J Hepatobiliary Pancreat Sci (2015) 22:618–622 DOI: 10.1002/jhbp.227
TOPIC
Biotherapy of pancreatic neuroendocrine tumors using somatostatin analogs Hisato Igarashi · Masayuki Hijioka · Lingaku Lee · Tetsuhide Ito Published online: 16 February 2015 © 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery
Abstract Basically, pancreatic neuroendocrine tumor (PNET) should be treated surgically; however, in unresectable cases, a treatment that aims to improve the prognosis by inhibiting the growth of the tumor and control the clinical symptoms becomes necessary. In the case of functional tumors, the quality of life of patients is decreased by not only the symptoms with tumor invasion and/or metastasis but also by the symptoms of hormone excess. The efficacy of somatostatin analogs against the latter has been previously reported, and their sustained release formulations have been developed. Somatostatin analogs are recommended to treat the endocrine symptoms of functional PNET; however, in case they can cause hypoglycemia in patients with insulinoma. On the other hand, results from the PROMID study demonstrated a tumorstabilizing effect when octreotide LAR (long acting repeatable) was used to treat patients with advanced midgut NET; however, there has been no consensus regarding its antitumor effect for PNET. Additionally, a recent result from the CLARINET study suggests that lanreotide autogel has an antitumor effect against nonfunctional NET including PNET. Further clinical study results are awaited. Keywords Lanreotide · Octreotide · Pancreatic neuroendocrine tumors · Somatostatin analog Introduction Pancreatic neuroendocrine tumors (PNETs) are generally categorized into functional tumors and nonfunctional tumors. Basically, PNET should be treated surgically, and H. Igarashi Clinical Education Center, Kyushu University Hospital, Fukuoka, Japan H. Igarashi (✉) · M. Hijioka · L. Lee · T. Ito Department of Medicine and Bioregulatory Science, School of Medical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 8128582, Japan e-mail: [email protected]
when resection of whole tumor cannot be possible, debulking surgery is often performed. In the case of patients with unresectable PNET, the treatment objective is to improve the prognosis by inhibiting the growth of the tumor and to improve the quality of life of patients by control of clinical symptoms [1]. According to analysis of the Surveillance, Epidemiology, and End Results (SEER) database in the US, the median survival time of patients diagnosed with metastatic NET in the years 1973–1987 was 18 months; however, this had improved to 39 months for the years 1988–2004 [2]. This is considered to be due to the introduction of octreotide, a somatostatin analog, in 1987. Somatostatin analogs are not only reported to be effective against the symptoms of excess hormones that are related to functional PNET but they have also shown effectiveness at stabilizing advanced tumors [3]. They are therefore expected to play an important role in the medical treatment of PNET. In this article, we outline the recent findings of treatment of PNET with somatostatin analogs. Somatostatin and its analogs Somatostatin was discovered serendipitously. It is a cyclic peptide and a factor that strongly inhibits the secretion of growth hormone from the pituitary gland [4]. It was later found that somatostatin also inhibited the synthesis and secretion of peptide hormones in a wide variety of neuroendocrine cells [3]. Somatostatin receptors (SSTRs) have five subtypes (SSTR 1-5; The genes that code these subtypes are found on five different chromosomes. In addition, SSTR 2 has two subtypes, SSTR 2A and SSTR 2B, depending on the presence or absence of splicing) [3–5] and are expressed in many NETs; the various subtypes are overexpressed to different degrees in different tumors (Table 1) [6]. The expression of different SSTRs also depends on the degree of pathohistological differentiation. SSTR 2 is highly expressed in most
J Hepatobiliary Pancreat Sci (2015) 22:618–622
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Table 1 Rate of expression of somatostatin receptors in pancreatic neuroendocrine tumor (PNET) (%) SSTR 1 Pancreatic endocrine tumors All tumors Insulinoma Gastrinoma Glucagonoma VIPoma Nonfunctional tumor Midgut NET
SSTR 2
SSTR 3
SSTR 4
Somatostatin therapy for the symptoms of excess hormones caused by PNET
SSTR 5
68
86
46
93
57
33 33 67 100 80 80
100* 50 100 100 100 95
33 17 67 100 40 65
100 83 67 100 100 35
67 50 67 100 60 75
* Malignant insulinoma Modified from Öberg et al. [6]
well-differentiated NETs; however, it is only expressed slightly in poorly differentiated NETs [1]. Somatostatin exhibits different types of effects depending on the SSTR subtypes it binds: SSTR 2 and SSTR 5 are considered to have a role in the inhibition of the secretion of endocrine hormones; SSTR 1, 2, 4, and 5 have a role in the progression inhibition of growth factor-induced cell division cycle; and SSTR 2 and 3 have a role in the induction of apoptosis [7, 8]. Somatostatin and its analogs have two types of mechanism, i.e. a direct and an indirect mechanism for the inhibition of tumor growth. The direct mechanism is reported via the SSTRs described above, and the indirect mechanism involves the inhibition of growth factors, such as the insulin-like growth factor (IGF), and the inhibition of tumor angiogenesis [9]. Somatostatin is readily decomposed, with a half-life of less than 3 min [10]; therefore, its clinical application is limited. To compensate for this, synthetic somatostatin analogs with improved pharmacological stability and sustained SSTR affinity were developed [6–8, 11]. The somatostatin analogs octreotide and lanreotide are synthetic cyclic octapeptides consisting of eight amino acids with a high affinity for SSTR 2 and an intermediate affinity for SSTR 5 [9]. Octreotide was developed in 1983 and was the first somatostatin analog. It was developed as a subcutaneous injection formulation and clinical use requires multiple administrations per day. Octreotide LAR is a sustained release formulation of octreotide that can be intramuscularly administered once every 4 weeks – a great improvement over the multiple subcutaneous injections required by the original formulation. Octreotide LAR was approved for use in Japan in April 2004 and lanreotide was approved for the treatment of endocrine symptoms related to NET in Europe in 1998. A sustained release formulation (Lanreotide Autogel) was also developed [9].
The Guidelines for the Treatment of Pancreatic and Gastrointestinal NET were recently published in Japan and recommend somatostatin analogs and other drug therapies for the treatment of endocrine symptoms (Grade A) [12]. Functional tumors of PNET include insulinoma, gastrinoma, somatostatinoma, VIPoma, and in rare cases tumors producing calcitonin and ACTH [9]. As mentioned above, octreotide principally binds to SSTR 2 and inhibits the symptoms of hormone excess. SSTR 2 expression is observed in most PNETs; however, with regard to insulinoma, it is reported that there are some cases in which the level of SSTR 2 expression is low [13] (specifically, some studies reported that the expression of SSTR 2 is observed in 50% to 70% of patients; in addition, other studies reported that the expression is high in the case of malignant insulinoma). In cases of insulinoma in which the inhibition of insulin by somatostatin analogs is weak, the patients should be taken cared because the somatostatin analogs may exacerbate hypoglycemia by inhibiting the secretion of competitive hormones, such as glucagon [14]. Proton pump inhibitors are effective for treating ZollingerEllison syndrome due to gastrinoma, but octreotide is also used concomitantly in some cases [15]. Symptoms such as glucagonoma-induced necrotic migratory erythema are swiftly ameliorated following the administration of octreotide; however, a decrease in the blood hormone levels is not necessarily associated with the improvement of these symptoms [16]. Somatostatinoma is very rare; however, there is a study reporting that symptoms such as diarrhea and diabetes mellitus were improved after the administration of octreotide [17]. WDHA syndrome brought about by VIPoma is sometimes life threatening but is reported to swiftly respond to somatostatin analogs. However, their efficacy is reported to decrease over time in some cases [18]. Many studies have reported efficacy of somatostatin analogs, including octreotide, against functional NET, and the mean response rate against the signs and symptoms of functional PNET is reported to be 73% (50–100%) [3–6]. Antitumor effect against PNET Many NETs grow slowly, and somatostatin analogs show tumor-stabilizing effects against them [1]. According to a recently published review summarizing the antitumor effects of somatostatin analogs in patients with NET, the antitumor effect of octreotide LAR on advanced NET was observed in the patient population and it was found that 15% to 88% of them achieved stable disease [9]. According to another report,
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J Hepatobiliary Pancreat Sci (2015) 22:618–622
Table 2 Results of PROMID study [20]
Patients No. patients Male/female Age (median, years) Carcinoid syndrome Ki-67 up to 2% Liver involvement (77.4
73.7
0 2.3 66.7
0 2.3 37.2
HR = 0.34; 95% CI, 0.20-0.59; P = 0.000072 HR = 0.81: 95% CI, 0.30-2.18; P = 0.77
P = 0.0079
CI confidence interval, CR complete response, HR hazard ratio, LAR long acting repeatable, NET neuroendocrine tumor, PR partial response, SD stable disease, TTP time to tumor progression
although approximately two-thirds of the patients with NETs who were treated with octreotide remained at stable disease for 5 years, the rate of the patients in whom objective response was obtained was approximately 5% [19]. A prospective randomized placebo-controlled double blind study investigating the antitumor effect of octreotide LAR in patients with metastatic well-differentiated NET derived from the midgut was performed in 2009 [20] (PROMID study). Of 85 patients with locally unresectable or metastatic welldifferentiated midgut NET, 42 were randomly assigned to an octreotide LAR 30 mg group and 43 to a placebo group (Table 2). Octreotide LAR was administered once every 4 weeks, and the primary endpoint was time to tumor progression (TTP) [20]. Octreotide LAR significantly prolonged the TTP, with the median TTP for the octreotide LAR group being 14.3 months and that for the placebo group being 6.0 months (Table 2). The antitumor effects were observed most clearly in patients with either a liver tumor volume of 10% or less, or in patients in whom the primary lesions had been resected. The antitumor effects were shown to be independent of whether or not the NET was functional or nonfunctional and independent of serum chromogranin A
levels, performance status, and age. The rate of patients showing stable disease 6 months after the start of the treatment was 67% in the octreotide LAR group and 37.2% in the placebo group [20]. Based on this result, octreotide LAR became reimbursable for gastrointestinal NET in Japan. In the Japanese guidelines, octreotide is recommended as a Grade B antitumor drug for gastrointestinal NET, which corresponds to G1/G2 of the World Health Organization (WHO) 2010 classification [12]. Some studies also reported that octreotide had an antitumor effect against PNET [9, 10, 12–21]. Panzuto et al. [22] administered an sustained release formulation of somatostatin analog to 31 patients with metastatic, well-differentiated endocrine cancer of the gastrointestinal tract and pancreas and examined its efficacy. Of these patients, 18 had PNET. A tumor-stabilizing effect was observed in five patients half a year after the start of the treatment (responders). In the case of gastrointestinal NET, nine out of 13 patients were responders. The 3-year survival rate of all the responders was 100%, and that of non-responders were 52.3%. There were no significant differences between the functional and nonfunctional tumors [22].
J Hepatobiliary Pancreat Sci (2015) 22:618–622
However, the evidence of the efficacy of octreotide against PNET has not yet been definitively established, because there have been no randomized controlled studies. Therefore, the use of octreotide therapy for PNET has not been approved for health insurance reimbursement. The efficacy of the concomitant use of octreotide and everolimus against PNET has also been investigated. The result of the phase II study of RAD001 (everolimus) in patients with advanced PNET (corresponding to NET G1/G2) in whom cytotoxic chemotherapy was ineffective has been reported [9] (RADIANT-1:RAD001 in advanced neuroendocrine tumors). The patients were randomized to Stratum 1 (a group with the administration of RAD001 10 mg daily) and Stratum 2 (a group with concomitant administration of RAD001 10 mg daily and octreotide LAR), and the results of the strata were compared. The response rate for Stratum 1 was 9.6%. The clinical benefit rate for Stratum 1 was 77.4% and that for Stratum 2 was 84.4%. The median progressionfree survival (PFS) were 9.7 months and 16.7 months, respectively; this suggested that concomitant use of octreotide LAR with everolimus seemed to be more effective than using everolimus alone [23]. The result of a randomized comparative study investigating the antitumor effect of lanreotide against pancreatic and gastrointestinal NET has also been recently reported [24] (a randomized double-blind placebo-controlled study of lanreotide: Antiproliferative response in patients with enteropancreatic neuroendocrine tumors: CLARINET study). A group of 204 patients with locally advanced metastatic pancreatic and gastrointestinal NET with Ki-67 indexes of less than 10% (of whom 91 patients were with PNET) were randomized to a lanreotide autogel group and a placebo group. The primary endpoint was PFS. Whereas the PFS for the placebo group was 18 months, the PFS for the lanreotide autogel group did not reach the median value. In the end, lanreotide autogel significantly prolonged the PFS (P = 0.0002; HR = 0.47; 95% confidence interval [CI], 0.30–0.73). The rate of PFS 2 years after the start of treatment was 62% for the lanreotide and 22% for the placebo group [24]. With regard to PNET, however, lanreotide autogel did not show a significant PFS-prolonging effect in the subgroup analysis (HR, 0.58; 95% CI, 0.32–1.04). A phase II study of lanreotide is also underway in Japan. Future outlook for somatostatin analogs Somatostatin analogs are useful for the treatment of NET; however, it is reported that the efficacy of octreotide and lanreotide may be decreased after 6–18 months from the start of the treatment [19]. This phenomenon is called drug resistance or escape phenomenon; however, its precise mechanism is yet to be elucidated. For patients experiencing escape
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phenomenon, somatostatin analogs with affinities with multiple receptor subtypes are expected to be effective. In a preliminary study, SOM230 (pasireotide) [25], a drug with high affinities for SSTR 1–3 and 5 effectively controlled the signs and symptoms of patients with NET who were nonresponsive or resistant to octreotide LAR. SOM230 is under clinical study along with KE108, which is reported to have affinities to all five receptor subtypes [19]. Among other things, the analysis of the CO-OPERATIVE study (a randomized phase II study of pasireotide LAR vs. pasireotide LAR + everolimus) in patients with advanced PNET is ongoing, and the publication of its result is awaited. We have outlined recent findings about somatostatin analog therapies. The results of additional, currently ongoing clinical trials are awaited, and it is hoped that the spectrum of treatment options for PNET will eventually become even wider. Conflict of interest
None declared.
Author contribution Igarashi H and Ito T participated in this article conception. The manuscript was drafted by Igarashi H, Hijioka M, Lee L, and Ito T. All authors reviewed and provided comments on the manuscript.
References 1. Ito T, Igarashi H, Jensen RT. Therapy of metastatic pancreatic neuroendocrine tumors (pNETs): recent insights and advances. J Gastroenterol. 2012;47:941–60. 2. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE et al. One hundred years after “carcinoid”: Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063–72. 3. Öberg K, Reubi JC, Kwekkeboom DJ, Krenning EP. Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy. Gastroenterology. 2010;139:742–53. 4. Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, et al. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science. 1973;179:77–9. 5. Moller LN, Stidsen CE, Hartmann B, Holst JJ. Somatostatin receptors. Biochim Biophys Acta. 2003;1616:1–84. 6. Öberg K, Kvois L, Caplin M, Delle Fave G, de Herder W, Rindi G, et al. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004;15:966–73. 7. Janson ET. Treatment of neuroendocrine tumors with somastostatin analogs. Pituitary. 2006;9:249–56. 8. Igarashi H, Ito T, Lee R, Niina Y, Takayanagi R. Medical management of pancreatic neuroendocrine tumors. In: Pramod Kumar G, editor. Pancreatic tumors, New Delhi: Elsevier India; 2013. p. 154–70. 9. Sideris L, Dube P, Rinke A. Antitumor effects of somatostatin analogs in neuroendocrine tumors. Oncologist. 2012;17:747–55. 10. Appetecchia M, Baldelli R. Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine tumors, current aspects and new perspectives. J Exp Clin Cancer Res. 2010;29:19.
622 11. Reubi JC, Kvois LK, Waser B, Nagorney DM, Heitz PU, Charboneau JW, et al. Detection of somatostatin receptors in surgical and percutaneous needle biopsy samples of carcinoids and islet cell carcinomas. Cancer Res. 1990;50:5969–77. 12. Japan Neuroendocrine Tumor Society (JNETS). A clinical guideline for gastroenteropancreatic neuroendocrine tumors, ver. 1. http:// jnets.umin.jp (Japanese). 13. Vezzosi D, Bennet A, Rochaix P, Courbon F, Selves J, Pradere B, et al. Octreotide in insulinoma patients: efficacy on hypoglycemia, relationships with Octreoscan scintigraphy and immunostaining with anti-ss2A and anti-ss5 antibodies. Eur J Endocrinol. 2005;152:757–67. 14. Stehouwer CD, Lems WF, Fischer HR, Hackeng WH, Naafs MA. Aggravation of hypoglycemia in insulinoma patients by the longacting somatostatin analogue octreotide (Sandostatin). Acta Endocrinol (Copenh). 1989;121:34–40. 15. Maton PN, Vinayek R, Frucht H, McArthur KA, Miller LS, Saeed ZA, et al. Long-term efficacy and safety of omeprazole in patients with Zollinger-Ellison syndrome: a prospective study. Gastroenterology. 1989;97:827–36. 16. Alexander EK, Robinson M, Staniec M, Dluhy RG. Peripheral amino acid and fatty acid infusion for the treatmentof necrolytic migratory erythema in the glucagonoma syndrome. Clin Endocrinol (Oxf). 2002;57:827–31. 17. Angeletti S, Corleta VD, Schillaci O, Marignani M, Annibale B, Moretti A, et al. Use of the somatostatin analogue octreotide to localize and manage somatostatin-producing tumors. Gut. 1998;42:792–4.
J Hepatobiliary Pancreat Sci (2015) 22:618–622 18. O’Dorisio TM, Mekhjian HS, Gaginella TS. Medical therapy of VIPomas. Endocrinol Metab Clin North Am. 1989;18:545–56. 19. Öberg K. Gastrointestinal neuroendocrine tumors. Ann Oncol. 2010;21:72–80. 20. Rinke A, MÜller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27:4656–63. 21. Strosberg J, Kvols L. Antiproliferative effect of somatostatin analogs in gastroenteropancreatic neuroendocrine tumors. World J Gastroenterol. 2010;16:2963–70. 22. Panzuto F, Di Fonzo M, Iannicelli E, Sciuto R, Maini CL, Capurso G, et al. Long-term clinical outcome of somatostatin analogues for treatment of progressive, metastatic, well-differentiated enteropancreatic endocrine carcinoma. Ann Oncol. 2006;17:461–6. 23. Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371:224–33. 24. Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: A phase II trial. J Clin Oncol. 2010;28:69–76. 25. Schmid HA, Schoeffter P. Functional activity of the multiligand analog SOM230 at human recombinant somatostatin receptor subtypes supports its usefulness in neuroendocrine tumors. Neuroendocrinology. 2004;80:47–50.
TOPIC
Biotherapy of pancreatic neuroendocrine tumors using somatostatin analogs Hisato Igarashi · Masayuki Hijioka · Lingaku Lee · Tetsuhide Ito Published online: 16 February 2015 © 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery
Abstract Basically, pancreatic neuroendocrine tumor (PNET) should be treated surgically; however, in unresectable cases, a treatment that aims to improve the prognosis by inhibiting the growth of the tumor and control the clinical symptoms becomes necessary. In the case of functional tumors, the quality of life of patients is decreased by not only the symptoms with tumor invasion and/or metastasis but also by the symptoms of hormone excess. The efficacy of somatostatin analogs against the latter has been previously reported, and their sustained release formulations have been developed. Somatostatin analogs are recommended to treat the endocrine symptoms of functional PNET; however, in case they can cause hypoglycemia in patients with insulinoma. On the other hand, results from the PROMID study demonstrated a tumorstabilizing effect when octreotide LAR (long acting repeatable) was used to treat patients with advanced midgut NET; however, there has been no consensus regarding its antitumor effect for PNET. Additionally, a recent result from the CLARINET study suggests that lanreotide autogel has an antitumor effect against nonfunctional NET including PNET. Further clinical study results are awaited. Keywords Lanreotide · Octreotide · Pancreatic neuroendocrine tumors · Somatostatin analog Introduction Pancreatic neuroendocrine tumors (PNETs) are generally categorized into functional tumors and nonfunctional tumors. Basically, PNET should be treated surgically, and H. Igarashi Clinical Education Center, Kyushu University Hospital, Fukuoka, Japan H. Igarashi (✉) · M. Hijioka · L. Lee · T. Ito Department of Medicine and Bioregulatory Science, School of Medical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 8128582, Japan e-mail: [email protected]
when resection of whole tumor cannot be possible, debulking surgery is often performed. In the case of patients with unresectable PNET, the treatment objective is to improve the prognosis by inhibiting the growth of the tumor and to improve the quality of life of patients by control of clinical symptoms [1]. According to analysis of the Surveillance, Epidemiology, and End Results (SEER) database in the US, the median survival time of patients diagnosed with metastatic NET in the years 1973–1987 was 18 months; however, this had improved to 39 months for the years 1988–2004 [2]. This is considered to be due to the introduction of octreotide, a somatostatin analog, in 1987. Somatostatin analogs are not only reported to be effective against the symptoms of excess hormones that are related to functional PNET but they have also shown effectiveness at stabilizing advanced tumors [3]. They are therefore expected to play an important role in the medical treatment of PNET. In this article, we outline the recent findings of treatment of PNET with somatostatin analogs. Somatostatin and its analogs Somatostatin was discovered serendipitously. It is a cyclic peptide and a factor that strongly inhibits the secretion of growth hormone from the pituitary gland [4]. It was later found that somatostatin also inhibited the synthesis and secretion of peptide hormones in a wide variety of neuroendocrine cells [3]. Somatostatin receptors (SSTRs) have five subtypes (SSTR 1-5; The genes that code these subtypes are found on five different chromosomes. In addition, SSTR 2 has two subtypes, SSTR 2A and SSTR 2B, depending on the presence or absence of splicing) [3–5] and are expressed in many NETs; the various subtypes are overexpressed to different degrees in different tumors (Table 1) [6]. The expression of different SSTRs also depends on the degree of pathohistological differentiation. SSTR 2 is highly expressed in most
J Hepatobiliary Pancreat Sci (2015) 22:618–622
619
Table 1 Rate of expression of somatostatin receptors in pancreatic neuroendocrine tumor (PNET) (%) SSTR 1 Pancreatic endocrine tumors All tumors Insulinoma Gastrinoma Glucagonoma VIPoma Nonfunctional tumor Midgut NET
SSTR 2
SSTR 3
SSTR 4
Somatostatin therapy for the symptoms of excess hormones caused by PNET
SSTR 5
68
86
46
93
57
33 33 67 100 80 80
100* 50 100 100 100 95
33 17 67 100 40 65
100 83 67 100 100 35
67 50 67 100 60 75
* Malignant insulinoma Modified from Öberg et al. [6]
well-differentiated NETs; however, it is only expressed slightly in poorly differentiated NETs [1]. Somatostatin exhibits different types of effects depending on the SSTR subtypes it binds: SSTR 2 and SSTR 5 are considered to have a role in the inhibition of the secretion of endocrine hormones; SSTR 1, 2, 4, and 5 have a role in the progression inhibition of growth factor-induced cell division cycle; and SSTR 2 and 3 have a role in the induction of apoptosis [7, 8]. Somatostatin and its analogs have two types of mechanism, i.e. a direct and an indirect mechanism for the inhibition of tumor growth. The direct mechanism is reported via the SSTRs described above, and the indirect mechanism involves the inhibition of growth factors, such as the insulin-like growth factor (IGF), and the inhibition of tumor angiogenesis [9]. Somatostatin is readily decomposed, with a half-life of less than 3 min [10]; therefore, its clinical application is limited. To compensate for this, synthetic somatostatin analogs with improved pharmacological stability and sustained SSTR affinity were developed [6–8, 11]. The somatostatin analogs octreotide and lanreotide are synthetic cyclic octapeptides consisting of eight amino acids with a high affinity for SSTR 2 and an intermediate affinity for SSTR 5 [9]. Octreotide was developed in 1983 and was the first somatostatin analog. It was developed as a subcutaneous injection formulation and clinical use requires multiple administrations per day. Octreotide LAR is a sustained release formulation of octreotide that can be intramuscularly administered once every 4 weeks – a great improvement over the multiple subcutaneous injections required by the original formulation. Octreotide LAR was approved for use in Japan in April 2004 and lanreotide was approved for the treatment of endocrine symptoms related to NET in Europe in 1998. A sustained release formulation (Lanreotide Autogel) was also developed [9].
The Guidelines for the Treatment of Pancreatic and Gastrointestinal NET were recently published in Japan and recommend somatostatin analogs and other drug therapies for the treatment of endocrine symptoms (Grade A) [12]. Functional tumors of PNET include insulinoma, gastrinoma, somatostatinoma, VIPoma, and in rare cases tumors producing calcitonin and ACTH [9]. As mentioned above, octreotide principally binds to SSTR 2 and inhibits the symptoms of hormone excess. SSTR 2 expression is observed in most PNETs; however, with regard to insulinoma, it is reported that there are some cases in which the level of SSTR 2 expression is low [13] (specifically, some studies reported that the expression of SSTR 2 is observed in 50% to 70% of patients; in addition, other studies reported that the expression is high in the case of malignant insulinoma). In cases of insulinoma in which the inhibition of insulin by somatostatin analogs is weak, the patients should be taken cared because the somatostatin analogs may exacerbate hypoglycemia by inhibiting the secretion of competitive hormones, such as glucagon [14]. Proton pump inhibitors are effective for treating ZollingerEllison syndrome due to gastrinoma, but octreotide is also used concomitantly in some cases [15]. Symptoms such as glucagonoma-induced necrotic migratory erythema are swiftly ameliorated following the administration of octreotide; however, a decrease in the blood hormone levels is not necessarily associated with the improvement of these symptoms [16]. Somatostatinoma is very rare; however, there is a study reporting that symptoms such as diarrhea and diabetes mellitus were improved after the administration of octreotide [17]. WDHA syndrome brought about by VIPoma is sometimes life threatening but is reported to swiftly respond to somatostatin analogs. However, their efficacy is reported to decrease over time in some cases [18]. Many studies have reported efficacy of somatostatin analogs, including octreotide, against functional NET, and the mean response rate against the signs and symptoms of functional PNET is reported to be 73% (50–100%) [3–6]. Antitumor effect against PNET Many NETs grow slowly, and somatostatin analogs show tumor-stabilizing effects against them [1]. According to a recently published review summarizing the antitumor effects of somatostatin analogs in patients with NET, the antitumor effect of octreotide LAR on advanced NET was observed in the patient population and it was found that 15% to 88% of them achieved stable disease [9]. According to another report,
620
J Hepatobiliary Pancreat Sci (2015) 22:618–622
Table 2 Results of PROMID study [20]
Patients No. patients Male/female Age (median, years) Carcinoid syndrome Ki-67 up to 2% Liver involvement (77.4
73.7
0 2.3 66.7
0 2.3 37.2
HR = 0.34; 95% CI, 0.20-0.59; P = 0.000072 HR = 0.81: 95% CI, 0.30-2.18; P = 0.77
P = 0.0079
CI confidence interval, CR complete response, HR hazard ratio, LAR long acting repeatable, NET neuroendocrine tumor, PR partial response, SD stable disease, TTP time to tumor progression
although approximately two-thirds of the patients with NETs who were treated with octreotide remained at stable disease for 5 years, the rate of the patients in whom objective response was obtained was approximately 5% [19]. A prospective randomized placebo-controlled double blind study investigating the antitumor effect of octreotide LAR in patients with metastatic well-differentiated NET derived from the midgut was performed in 2009 [20] (PROMID study). Of 85 patients with locally unresectable or metastatic welldifferentiated midgut NET, 42 were randomly assigned to an octreotide LAR 30 mg group and 43 to a placebo group (Table 2). Octreotide LAR was administered once every 4 weeks, and the primary endpoint was time to tumor progression (TTP) [20]. Octreotide LAR significantly prolonged the TTP, with the median TTP for the octreotide LAR group being 14.3 months and that for the placebo group being 6.0 months (Table 2). The antitumor effects were observed most clearly in patients with either a liver tumor volume of 10% or less, or in patients in whom the primary lesions had been resected. The antitumor effects were shown to be independent of whether or not the NET was functional or nonfunctional and independent of serum chromogranin A
levels, performance status, and age. The rate of patients showing stable disease 6 months after the start of the treatment was 67% in the octreotide LAR group and 37.2% in the placebo group [20]. Based on this result, octreotide LAR became reimbursable for gastrointestinal NET in Japan. In the Japanese guidelines, octreotide is recommended as a Grade B antitumor drug for gastrointestinal NET, which corresponds to G1/G2 of the World Health Organization (WHO) 2010 classification [12]. Some studies also reported that octreotide had an antitumor effect against PNET [9, 10, 12–21]. Panzuto et al. [22] administered an sustained release formulation of somatostatin analog to 31 patients with metastatic, well-differentiated endocrine cancer of the gastrointestinal tract and pancreas and examined its efficacy. Of these patients, 18 had PNET. A tumor-stabilizing effect was observed in five patients half a year after the start of the treatment (responders). In the case of gastrointestinal NET, nine out of 13 patients were responders. The 3-year survival rate of all the responders was 100%, and that of non-responders were 52.3%. There were no significant differences between the functional and nonfunctional tumors [22].
J Hepatobiliary Pancreat Sci (2015) 22:618–622
However, the evidence of the efficacy of octreotide against PNET has not yet been definitively established, because there have been no randomized controlled studies. Therefore, the use of octreotide therapy for PNET has not been approved for health insurance reimbursement. The efficacy of the concomitant use of octreotide and everolimus against PNET has also been investigated. The result of the phase II study of RAD001 (everolimus) in patients with advanced PNET (corresponding to NET G1/G2) in whom cytotoxic chemotherapy was ineffective has been reported [9] (RADIANT-1:RAD001 in advanced neuroendocrine tumors). The patients were randomized to Stratum 1 (a group with the administration of RAD001 10 mg daily) and Stratum 2 (a group with concomitant administration of RAD001 10 mg daily and octreotide LAR), and the results of the strata were compared. The response rate for Stratum 1 was 9.6%. The clinical benefit rate for Stratum 1 was 77.4% and that for Stratum 2 was 84.4%. The median progressionfree survival (PFS) were 9.7 months and 16.7 months, respectively; this suggested that concomitant use of octreotide LAR with everolimus seemed to be more effective than using everolimus alone [23]. The result of a randomized comparative study investigating the antitumor effect of lanreotide against pancreatic and gastrointestinal NET has also been recently reported [24] (a randomized double-blind placebo-controlled study of lanreotide: Antiproliferative response in patients with enteropancreatic neuroendocrine tumors: CLARINET study). A group of 204 patients with locally advanced metastatic pancreatic and gastrointestinal NET with Ki-67 indexes of less than 10% (of whom 91 patients were with PNET) were randomized to a lanreotide autogel group and a placebo group. The primary endpoint was PFS. Whereas the PFS for the placebo group was 18 months, the PFS for the lanreotide autogel group did not reach the median value. In the end, lanreotide autogel significantly prolonged the PFS (P = 0.0002; HR = 0.47; 95% confidence interval [CI], 0.30–0.73). The rate of PFS 2 years after the start of treatment was 62% for the lanreotide and 22% for the placebo group [24]. With regard to PNET, however, lanreotide autogel did not show a significant PFS-prolonging effect in the subgroup analysis (HR, 0.58; 95% CI, 0.32–1.04). A phase II study of lanreotide is also underway in Japan. Future outlook for somatostatin analogs Somatostatin analogs are useful for the treatment of NET; however, it is reported that the efficacy of octreotide and lanreotide may be decreased after 6–18 months from the start of the treatment [19]. This phenomenon is called drug resistance or escape phenomenon; however, its precise mechanism is yet to be elucidated. For patients experiencing escape
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phenomenon, somatostatin analogs with affinities with multiple receptor subtypes are expected to be effective. In a preliminary study, SOM230 (pasireotide) [25], a drug with high affinities for SSTR 1–3 and 5 effectively controlled the signs and symptoms of patients with NET who were nonresponsive or resistant to octreotide LAR. SOM230 is under clinical study along with KE108, which is reported to have affinities to all five receptor subtypes [19]. Among other things, the analysis of the CO-OPERATIVE study (a randomized phase II study of pasireotide LAR vs. pasireotide LAR + everolimus) in patients with advanced PNET is ongoing, and the publication of its result is awaited. We have outlined recent findings about somatostatin analog therapies. The results of additional, currently ongoing clinical trials are awaited, and it is hoped that the spectrum of treatment options for PNET will eventually become even wider. Conflict of interest
None declared.
Author contribution Igarashi H and Ito T participated in this article conception. The manuscript was drafted by Igarashi H, Hijioka M, Lee L, and Ito T. All authors reviewed and provided comments on the manuscript.
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