 3 confusion responsible for treatment cessation (considered a cortical neurologic toxic effect) in the study by Fjallskog et al.35 The randomized trial by Faiss et al reported that toxic effects that led to treatment cessation were more frequent with combination therapy (7/28) than with each agent taken separately (4/27 with interferon alfa and 3/25 with lanreotide). However, these differences were not statistically significant. Hormonal control and objective response have been observed with the combination of interferon alfa and SST Mayo Clin Proc.

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analogues in patients previously treated with one of the agents. However, the combination of both agents in therapy-naive patients does not seem to be superior to monotherapy with either interferon alfa or SST analogue for objective response. RADIOLABELED SST ANALOGUES The high-level expression of SSTRs on various tumor cells has provided the molecular basis for successful use of radiolabeled SST analogues as either tumor tracers or therapeutic agents. Several radionuclide agents have been combined with SST analogues, allowing successful detection of tumors that express SSTR. Pairing SST analogues with therapeutic high-energy–emitting radionuclides therefore represents a clear opportunity to treat GEPNETs. Several preclinical and clinical studies have assessed the feasibility, efficacy, and tolerability of different radiolabeled peptides in the treatment of tumor-expressing SSTRs, most commonly with 90Y-DOTA-octreotide, an yttrium-90 labeled octreotide analogue.37 Neuroendocrine tumors are not only characterized by a usually high level of SSTR but also are well vascularized, an important condition for proper diffusion of radiolabeled peptides into the tumor mass. A phase 2 study published by Waldherr et al38 evaluated 90Y-DOTA-octreotide in the treatment of 39 patients with gastroenteropancreatic and bronchial carcinoid tumors. Overall, clinical symptoms were reduced significantly in 63% of the patients, whereas the objective response rate was 23%. Approximately one fourth of the patients experienced grade 3 or higher lymphocytopenia. Nausea and vomiting were the most common nonhematologic toxic effects, encountered in approximately one third of the cohort. Paganelli et al39 studied the efficacy of 90Y-DOTAoctreotide in 87 patients with neuroendocrine tumors that expressed SSTR-2, 50 of whom had GEPNETs. Interestingly, among 66 patients who were responding to therapy before 90Y-DOTA-octreotide treatment, 28% achieved an objective response, including a 5% complete response and 23% PR. The median duration of response was 24 months. Gastrointestinal adverse effects were mild and included nausea and vomiting, which occurred in approximately 50% of patients. Overall, radiolabeled SST analogues have shown some activity in controlling tumor growth of GEPNETs. Also, clinical symptoms have been reduced significantly. Toxic effects encountered have been manageable with adequate supportive care. Therefore, radiolabeled SST analogues constitute a promising alternative for treating patients with progressive and symptomatic disease. The results of larger ongoing studies are eagerly awaited.

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SOMATOSTATIN ANALOGUES IN GEPNETS

CONCLUSION Somatostatin analogues are clearly safe and effective in controlling symptoms and hormonal secretions in GEPNETs but have limited ability to induce responses. Combination therapy with interferon alfa offers another approach to controlling disease symptoms in patients responding to treatment with SST analogues, although at the cost of increased toxic effects and little evidence of objective responses. Also, radiolabeled SST analogues may be helpful in controlling tumor growth and symptoms related to hormonal secretions and/or bulky disease. More knowledge about the SSTR subtypes, particularly SSTR-3, and their interrelation with intracellular pathways involved in proliferation and apoptosis may eventually lead to new palliative treatments for patients with GEPNETs. Combinations with novel targeted therapies that inhibit angiogenic and growth factor receptor pathways hold promise for improved outcome for these patients. REFERENCES 1. Moertel CG. Karnofsky memorial lecture: an odyssey in the land of small tumors. J Clin Oncol. 1987;5:1502-1522. 2. Oberg K. Neuroendocrine gastrointestinal tumors—a condensed overview of diagnosis and treatment. Ann Oncol. 1999;10(suppl 2):S3-S8. 3. Hejna M, Schmidinger M, Raderer M. The clinical role of somatostatin analogues as antineoplastic agents: much ado about nothing? Ann Oncol. 2002;13:653-668. 4. Buscail L, Delesque N, Esteve JP, et al. Stimulation of tyrosine phosphatase and inhibition of cell proliferation by somatostatin analogues: mediation by human somatostatin receptor subtypes SSTR1 and SSTR2. Proc Natl Acad Sci U S A. 1994;91:2315-2319. 5. Buscail L, Esteve JP, Saint-Laurent N, et al. Inhibition of cell proliferation by the somatostatin analogue RC-160 is mediated by somatostatin receptor subtypes SSTR2 and SSTR5 through different mechanisms. Proc Natl Acad Sci U S A. 1995;92:1580-1584. 6. Sharma K, Patel YC, Srikant CB. Subtype-selective induction of wildtype p53 and apoptosis, but not cell cycle arrest, by human somatostatin receptor 3. Mol Endocrinol. 1996;10:1688-1696. 7. Imam H, Eriksson B, Lukinius A, et al. Induction of apoptosis in neuroendocrine tumors of the digestive system during treatment with somatostatin analogs. Acta Oncol. 1997;36:607-614. 8. Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ. Octreotide. N Engl J Med. 1996;334:246-254. 9. Wulbrand U, Wied M, Zofel P, Goke B, Arnold R, Fehmann H. Growth factor receptor expression in human gastroenteropancreatic neuroendocrine tumours. Eur J Clin Invest. 1998;28:1038-1049. 10. Kvols LK, Reubi JC, Horisberger U, Moertel CG, Rubin J, Charboneau JW. The presence of somatostatin receptors in malignant neuroendocrine tumor tissue predicts responsiveness to octreotide. Yale J Biol Med. 1992;65:505-518. 11. Rubin J, Ajani J, Schirmer W, et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol. 1999;17:600-606. 12. Dogliotti L, Tampellini M, Stivanello M, Gorzegno G, Fabiani L. The clinical management of neuroendocrine tumors with long-acting repeatable (LAR) octreotide: comparison with standard subcutaneous octreotide therapy. Ann Oncol. 2001;12(suppl 2):S105-S109. 13. Saltz L, Kemeny N, Schwartz G, Kelsen D. A phase II trial of alphainterferon and 5-fluorouracil in patients with advanced carcinoid and islet cell tumors. Cancer. 1994;74:958-961. 14. Arnold R, Trautmann ME, Creutzfeldt W, et al. Somatostatin analogue octreotide and inhibition of tumour growth in metastatic endocrine gastroenteropancreatic tumours. Gut. 1996;38:430-438. 15. di Bartolomeo M, Bajetta E, Buzzoni R, et al. Clinical efficacy of octreotide in the treatment of metastatic neuroendocrine tumors: a study by the Italian Trials in Medical Oncology Group. Cancer. 1996;77:402-408.

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