Neuroendocrine tumours – Medical therapy: Biological

Best Practice & Research Clinical Endocrinology & Metabolism xxx (2015) 1e13

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Neuroendocrine tumours e Medical therapy: Biological Anja Rinke, Dr., Consultant Internal Medicine a, *, Sebastian Krug, Dr. med. b a b

Department of Gastroenterology, Philipps University Marburg, Germany Department of Internal Medicine I, Martin Luther University Halle, Germany

a r t i c l e i n f o Article history: Available online xxx Keywords: somatostatin analogue octreotide lanreotide pasireotide interferon-a symptomatic treatment antiproliferative treatment

Somatostatin analogues (SSA) are well established antisecretory drugs that have been used as first line treatment for symptomatic control in hormonally active neuroendocrine tumours (NET) for three decades. Both available depot formulations of SSA, longacting repeatable (LAR) octreotide and lanreotide autogel, seem similarly effective and well tolerated, although comparative trials in NET have not been performed. The importance of SSA as antiproliferative treatment has been increasingly recognized during recent years. Two placebo-controlled trials demonstrated significant prolongation of progression free survival under SSA treatment. However, objective response as assessed by imaging is rare. Interferon-a (IFNa) also has antisecretory and antiproliferative efficacy in NET. Due to the less favourable toxicity profile it mainly has a role as add-on option in the refractory setting, especially in carcinoid syndrome patients. Further studies are needed to evaluate the antiproliferative efficacy of the multiligand SSA pasireotide and the role of pegylated IFNa. © 2015 Elsevier Ltd. All rights reserved.

Introduction and definition of biotherapy Medical therapy of neuroendocrine tumours (NETs) aims to ameliorate hormonal symptoms caused by the tumour and/or to control tumour growth. Traditionally, systemic treatments are divided into biotherapy, chemotherapy and so-called molecular targeted agents. Biotherapy implies that substances occurring naturally within the body or pharmacological derivatives thereof are used for medical * Corresponding author. Department of Gastroenterology University Hospital Marburg Baldingerstraße 1 35043 Marburg, Germany. Tel.: þ49 6421 58 66460; Fax: þ49 6421 58 68922. E-mail address: [email protected] (A. Rinke). http://dx.doi.org/10.1016/j.beem.2015.09.004 1521-690X/© 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Rinke A, Krug S, Neuroendocrine tumours e Medical therapy: Biological, Best Practice & Research Clinical Endocrinology & Metabolism (2015), http://dx.doi.org/10.1016/ j.beem.2015.09.004

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treatment. Biotherapy of NETs mainly comprises somatostatin analogues (SSAs) and interferon-a (IFNa). SSA: history, available drugs Somatostatin and somatostatin receptors Somatostatin (SST) is a natural polypeptide with two bioactive forms of 14 and 28 amino acids, respectively, discovered incidentally as growth hormone (GH) inhibitor in 1972 [1,2]. SST was subsequently found to inhibit not only GH but also the release of many gastrointestinal hormones including insulin, gastrin and glucagon. It additionally reduces exocrine gastric and pancreatic secretion and motility, portal blood flow and intestinal absorption [2]. The physiological effects of SST are the result of specific interaction with somatostatin receptors, a family of G-coupled proteins with five receptor subtypes (SSTR1-5). Natural SST binds to all five subtypes with high affinity [2]. NETs often express SSTRs at high levels with SSTR2 being the most prevalent subtype [3,4]. Levels of SSTR expression and predominant subtype vary between tumour types. While half of the insulinoma patients express SSTR2, high levels of SSTR2 are found in more than 90% of gastrinoma patients [2]. In patients with bronchopulmonary NETs SSTR1 was recently reported to be the most prevalent subtype [5]. Somatostatin analogues (SSAs) e developmental history The natural SSTs have a very short circulation half-life of about two minutes. For clinical use a continuous infusion is necessary. The development of synthetic peptides with longer half-lives e including the octapeptides octreotide and lanreotide - in the early eighties was a major step towards therapeutic applicability [6]. These synthetic SSAs retain the binding affinity for SSTRs e at least with high affinity for SSTR2 and moderate affinity for SSTR5 e and are more resistant to peptidases. In 1988 octreotide was approved for treatment of hormone syndromes like carcinoid syndrome. With a halflife of two hours this first clinically available SSA provided control of symptoms by subcutaneous (sc) injections three times a day. In the 1990ies the development of depot formulations of SSA provided more sustained drug levels and improved quality of life. In 1995 octreotide long-acting repeatable (LAR) was introduced which is an incorporation of octreotide into microspheres of the biodegradable polymer Poly-DL-lactide-co-glycolide [2]. Octreotide LAR is typically administered intramuscularly (im) every 4 weeks. For initiation of octreotide LAR treatment application of subcutaneous octreotide for about two weeks is recommended until the plateau level of serum concentration is reached. Simultaneously with octreotide LAR a slow release formulation of lanreotide e lanreotide microparticles (MP) e was licensed in France. This formulation was injected im every 14 days. Lanreotide autogel is a viscous aqueous solution composed of only lanreotide and water that is usually administered deep sc every four weeks. After a single injection the peak serum concentration is reached on the first day, a steady state level after four injections [7]. This formulation was licensed in France in 2001, in Germany in 2007 and was very recently also approved by the FDA. The depot formulations octreotide LAR and lanreotide autogel are the most widely used SSAs in clinical practice today. They are similar with regard to SSTR binding affinity, clinical efficacy and side effects. There are no comparative randomized trials of both formulations available in NET patients. In 2004 pasireotide was developed. Its binding affinity to SSTR2 is lower compared to octreotide and lanreotide. However, its affinity to SSTR1, 3 and 5 is much higher [8]. The drug is available as shortacting subcutaneous formulation and long-acting release intramuscular formulation, usually administered at 60 mg monthly. While pasireotide has been approved for Cushing's disease and acromegaly, the role in NET still has to be defined. Mechanism of biological activity Binding of SSA results in inhibition of calcium channels and stimulation of various potassium channels, thus leading to depletion of intracellular calcium concentration and inhibition of adenylate Please cite this article in press as: Rinke A, Krug S, Neuroendocrine tumours e Medical therapy: Biological, Best Practice & Research Clinical Endocrinology & Metabolism (2015), http://dx.doi.org/10.1016/ j.beem.2015.09.004

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cyclase. Decrease in cyclic adenosine monophosphate (cAMP) levels and inhibition of protein phosphatases leads to inhibition of exocytosis. This mechanism explains the antisecretory effects of SSA [2]. In addition, direct antiproliferative mechanisms as a result of SSA binding to SSTR on the tumour cell and indirect mechanisms have been described. Indirect mechanisms include inhibition of circulating growth factors as well as antiangiogenic effects through interaction with SSTRs on cells of the surrounding microenvironment [2]. Upon activation, all SSTRs induce cell cycle inhibitors such as p27 and p21, thus leading to cell cycle arrest [9]. Binding of SSA to SSTR activates phosphotyrosine phosphatases resulting in suppression of mitogenic pathways such as the ERK1/2/PI3K/AKT pathway. Further potential antiproliferative mechanisms of SSA that have been described in various reports include: direct induction of apoptosis, restoration of functional gap junctions and changes in natural killer cell activity [10,11]. SSAs in hypersecretion syndromes SSAs have been the mainstay for the control of hormonal syndromes for three decades. Symptomatic relief is reported in about 70% (40e100%) of treated patients, biochemical response (decrease of the marker hormones of at least 50%) in about 50% of patients (18%e100%) [2]. Symptom control is dose dependent [12]. The duration of symptom control is variable. Escape mechanisms include desensitization to the inhibitory SST effects (tachyphylaxis) [13]. SSAs in carcinoid syndrome SSAs are the treatment of choice for palliating flushing and diarrhoea in patients with carcinoid syndrome. An early trial reported symptom control in 88% of the patients with octreotide 150 mg three times daily [14]. A randomized trial of subcutaneous octreotide versus octreotide LAR demonstrated equivalence of both formulations [15]. Numerous studies confirmed similar results for octreotide and lanreotide in terms of symptomatic response [16e21]. A cross over study on 33 patients with carcinoid syndrome compared the efficacy of 30 mg lanreotide MP every 10 days and 200 mg octreotide three times a day. Both drugs were equally efficacious in terms of symptom control and reduction in biomarkers [16]. 71 patients with carcinoid syndrome were included in an open multicentric trial of lanreotide autogel for 6 months [19]. At the end of the study 80% of patients with flushing and 75% of patients with diarrhoea had an improvement of symptoms compared to baseline. A release of at least 50% of flushing episodes was reported in 65%, a 50% reduction of diarrhoea in 18% of patients. The less pronounced effect on diarrhoea may be explained by other causes for diarrhoea than hormone hypersecretion like bile acid malabsorption after ileal resection, short bowel syndrome and side effects of SSAs. In a study of 108 patients with metastatic midgut NETs and carcinoid syndrome, octreotide LAR treatment resulted in sufficient long term symptomatic control in 45% of cases [20]. The same centre provided data on long term treatment with lanreotide autogel in 69 patients with carcinoid syndrome. In 74% of patients the carcinoid syndrome was well controlled with lanreotide autogel alone throughout the study period [21]. The international non-interventional SymNET trial (NCT01234168) assessed patient-reported satisfaction with diarrhoea control in 273 patients with carcinoid syndrome. 75.7% of patients were satisfied with the control of diarrhoea after lanreotide autogel treatment [22]. Pasireotide was evaluated in NETs with carcinoid syndrome refractory to available SSAs. In a phase II study subcutaneous pasireotide was effective in controlling the symptoms of carcinoid syndrome in 27% of the cohort [23]. However, a randomized phase III study of pasireotide LAR versus high-dose octreotide LAR (40 mg every 28 days) among patients with refractory carcinoid syndrome failed to prove an advantage of pasireotide LAR in symptom control [24]. Treatment with SSAs is associated with >50% decrease of urinary 5- hydroxyindoleacetic acid (5HIAA) in about half of the patients treated with octreotide and 40% of patients treated with lanreotide [2,21]. Carcinoid heart disease (CHD) is a severe complication of the carcinoid syndrome, usually involving the right-sided heart valves and eventually leading to right heart failure. As high levels of 5-HIAA are associated with increased risk for CHD [25], decrease in hormone levels under SSA treatment could Please cite this article in press as: Rinke A, Krug S, Neuroendocrine tumours e Medical therapy: Biological, Best Practice & Research Clinical Endocrinology & Metabolism (2015), http://dx.doi.org/10.1016/ j.beem.2015.09.004

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contribute to reduced risk or delay of development of CHD. A clear proof of an SSA effect on CHD, however, is lacking so far. Carcinoid crisis manifests by extreme fluctuations of blood pressure, flushing, bronchoconstriction and arrhythmias that can occur during anaesthetic induction and manipulation of tumour masses during surgical or radiological procedures. Therefore, in patients with known carcinoid syndrome who undergo surgery or radiological interventions prophylactic supplementary sc or iv octreotide is recommended [26,27]. SSAs in insulinomas Most insulinomas are benign and can be cured by surgery. In the rare metastasizing insulinomas SSA treatment often is of limited value for glycaemic control. One probable reason is the low expression of SSTR2 [28]. Even deterioration of hypoglycaemia may occur as a result of inhibition of the counter regulatory hormone glucagon [29]. Therefore, in this indication SSA treatment should not be commenced in an outpatient setting. Further studies are needed to evaluate the potential role of pasireotide in patients with malignant insulinoma. Pasireotide does not inhibit counter regulatory glucagon secretion and often induces hyperglycaemia. Therefore, it could be helpful for treating hypoglycaemia in insulinoma patients. SSAs in Zollinger Ellison Syndrome (gastrinoma) SSA lower gastrin levels and can ameliorate symptoms of Zollinger Ellison Syndrome [30]. However, proton pump inhibitors are the treatment of choice for symptom control as they are highly effective and oral available [31]. SSAs in Verner Morrison Syndrome (VIPoma) Treatment with SSAs results in a rapid reduction of the excessive secretory diarrhoea caused by vasoactive intestinal polypeptide (VIP) secreting pancreatic NETs [32,33] and is therefore indicated in this rare disease. SSAs in glucagonoma syndrome The necrolytic migratory erythema-a characteristic skin rash caused by glucagon secreting pancreatic NETs e can resolve rapidly after initiation of SSA treatment [34,35]. The European Neuroendocrine Tumour Society (ENETS) therefore recommends treatment with SSA in patients with glucagonoma syndrome [36]. SSAs in ectopic ACTH syndrome A Cushing's syndrome caused by release of adrenocorticotropin (ACTH) rarely occurs in patients with NETs and there is insufficient data to conclude on the role of SSA in this condition. Some reports have described relief of symptoms following treatment with SSA [37,38] although other medical (ketoconazole, metyrapone) and non-medical treatments (adrenalectomy) may be necessary. Pasireotide is approved for Cushing's disease but its role for Cushing's syndrome due to ectopic ACTH release by NETs needs further investigation. Adverse effects of SSA SSAs are generally well tolerated. Most common side effects are diarrhoea, abdominal discomfort, flatulence, nausea and local reactions at the site of injection. Gastrointestinal side effects often decrease in intensity with duration of treatment. Cholelithiasis is reported in 3e11% [21,39,40] of patients, in most cases asymptomatic but complications such as acute cholecystitis, bilious attacks or acute pancreatitis may occur. Therefore, a Please cite this article in press as: Rinke A, Krug S, Neuroendocrine tumours e Medical therapy: Biological, Best Practice & Research Clinical Endocrinology & Metabolism (2015), http://dx.doi.org/10.1016/ j.beem.2015.09.004

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prophylactic cholecystectomy should be discussed in patients on SSAs who undergo surgery for other reasons [41]. Steatorrhoea is reported in different frequencies, most cases can be sufficiently treated with pancreatic enzymes. Octreotide and lanreotide can cause hyperglycaemia in about 5%e10% of patients. Rare side effects include hypoglycaemia, hair loss, hypothyreoidism, headache, myalgia, acute hepatitis, hyperbilirubinaemia, bradycardia, obstipation and paralytic ileus. Pasireotide has a similar tolerability profile except for a higher rate of hyperglycaemia [23,24]. Interferon (IFN) short history and mechanism of action Interferons (IFN) form a family of cytokines, initially described in the middle of the 20th century by Isaacs and Lindenmann [42]. To date, three IFN types are characterized, based on their respective cell surface receptors, of which the type I IFN (IFNeI) comprises IFN-a and IFN-b [43]. The IFN-I members bind the heterodimeric IFNa/b receptor, thereby leading to phosphorylation and initiation of signal transduction [44]. Since 1971 IFN-a has been used for the treatment of certain solid tumours. Direct as well as indirect antitumour effects of IFN-a have been described: IFN-a can target tumour cells itself and induce cell cycle arrest and apoptosis, but also has immunomodulatory and anti-angiogenic activities [45,46]. However, the complexity of its impact in neuroendocrine tumours is not fully understood [47e50]. Interferon (IFN), available drugs IFN-a has been approved for treatment of carcinoid syndrome. Most data have been acquired using human leucocyte IFN-a. Nowadays, however, predominantly recombinant IFN-a2a, IFN-a2b and polyethylene glycol-modified (pegylated) forms of IFN-a are in clinical use. The dose has to be individually titrated based on a balance between effect and quality of life. Following schedules can be applied:  IFN-a2A 3e9 MU/day sc 3e5/week  IFN-a2B 3e9 MU/day sc 3e5/week  Pegylated IFN-a2A or IFN-a2B 50e150 mg sc 1/week

IFN-a in hypersecretion syndromes € In 1983 Oberg published first data on the clinical efficacy of IFN-a in six patients with carcinoid syndrome [51]. Subsequently, various non-randomized, mainly retrospective trials of heterogeneous cohorts reported symptom control and biochemical response between 30e70% and 50e60%, respec€lby and colleagues compared monotherapy with tively [52e56]. The randomized prospective trial by Ko octreotide (100e200 mg 3x/day) with combination treatment (octreotide plus IFN-a 3e5 MU 3/week) in a homogeneous population of patients with carcinoid syndrome [57]. Both treatment regimens resulted in significant reduction of 5-HIAA excretion without differences between the treatment arms. Data for efficacy of IFN-a with regard to symptomatic control in other hormone syndromes caused by NETs are limited. According to the ENETS guidelines IFN-a can be considered for symptomatic treatment of functional pNET and carcinoid syndrome [58,59] in case of intolerance of SSAs and insufficient antisecretory effects of SSA. However, due to the unfavourable toxicity profile, IFN-a is not first therapeutic choice in functioning NETs. Adverse effects of IFN-a Compared to SSA, IFN-a is associated with more side effects, mostly grade 1 and 2. Temporary flulike symptoms, fatigue and discrete weight loss are common adverse events occurring in 50e80% of the patients [60]. Additionally, myelodepression comprising anaemia (~25%), leukopenia (up to 40% grade Please cite this article in press as: Rinke A, Krug S, Neuroendocrine tumours e Medical therapy: Biological, Best Practice & Research Clinical Endocrinology & Metabolism (2015), http://dx.doi.org/10.1016/ j.beem.2015.09.004

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I/II and 20% grade III/IV) and thrombocytopenia (~10e20%) as well as elevated liver enzymes (~30%) frequently occur during therapy [60e62]. Abdominal complaints with pain, diarrhoea, vomiting and nausea were less frequently reported (10e40%) [62e64]. Rare adverse events include depression, autoimmune phenomena, skin rash, headache and renal impairment.

Practice Points Hypersecretion syndromes  SSA are well established for the control of symptoms of patients suffering from carcinoid syndrome, Verner Morrison Syndrome and glucagonoma syndrome  Lanreotide and Octreotide seem to be equally effective in controlling hypersecretion syndromes  Perioperative and periinterventional application of iv octreotide is indicated to prevent carcinoid crisis  In patients with refractory carcinoid syndrome medical treatment options include increasing doses of SSA, addition of IFNa and treatment with pasireotide (not approved for this indication)

Biotherapy in antiproliferative intention SSA for tumour control In addition to their well established role in symptom control, somatostatin analogues also demonstrated inhibition of growth in cancer cell lines. Initial case reports showed tumour shrinkage under octreotide treatment [65], in the following years the antiproliferative efficacy was questioned as remissions were rarely found. Most of these uncontrolled phase II studies included only small numbers and heterogeneous cohorts. They reported high rates of stabilization (30e80%), but tumour progression at study entry was not always required. As expected, the rate of stabilization was usually higher for patients without disease progression at treatment onset [66,67]. It was also higher in intestinal than in pancreatic NETs [68]. Prognosis in non-responders to SSA treatment was worse [63,68]. In the recent Spanish study with lanreotide autogel in GEP-NET patients with documented tumour progression within 6 months prior to study entry, Martin-Richard reported a progression free survival (PFS) of 12.9 months [69]. The results on morphologic response under SSA treatment are summarized in Table 1. A significant antitumour activity of SSAs was documented in two prospective randomized placebo controlled trials in recent years. The PROMID study [39] compared octreotide LAR 30 mg every 4 weeks versus placebo in 85 treatment naïve patients with well-differentiated midgut NETs. Both patients with nonfunctioning tumours or mild carcinoid syndrome were included. The primary endpoint was time to tumour progression (TTP). TTP in the octreotide LAR group was significantly longer with 14.3 months compared to 6 months in the placebo group (HR 0.34; p ¼ 0.000072). The most favourable results were seen in patients with low hepatic tumour load (<10% liver involvement). More recently, the phase III placebo-controlled CLARINET trial expanded the role of SSAs for tumour control in NET [40]. Within this protocol 204 patients with well- or moderately differentiated, nonfunctioning, somatostatin receptor-positive GEP-NETs with a Ki-67 of <10% were randomized to receive either lanreotide autogel 120 mg every 4 weeks or placebo. Patients had to have documented disease status during a three to six months preobservation period prior to randomization. The vast majority of patients (96%) had stable disease at randomization. Lanreotide was associated with a significant prolongation of PFS, with a median not reached versus a median of 18 months in the placebo arm (hazard ratio (HR) 0.47; p < 0.001). The estimated rates of PFS at 24 months were 65.1% in the lanreotide group and 33% in the placebo group. The benefit in the patients with midgut NET (HR 0.35; p ¼ 0.009) was greater than in the pancreatic subset (HR 0.58; p ¼ 0.06). It is important to note that the study was not powered for statistical significance of the subgroups. No benefit could be demonstrated for the small subgroup of patients with hindgut NET (HR 1.47). Please cite this article in press as: Rinke A, Krug S, Neuroendocrine tumours e Medical therapy: Biological, Best Practice & Research Clinical Endocrinology & Metabolism (2015), http://dx.doi.org/10.1016/ j.beem.2015.09.004

Author, year

Na

Included patients

Progression at start documented?

Treatment

Tumour response (% of patients) PR

SD

Oberg et al., 1991 [78] Saltz et al., 1993 [79] Arnold et al., 1996 [67]

22 34 103

Metastatic midgut NET Metastatic GEPNET Metastatic GEPNET

Octreotide sc 50 mg bid to 200 mg tid Octreotide sc 50 mg bid to 250 mg tid Octreotide sc 200 mg tid

28 0 0

36 50 PD at entry:36.5 SD at entry: 53.8

Di Bartolomeo et al., 1996 [17] Wymenga et al., 1999 [66]

58 31

Mixed cohort, mainly midgut NET Functioning GI-NET

no yes PD prior to start in 52 pts, SD in 13pts, Unknown in 38pts yes no

3 6

47 81

Faiss et al., 1999 [80] Ducreux et al., 2000 [81] Ricci et al., 2000 [18] Faiss et al., 2003 [64] Arnold et al., 2005 [63]

24 39 25 25 48

yes yes no yes yes

4 5 8 4 2

46 49 40 28 46

Bajetta et al., 2005 [82]

31

no

Octreotide LAR im 30 mg q28d

6

52

Bajetta et al., 2006 [83]

28 each

Progressive, metastatic GEP-NET GI-NET Metastatic NET Progressive GEP-NET Progressive advanced midgut or pancreatic NET Treatment naïve well-differentiated NET Well-differentiated NET

Octreotide sc 500 mge1000 mg tid Lanreotide ATG 30 mg q2wk, escalated to weekly in 27% Lanreotide 5 mg SC tid Lanreotide 30 mg IM q10-14d Lanreotide 30 mg IM q2wk Lanreotide 1 mg SC tid Octreotide sc 200 mg tid

no

Panzuto et al., 2006 [68]

31

advanced pNET and intestinal

yes

Lanreotide ATG: 0 Lan LA: 4 0

Lanreotide ATG: 68 Lan LA: 64 45

Butturini et al., 2006 [84]

21

no

0

38

Rinke et al., 2009 [39] Khan et al., 2011 [21] Bianchi et al., 2011 [85] Martin-Richard et al., 2013 [69]

42 76 23 30

no no yes yes

Octreotide LAR 30 mg q28d Lanreotide ATG 60e120 mg q28d Lanreotide ATG 120 mg q28d Lanreotide ATG 120 mg q28d

2 0 8.7 4

67 75 at 3 years 65 89

Caplin et al., 2014 [40]

101

NA

65 at 24 months

28

96% SD prior treatment no

Lanreotide ATG 120 mg q28d

Cives M et al., 2015 [71]

Well-differentiated nonfunctioning pNET, somatostatin receptor positive Well-differentiated midgut Midgut with carcinoid syndrome Well-differentiated metastatic NET Advanced and/or metastatic, welldifferentiated NET Nonfunctioning somatostatin receptor positive GEPNET Treatment naïve grade 1 and 2 NET

Lanreotide LA 60 mg q3wk or Lanreotide ATG 120 mg q6wk (1:1) Octreotide LAR 30 mg q28d: 21patients Lanreotide SR 60 mg q28d: 10 patients Octreotide LAR 20 mg q28d

Pasireotide LAR 60 mg q28d

4

60

7

ATG ¼ autogel; bid ¼ two times daily; GEP ¼ gastroenteropancreatic; GI ¼ gastrointestinal; IM ¼ intramuscular; LA ¼ long acting; Lan ¼ lanreotide; NET ¼ neuroendocrine tumour(s); pNET ¼ pancreatic neuroendocrine tumour(s); pts ¼ patients; q ¼ every; SC ¼ subcutaneous; SR ¼ Slow release; tid ¼ three times daily. NA: not assessed. a N is for those patients with result for morphological tumour response.

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Please cite this article in press as: Rinke A, Krug S, Neuroendocrine tumours e Medical therapy: Biological, Best Practice & Research Clinical Endocrinology & Metabolism (2015), http://dx.doi.org/10.1016/ j.beem.2015.09.004

Table 1 Studies with reported morphological response under SSA treatment (only trials with at least 20 patients included).

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The main characteristics of both placebo-controlled trials are summarized in Table 2. Due to the small number of deaths, the crossover to open treatment and the impact of other poststudy treatments neither the PROMID trial nor the CLARINET trial was able to demonstrate a significant overall survival benefit. Therefore, it is a matter of debate whether there is still a place for a “watch and wait” approach or whether the treatment with SSA should start immediately to prevent tumour progression. Indirect data to support a possible overall survival benefit of SSA therapy originate from the Surveillance, Epidemiology and End Results (SEER) database: Longer survival durations have been shown in patients diagnosed from 1988 to 2004 if compared to survival durations in NET patients who were diagnosed in the pre-SSA period (1973e1987) [70]. The antiproliferative data for pasireotide are limited. In a recent phase II trial of pasireotide LAR 60 mg every four weeks in treatment naïve patients with NET G1 and G2 of different origins the PFS was 11 months [71]. Interestingly, the randomized trial in patients with refractory carcinoid syndrome which failed to demonstrate an advantage of pasireotide over high dose octreotide with regard to symptom control, showed a significant longer PFS for pasireotide compared to octreotide [24]. Further investigations of the antiproliferative capacity of pasireotide are warranted. IFN-a for tumour control After first reports of IFN-a (3e5 MU/d, 3e5/w sc) demonstrating notable anti-tumour effects in € neuroendocrine tumours [51,53], the Oberg's group published the largest series of IFN-a in 111 patients with metastatic NETs (75% midgut) with a disease control rate (DCR) of 54% (including 15% objective response (OR)) and median duration of response of 32 months [55]. Data for pNET patients are more limited with the largest retrospective cohort published again from the Uppsala group. They reported 12% and 24.5% OR and stabilization, respectively, in 57 pNET patients [72]. There are only few prospective data of IFN-a monotherapy available, placebo-controlled data are lacking. In the randomized GEPNET study of Faiss et al. DCR at 12 months was 29.6% [64]. In Dahan's trial the median PFS was 14.1 months with 1-year and 2-year PFS rates of 53% and 33%, respectively [62]. Combination treatment for tumour control The combination of SSA and IFN-a has been investigated in various non-randomized and five randomized trials over the past decades. Reasons for simultaneous administration were possible synergistic effects as well as better tolerability than IFN monotherapy. Four small non-randomized studies reported promising efficacy data of the combination treatment of SSA plus IFN-a after biochemical or morphological progression under SSA monotherapy: Biochemical response rates and disease control rates ranged from 62.5% to 77% and 21%e100%, respectively. OR was achieved in 4%e 36% [73e76].

Table 2 Comparison of the 2 placebo controlled randomized trials of SSA in well-differentiated NET.

Study drug and dose Primary tumour localization Number of patients included Functional status Preobservation period Histology SSTR positivity Primary end point Assessment of imaging Primary end point met?

PROMID

CLARINET

Ocreotide LAR 30 mg every 28 days versus placebo midgut and unknown 85 FNA and mild carcinoid syndrome no Well differentiated, >90% G1 Majority positive, but no inclusion criterion TTP WHO Yes

Lanreotide autogel 120 mg every 28 days versus placebo pNET, midgut, hindgut, unknown 204 FNA (and gastrinoma controlled by PPI) Yes, 96% SD before randomization G1 and G2 up to Ki67 10% Required for inclusion PFS RECIST 1.0 Yes

Please cite this article in press as: Rinke A, Krug S, Neuroendocrine tumours e Medical therapy: Biological, Best Practice & Research Clinical Endocrinology & Metabolism (2015), http://dx.doi.org/10.1016/ j.beem.2015.09.004

Author, year

Study design

n

Location Functionality Characteristics primary

€lby, 2003 [57] Ko

Randomized prospective 2 arms multicentric

68 midgut

Faiss, 2003 [64]

Open randomized prospective 3 arms imulticentric

80 GEPNET 29 (36.3%)

68 (100%)

105 GEPNET 47 (44.8%) Arnold, 2005 [63] Randomized prospective 2 arms multicentric

Yao, 2008 [61]

Randomized prospective phase II 2 arms cross-over design

Dahan, 2009 [62] Randomized prospective phase III 2 arms multicentric

44 GEPNET n.a.

64 GEPNET n.a.

Treatment

Octreotide 100 e200ug 2e3/ d sc ± IFN-a 3e5 MU 3e5/w sc Treatment naive; Lanreotide 1 mg PD at entry 3/d sc vs. IFN-a 5 MU 3/w sc vs. combination Prior primary tumour resection þ TAE

PFS þ OS

Symptomatic response

Biochemical response

Disease control rate

n.a.

5-HIAA overall P ¼ 0.005

45.7%vs. 81.8% PD 5-year survival rate 36.6 vs. 19 vs. 6 pts. 56.8% P ¼ 0.132 P ¼ 0.008

Serotonin þ CgA decreased sig. in all arms

32 vs. 29.6 vs. 25% PFS 1-year rate at 12 m 44% vs. 44.4% vs. 50%

Only combination achieved response P ¼ 0.037 for diarrhoea and flush PD at entry Octreotide 200ug Flushing, 3/d sc ± 4.5 MU diarrhoea and IFN-a 3/w sc abd. complaints improved between 33e83% Concomitant SSA Bevacizumab n.a. 15 mg/kg every (100%) therapy 3w iv vs. PEG IFN52.3% PD a-2b 0.5 mcg/kg 2/w sc Concomitant SSA 5-FU 400 mg/ Stool frequency m2 þ STZ (17.2%) 63 pts. and flushing 500 mg/m2 d1-5 decreased with prior PD every 6w iv vs. P ¼ 0.072 and IFN-a 3MU 3/w sc P ¼ 0.26 without differences

CgA 33.3 vs. 50% 45% vs. 50% at 3 m OS 35 vs. 51 m (P ¼ 0.55) (P ¼ 0.46) 5-HIAA 35.3 vs. 66.7% (P ¼ 0.22) Survival rates 5-HIAA 19 vs. 33% 95 vs. 68% P ¼ 0.33 CgA 6 vs. P ¼ 0.02 at week 1-year 93% 2-year 67% 18 14% P ¼ 0.43 3-year 56% mPFS 63w mPFS 5.5 m vs. 59 vs. 72% Biochemical 14.1 m P ¼ 0.12 progression 22 (midguts: 65 vs. P ¼ 0.34 vs. 9% mOS 88% P ¼ 0.31) 30.4 m vs. 44.3 m P ¼ 0.83

GEPNET ¼ gastroenteropancreatic-neuroendocrine tumours; TAE ¼ transarterial embolization; n.a. ¼ not assessed; PD ¼ progressive disease; SSA ¼ somatostatin analogues; vs ¼ versus; w ¼ week; d ¼ day; m ¼ months; sc ¼ subcutaneous; iv ¼ intravenous; 5-HIAA ¼ 5-hydroxyindoleacetic acid; CgA ¼ chromogranin A; (m)PFS ¼ (median) progression-free survival; (m) OS ¼ (median) overall survival.

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Table 3 Prospective randomized trials with IFN-a in NETs.

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Encouraged by these results three randomized trials were initiated to further evaluate the role of SSA and IFN-a combination treatment compared to monotherapies. As described above, the first €lby, exclusively focused on metastatic midgut NETs with carcinoid randomized trial, published by Ko syndrome (n ¼ 68) [57]. Intention-to-treat analysis showed no significant differences in 5-year survival rates (36.6% octreotide versus 56.8% combination, HR 0.62, P ¼ 0.132). However, the risk of tumour progression was lower in the combination treatment (HR 0.28, P ¼ 0.008). The three-arm study of Faiss included 80 progressive GEPNET patients [64]. No difference in PFS rate after 1 year was demonstrated: 56%, 55% and 50% for lanreotide, IFN-a and the combination group, respectively (P ¼ 0.69). The largest randomized trial (n ¼ 109) to explore the role of combined treatment (octreotide 200 mg 3/d ± 4.5 MU IFN-a 3/w sc) was published by our group [63]. Only progressive duodenopancreatic and midgut NETs were included. Median time to treatment failure was 6 months in both treatment arms (P ¼ 0.59). Response to treatment after 12 months exhibited no significant differences (2.0% vs. 9.3%, stable disease 15.8% vs. 14.7% and progressive disease 49% vs. 25.9%). Additionally, median survival with 35 months for mono- and 51 months for combination therapy was not statistically different (P ¼ 0.55). The data of the randomized trials are summarized in Table 3. Although nowadays in clinical practice pegylated IFN-a is used more frequently than IFN-a, there is insufficient data published to draw conclusions on its value in NETs. One small study of 17 GEPNET patients treated with pegylated IFN-a2b in combination with SSA showed promising results with 2 partial responses and 11 stabilizations. Tolerability of pegylated IFN-a2b seemed to be better than IFNa 2b [77]. In a second phase II study 22 patients received PEG IFN-a-2b 0.5 mg/kg 2/w sc with concomitant octreotide LAR (versus bevacizumab þ octreotide). This combination achieved 15 disease stabilizations (68%), while 6 patients progressed (27%). The median PFS was 56 weeks [61]. Insufficient statistical power of the randomized trials, heterogeneity of patient cohorts and different treatment schedules as well as methods of response evaluation hinders a final conclusion. As IFN-a adds toxicity and clear superiority of the combination treatment could not been demonstrated, the combination treatment is not recommended as first line therapy.

Research agenda for biotherapy  Conduction of a phase III trial of pasireotide versus octreotide or lanreotide in midgut tumours  Assessment of the role of pegylated IFN-a in patients with midgut tumours  Comparison of SSA plus IFN-a versus SSA monotherapy in patients with metastatic midgut tumours in a statistically adequate fashion  Evaluate high dose SSA in antiproliferative intention

Practice points biotherapy in antiproliferative purpose  SSA exert antiproliferative action by delaying tumour progression in patients with metastasized well-differentiated and low proliferative (Ki67 < 10%) GEPNETs  SSA treatment rarely leads to objective tumour response  SSA have a favourable toxicity profile  IFN-a treatment can induce tumour stabilization and e in a minority of patients e objective tumour response  The combination therapy of SSA and IFN-a is not recommended as first line treatment since no advantage of the combination treatment as compared to monotherapy has been demonstrated

Please cite this article in press as: Rinke A, Krug S, Neuroendocrine tumours e Medical therapy: Biological, Best Practice & Research Clinical Endocrinology & Metabolism (2015), http://dx.doi.org/10.1016/ j.beem.2015.09.004

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Summary Somatostatin analogues (SSA) and IFN-a have favourable antisecretory and antiproliferative effects in well-differentiated neuroendocrine tumours regardless of the origin of primary tumour site. Both biotherapeutic agents obtain similar results for symptomatic response and disease-control rate. However, due to the better tolerability of SSA and the landmark studies PROMID and CLARINET, SSA are considered to be first choice for functioning tumours as well as non-functioning tumours. Although the clinical use of IFN-a is restricted, its clinical impact as salvage therapy in patients not responding to SSA or progressive during SSA treatment should not be underestimated. So far, the combination of SSA and IFN-a did not present any statistically significant differences in prospective randomized trials. But to definitely clarify this issue well-designed randomized trials are needed with pegylated IFN-a and pasireotide being incorporated. To this end, biotherapies provide an ideal platform to investigate novel drugs and treatment approaches to receive synergistic or additive effects. Therefore, future trials should be measured against the clinical benefit of biotherapies. Conflict of interest AR has received travel grants for scientific meetings by Ipsen and Pfizer, honoraria for presentations by Novartis and Ipsen and was member of advisory boards of Ipsen, Novartis and Pfizer. SK has received travel grants for scientific meetings by Ipsen and Novartis. Acknowledgement We thank Patrick Michl for critical revision of the manuscript. References [1] Brazeau P, Vale W, Burgus R, et al. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 1973;179:77e9. *[2] Modlin IM, Pavel M, Kidd M, et al. Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther 2010;31:169e88. [3] Caplin M, Sundin A, Nillson O, et al. ENETS consensus guidelines for the management of patients with digestive neuroendocrine neoplasms: colorectal neuroendocrine neoplasms. Neuroendocrinology 2012;95:88e97. €ssler D, et al. Identification of somatostatin receptor subtypes 1, 2A, 3, and 5 in neuroendocrine [4] Kulaksiz H, Eissele R, Ro tumours with subtype specific antibodies. Gut 2002;50:52e60. €nger J, et al. Somatostatin receptors in bronchopulmonary neuroendocrine neoplasms: new [5] Kaemmerer D, Specht E, Sa diagnostic, prognostic, and therapeutic markers. J Clin Endocrinol Metab 2015;100:831e40. [6] Bauer W, Briner U, Doepfner W, et al. SMS 201-995: a very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci 1982;31:1133e40. [7] Bronstein M, Musolino N, Jallad R, et al. Pharmacokinetic profile of lanreotide autogel in patients with acromegaly after four deep subcutaneous injections of 60, 90 or 120 mg every 28 days. Clin Endocrinol (Oxf) 2005;63:514e9. [8] 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(Suppl. 1):47e50. [9] Weckbecker G, Lewis I, Albert R, et al. Opportunities in somatostatin research: biological, chemical and therapeutic aspects. Nat Rev Drug Discov 2003;2:999e1017. [10] Guillermet J, Saint-Laurent N, Rochaix P, et al. Somatostatin receptor subtype 2 sensitizes human pancreatic cancer cells to death ligand-induced apoptosis. Proc Natl Acad Sci U S A 2003;100:155e60. *[11] Susini C, Buscail L. Rationale for the use of somatostatin analogs as antitumor agents. Ann Oncol 2006;17:1733e42. [12] Eriksson B, Oberg K. Summing up 15 years of somatostatin analog therapy in neuroendocrine tumors: future outlook. Ann Oncol 1999;10(Suppl. 2):S31e8. [13] Hofland LJ, Lamberts SW. The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocr Rev 2003;24:28e47. [14] Kvols LK, Moertel CG, O'Connell MJ, et al. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med 1986;315:663e6. [15] 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;17:600e6. [16] O'Toole D, Ducreux M, Bommelaer G, et al. Treatment of carcinoid syndrome: a prospective crossover evaluation of lanreotide versus octreotide in terms of efficacy, patient acceptability, and tolerance. Cancer 2000;88:770e6. [17] 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;77:402e8. [18] Ricci S, Antonuzzo A, Galli L, et al. Long-acting depot lanreotide in the treatment of patients with advanced neuroendocrine tumors. Am J Clin Oncol 2000;23:412e5.

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