Digestive and Liver Disease

Digestive and Liver Disease 44 (2012) 95 105 Contents lists available at SciVerse ScienceDirect Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld Review Article New treatment strategies in advanced neuroendocrine tumours Thomas Walter a,, Hedia Brixi-Benmansour b, Catherine Lombard-Bohas a, Guillaume Cadiot b a Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Lyon CEDEX 03, France b Service d Hépato-Gastroentérologie et d Oncologie Digestive, CHU Reims, Hôpital Robert Debré, Reims CEDEX, France article info abstract Article history: Received 19 July 2011 Accepted 23 August 2011 Available online 7 October 2011 Keywords: Antiangiogenic Chemotherapy Hepatic embolization Somatostatin Targeted therapy Malignant well-differentiated neuroendocrine tumours of the pancreas and the gastrointestinal tract are rare and clinically challenging heterogeneous neoplasms. This review focuses on neuroendocrine tumours grade 1 and grade 2 (new WHO classification 2010), in comparison to the neuroendocrine tumours grade 3 group, corresponding to poorly differentiated neuroendocrine carcinomas. Surgical resection of the primary and metastases remains the only curative treatment, however many patients with neuroendocrine tumours are diagnosed once unresectable metastases have occurred; management of functioning syndromes with somatostatin analogues remains the priority. Pasireotide, a new somatostatin analogue, is currently undergoing evaluation for carcinoid syndrome. Treatment options for advanced neuroendocrine tumours differ from pancreatic gastrointestinal tract neuroendocrine tumours: (a) in pancreatic neuroendocrine tumours, streptozotocin-based chemotherapies are challenged by other cytotoxic agents (dacarbazine, temozolomide and oxaliplatin); two randomized, placebo-controlled phase III studies have demonstrated that everolimus and sunitinib significantly improved progressionfree-survival; (b) in midgut neuroendocrine tumours, octreotide improved time-to-progression in patients with a low proliferation index and low liver burden; preliminary data suggesting efficacy of bevacizumab are still to be confirmed; the effect of everolimus associated with octreotide was almost significant on progression-free-survival in a phase III trial. Liver-directed therapies are effective in both tumour types. New techniques of embolization need further evaluation and must be formally compared to other therapies. Finally, peptide receptor radionuclide therapy has shown promising activity in non-comparative studies in advanced neuroendocrine tumours. 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. 1. Introduction Well-differentiated neuroendocrine tumours (NETs) of the gastroenteropancreatic system are rare neoplasms that arise from the diffuse neuroendocrine cell system. They include pancreatic NETs (P-NETs), sometimes called islet-cell carcinomas, and NETs developed from the gastrointestinal tract (GI-NETs), also called carcinoid tumours by some authors. The 2000 WHO classification of gastro-entero-pancreatic NETs (GEPNETs) classifies tumours according to their primary tumour site and differentiation [1]; this review focuses on malignant well-differentiated endocrine carcinomas. The new WHO classification 2010 classified these tumours as NETs grade (G)1 and NETs G2, in comparison to the NETs G3 group which corresponds to poorly differentiated neuroendocrine carcinomas, either small cell or large cell neuroendocrine carcinomas [2]. GEPNETs are still considered rare with a 2004 estimated annual incidence of 5.25 per 100,000 population, but both their incidence and their prevalence are increasing [3]. Functioning Corresponding author at: Pavillon H, Hôpital Edouard Herriot, 69437 Lyon CEDEX 03, France. GEPNETs are characterized by specific secretion-related symptoms, which are present in less than 2 of patients with metastatic GEP- NETs. The patient prognosis with GEPNETs is very heterogeneous and is dependent upon the histological differentiation, the staging and the grading of the tumour [3,4]. The European NET Society (ENETS) and the American Joint Cancer Committee/Union Internationale Contre le Cancer (AJCC/UICC) tumour-nodes-metastasis (TNM) system were recently published in order to better address their prognosis and to better stratify patients in future trials [5 9]. Surgical resection of the primary and the metastases, when possible, remains the only curative treatment in patients with GEP- NETs. However, many patients are diagnosed once unresectable metastases have occurred and the treatment is then more challenging. The treatment of the carcinoid syndrome or other functioning syndrome is the first priority. Following this, different options are available in this situation ranging from close surveillance for indolent tumours, through liver-directed treatment (radiofrequency or transarterial embolization) to systemic therapy (somatostatin analogs (SSA) or interferon, cytotoxic and molecular targeted therapies, radionuclide treatment); however, no direct comparison between these strategies exists [10,11]. As a result, this disease is often managed based on expert recommendations from national 1590-8658/$36.00 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2011.08.022

96 T. Walter et al. / Digestive and Liver Disease 44 (2012) 95 105 or international societies: Groupe d étude des Tumeurs Endocrines (GTE), ENETS, National Comprehensive Cancer Network (NCCN), or North American NET Society (NANETS) for instance. Treatment should be highly individualised based on symptoms, general health status, comorbidities, tumour burden, degree of uptake of radionuclide, histological features, and tumour growth. This review will focus on the management of advanced GEPNETs as defined above, and exclude carcinoid of the lung and poorly differentiated endocrine carcinoma, i.e. NETs G3 from the 2010 WHO classification. 2. Treatment of functioning GEPNETs Functioning NETs are characterized by the symptoms related to their secretion. Carcinoid syndrome, but not for all other functioning syndromes, is usually only observed when metastases to the liver have occurred. The functioning syndrome must be treated in priority. SSA are the standard medical therapy for the treatment of the disease-related symptoms of functional GI-NETs (known as carcinoid syndrome) and functional P-NETs (vipoma, glucogonoma), except insulinoma and Zollinger-Ellison syndrome [12,13]. SSA act primarily via binding to SSTR2. Octreotide and lanreotide are considered equally effective in controlling symptoms related to functioning syndromes; they provide symptomatic improvement in approximately 50 9 of patients [13,14]. These drugs are well tolerated and safe. However, tachyphylaxis and resistance to octreotide or lanreotide can occur as early as 12 18 months after initiation of therapy. Pasireotide is a novel cyclohexapeptide SSA that exhibits a binding affinity which is 30 40 times higher for human SSTR1 and SSTR5, 5 times higher for human SSTR3, and 2.5 times lower for SSTR2 [13]. Pasireotide is currently being tested in patients with acromegaly, Cushing s disease, and functional as well as non-functional NETs. Preliminary results showed symptom improvement in 27% of 45 patients with carcinoid syndrome refractory/resistant to octreotide LAR with good tolerance except for episodes of hyperglycaemia [15]. A randomized multicenter phase III trial comparing octreotide LAR with pasireotide LAR in octreotide LAR refractory carcinoid syndromes is ongoing (www.clinicaltrials.gov). Lastly, everolimus seems to be effective in the control of hypoglycemia related to metastatic insulinoma [16]. 3. Surgical and radiological treatments 3.1. Surgery and local ablation Although not evaluated in randomized trials, surgery is considered to provide the best chance of prolonged survival with advanced NETs [11,17]. Resection or destruction of all liver metastases associated with that of the primary tumour and associated lymph nodes is the goal, although open studies showing that debulking surgery (>9 tumour mass) improved symptoms have been published [17,18]. Destruction of all the liver metastases has been rendered increasingly possible by the use of one or two-step surgery and/or with local ablation (radiofrequency, cryoablation) [19 22]. However, recurrence rate is very high, up to 81%, mainly depending on tumour grade [23]. It has been demonstrated that liver recurrence is due to very small liver metastases which are not detected on preoperative imaging and account for at least 5 of the metastases [24]. Unfortunately, adjuvant chemotherapy with streptozotocin and 5-fluorouracil (5-FU) after liver surgery does not seem to be efficient [25]. One major point concerns the indications of the surgical resection of the primary tumour in patients with non-resectable liver metastases. Although it is recommended that primary ileal tumours and the associated lymph nodes must be resected in patients with good personal health status to avoid local complications [17,26,27], the same has not been proven for P-NETs [11]. In a non-randomized study, Bettini et al have not been able to show a significant increase in survival in the group with surgery of the pancreatic primary, but suggested that resection should be considered as symptomatic palliative therapy when the proliferative index is below 1 [28]. Resection is also recommended when local complications have occurred or are expected [17]. Finally, liver transplantation is a therapeutic option in an highly selected group of patients with stable or slowly progressive disease and good prognostic criteria: age <55 years and without simultaneous pancreatic resection in a recent review of 89 transplanted patients with metastatic P-NETs [29] and 0 or 1 of the following criteria in a French experience of 85 cases: no upper abdominal exenteration, no duodenal/pancreatic primary and no hepatomegaly [30]. 3.2. Transarterial therapies Liver neuroendocrine metastases are mainly fed from the hepatic artery and the normal liver from the portal vein. Transarterial embolization (TAE) or transarterial chemoembolization (TACE), have been shown to be highly effective in case of liver predominant disease with diffuse non-resectable liver metastases with a reduction in symptoms of 60 95% [11,31] and response rate of approximately 5 (37 74%) in most studies (Table 1). In only one study the response rate was a low 6% [32]. However, this was a large multicentre retrospective study whose primary aim was not to evaluate tumour response rate but to compare survival rates in patients treated with transarterial therapies or surgery. Although the long duration of response rates or progression-free-survival (PFS) compares favourably with those obtained with chemotherapy or targeted therapies, transarterial therapies have not been compared to other therapies, its optimal regimen has not been determined, comparisons between embolization and chemoembolization have not been published, and its morbidity (and even mortality) rate is high, respectively 48% and 2% as seen in the largest study [32]. The efficacy seems similar whatever the primary location. Predictors of efficacy are arterial phase enhancement on CT or MRI and high body mass index [33]. Dong et al showed that lower age, high albumin level and low prothrombine time were associated with longer survival after transarterial therapies [34]. Transarterial chemotherapy has been studied in only one series with low response rates [35] (Table 1). TACE with drug-eluting beads has been performed in two small studies, giving results similar to TAE/TACE [36,37]. Comparative studies are required. Selective internal radiation therapy (SIRT) or radioembolization consists of the administration of resin Yttrium-90 microspheres in the hepatic artery. It gave 50 63% response rates, which seems similar to other transarterial therapies (Table 1). Specific complications including radiation-induced liver disease, hepatic abscess, acute cholecystitis or pancreatitis, gastric ulceration, arterial shunting to the lung should be well-understood by clinicians [11]. 4. Medical treatment 4.1. Somatostatin analogues In recent years, accumulating data has supported the role of SSA as antiproliferative agents: objective response occurs in only 3 8% of patients and disease stabilization in 35 8 of patients with metastatic NETs [13,38]. The PROMID study, a prospective, randomized, placebo-controlled, phase III trial has definitely shown that octreotide long-acting repeatable (LAR) significantly prolongs time to tumour progression among patients with advanced midgut (ileum and proximal colon) NETs (Table 2) [39]. The study

T. Walter et al. / Digestive and Liver Disease 44 (2012) 95 105 97 Table 1 Transarterial therapies: results of the main studies (2000 2011). First author (Ref), year n Technique OR (%) Duration of response (%) PFS (months) Dominguez [84], 2000 15 TACE 53 11 Gupta [85], 2003 81 TAE/TACE 67 17 19 Loewe [86], 2003 23 TAE 73 Roche [87], 2004 64 TACE 74 18 Strosberg [88], 2006 23 TAE 48 Marrache [32], 2007 67 TACE 37 14 15 Granberg [89], 2007 15 TAE 40 6 Ho [90], 2007 46 TAE/TACE 30 (in 33 pts) 19 Vogl [34], 2009 48 TAC 11 23 a Dong [33], 2010 123 TACE 62 Mayo [31], 2011 414 TAE/TACE/SIRT 6 Whitney [91], 2011 28 TACE 100 at 3 months 18 King [92], 2008 24 SIRT 50 Rhee [93], 2008 42 SIRT 51 Kennedy [94], 2008 148 SIRT 63 Saxena [21], 2010 48 SIRT 54 Whitney [91], 2011 15 SIRT 100 at 3 months 14 All studies but two ([85,86]) included patients with carcinoids and pancreatic neuroendocrine tumours. n: number of patients, OR: objective response rate, PFS: progression free survival, TACE: transarterial chemoembolization, TAE: transarterial embolization, TAC: transarterial chemotherapy, SIRT: selective internal radiation therapy with Yttrium-90 microspheres, : not available. a According to two different chemotherapy regimens. population of 85 patients was homogenous: 74% of patients had octreotide uptake; 39% of patients presented with mild carcinoid syndrome and who tolerated symptoms without SSA; 75% of patients had low liver tumour burden ( 1); and 95% of tumours had low proliferation index Ki67 (<2%). In multivariate analysis the most favourable effect was observed in patients with low liver burden ( 1) and resected primary tumours. The overall survival rate was not different. This study raises questions regarding whether octreotide should be initiated at the time of diagnosis in metastatic midgut NETs or only at the time of disease progression, and whether these data can be extrapolated to patients with a large tumour load or with high Ki67 or with P-NETs? Another similar multi-centre, placebo-controlled European Phase III study is ongoing to assess whether lanreotide autogel prolongs time to disease progression in patients with non-functioning GEPNETs, including P-NETs (www.clinicaltrials.gov). Ongoing studies are also evaluating pasireotide. Finally, the potential additive or synergetic antitumor effects of SSA in combination with other antitumor therapies such as mammalian target of rapamycin (mtor) inhibitors or anti-angiogenic agents have not yet been established. 4.2. Interferon Most of the studies that evaluated the anti-tumour effect of interferon (IFN) were not prospective and controlled. A phase III study comparing IFN- -2a (3 MU 3 per week) to chemotherapy with 5-FU and streptozotocin in 64 patients with advanced carcinoid tumours showed no significant difference in PFS and overall survival but a trend in favour of IFN with 14.1 months PFS in the IFN group versus 5.5 months in the chemotherapy group [40]. Comparative studies have shown a similar anti-tumour effect of IFN and SSA [41], but tolerance favours the use of SSA [11]. Finally, pegylated- IFN -2b has been studied in 17 patients with progressive disease under octreotide therapy, some having previously been switched to conventional IFN [42]. Stabilization was observed in 13 (76%). Tolerance was better than that of conventional IFN. 4.3. Peptide receptor radionuclide therapy (PRRT) PRRT is based on the high prevalence of somatostatin receptors on most neuroendocrine tumour cells, with somatostatin analogues acting as the ligand for the radionuclide [11,43]. Objective response rates with [ 111 In-DTPA 0 ]octreotide at high cytotoxic doses are low (3 8%) probably due to the short tissue penetration of gamma electrons emitted by the 111In isotope (Table 3). Both the beta-emitting radionuclides 90 Y and 177 Lu have shown promising antitumoral effects (Table 3); the largest study series showed a 39% tumor control rate [44]. Very heterogeneous results may reflect their heterogenous methodologies and recruitment methods (Table 3). The different types of PRRT have not been compared to each other or to any other anti-tumour therapy. Well-designed Table 2 Recent phase III randomized clinical trials in advanced neuroendocrine tumours (2009 2011). First author (Ref), year Tumour site Experimental versus control group n Type of PEP Results in PEP (months) HR (95% CI) P value OS QoL Rinke [38], 2009 Midgut Octreotide vs placebo Raymond [70], 2011 Pancreas Sunitinib vs placebo Yao [76], 2011 Pancreas Everolimus vs placebo Pavel [77], 2011 Carcinoid Everolimusoctreotide LAR vs placebooctreotide LAR 42 43 86 85 207 203 216 213 TTP 14.3 6.0 PFS 11.4 5.5 PFS 11.0 4.6 PFS 16.4 11.3 0.34(0.20 0.59) 0.000072 NSD NSD 0.42(0.26 0.66) <0.001 SD NSD 0.35(0.27 0.45) <0.0001 NSD 0.77(0.59 1.00) 0.026 NSD n: number of patients, PEP: Primary end point, HR: hazard ratio, CI: confidence interval, OS: overall survival, QoL: quality of life, PFS: progression-free survival, TTP: time to progression, NSD: not significantly different, SD: significantly different in favour of experimental group, : not available.

98 T. Walter et al. / Digestive and Liver Disease 44 (2012) 95 105 Table 3 Peptide receptor radionuclide therapy in well-differentiated neuroendocrine tumours: results of the main studies (2002 2011). First author (Ref), year n PD (%) at inclusion CR (%) PR (%) SD (%) PD (%) Outcome (months) 111In-Pentetreotide Valkema [95], 2002 40 0 3 50 47 Anthony [96], 2002 26 0 8 81 11 Nguyen [97], 2004 15 0 0 a 80 a 20 a TTP:17 Delpassand [98], 2008 18 0 11 88 0 90 Y-DOTA-TOC/ 90 Y-DOTA-TATE Paganelli [99], 2002 87 76 5 23 49 20 TTP:14 Valkema [100], 2006 58 76 0 9 62 24 TTP:29 Forrer [101], 2006 116 93 4 22 62 11 Cwikla [102], 2010 60 100 0 23 70 0 PFS:17 Pfeiffer [103], 2010 53 57 4 19 65 12 PFS:29 Imhof [43], 2011 1109 100 34 5 61 177 Lu-DOTA-TATE Kwekkeboom [104], 2008 310 43 2 28 50 20 PFS:33 90 Y-edotreotide Bushnell [105], 2010 90 100 0 4 70 12 PFS:16 n: number of patients, : not available, CR: complete response, PR: partial response, SD: stable disease, PD: progressive disease, TTP: time to tumour progression, PFS: progression free survival. a At 3 months. comparative studies are necessary. This must include long-term evaluation of tolerance, especially on the bone marrow and kidneys, because PRRT might preclude the further use of other therapies in cases of induced haematological or renal toxicity. Renal toxicity was much reduced when kidney protective agents were used [43]. However, permanent renal toxicity was noted in 9% of the largest series [44]. In this series, the initial kidney uptake was predictive of severe renal toxicity [44]. Combined (90)Y/(177)Lu-DOTATATE therapy has shown encouraging results in a small non-controlled study as compared to (90)Y-DOTATATE [45]. It should be further evaluated as should its combination with chemosensitisers. Best results are observed in patients in good condition without major liver involvement [43]. However, the same conclusion has been drawn with most other anti-tumour therapies. Treatment should be limited to patients with high tumour uptake at somatostatin receptor radionuclide scan (Grades 3 4) [43,44]. 4.4. Traditional chemotherapy The efficacy of chemotherapy varies according to the NET type: P-NETs, are often chemotherapy sensitive while GI-NETs are often chemotherapy resistant [11,17]. Streptozotocin-based chemotherapies are still the reference therapy of advanced progressive well-differentiated P-NETs [11,17,26]. However, recent data obtained using old drugs (dacarbazin) or new regimens (temozolomide, oxaliplatin) clearly show that streptozotocin-based therapies are challenged. There is no phase III, well-conducted prospective, randomized study comparing streptozotocin-based therapies with another therapy (especially targeted therapies, chemoembolization or other chemotherapy) in patients with P-NETs. Most series are phase II and retrospective. Some recent series are prospective, but few were conducted in chemotherapy-naive patients with progressive tumours and with well-defined prognostic criteria. Results obtained with the main associations are indicated in Table 4. Finally, a small retrospective study has suggested that the etoposidecisplatin combination might be as effective in well-differentiated NETs with high proliferative index (Ki67 15%) as in poorly differentiated NETs where it is the reference regimen [46]. This should be further evaluated. 4.4.1. Chemotherapy of advanced well-differentiated P-NETs The two studies published by Moertel et al. in 1980 and 1992 do not meet the current required levels of methodological quality and should no longer be cited as the reference for streptozotocinbased regimens in P-NETs [47]. Three recent uncontrolled phase II studies have shown 36 4 objective response rates using a doxorubicin-streptozotocin regimen [48,49] (Table 4); however, two much smaller studies have shown 6% objective response rates only [50,51]. Resulting cardiac and renal toxicities and hair loss limit its use, although liposomal doxorubicin might have less cardiac toxicity [52]. In the 5-fluorouracil, cisplatin, streptozotocin regimen that has been tested in chemotherapy-naive patients with several types of NETs including pancreas, intestine, well- and poorly differentiated tumours, the main factors of efficacy were low Ki67 and mitotic index [53]. In the 47 patients with P-NETs treated with that regimen, the objective response rate was 38% and stabilization 51% [53]. An alternative is based on dacarbazin or on temozolomide, an oral drug converted to the same active metabolite as dacarbazin: the methyl-triazeno-imidazole-carboxamide (Table 4). A recent retrospective study treated 30 patients naive of chemotherapy with progressive tumours with the combination of temozolomide and capecitabin and showed 7 objective response rate and 27% stabilization with a median PFS of 18 months [54]. Such high response rates have never been observed previously with any other therapy in P-NETs. Dacarbazin and temozolomide efficacy might be related to deficiency of O 6 -methylguanine DNA methyltransferase (MGMT) [55], but it has not been established by all authors [56]. MGMT deficiency is observed in up to 5 to P-NETs but in very few GI- NETs. The efficacy of dacarbazin has been established in several studies (Table 4). One of the most recent evaluated the association of dacarbazin, 5-fluorouracil and epirubicin in several types of NETs in patients previously treated with other therapies [57]. Of the 16 patients with P-NETs, the objective response rate was 58%, the stabilization rate 37% and a PFS of 17 months [57]. Oxaliplatin-based regimens have been tested in small series of various NETs types in association with gemcitabin, capecitabin or 5-fluororuracil, giving encouraging results (Table 4). Finally FOLFIRI, a regimen associating 5-fluorouracil, leucovorin and irinotecan has been prospectively tested in 20 chemotherapynaive patients with progressive, advanced and well-differentiated P-NETs. It showed stabilization in 75% of patients and an objective response in only one patient [58]. 4.4.2. Chemotherapy of advanced well-differentiated carcinoid tumours A recent randomized study compared 5-fluorouracilestreptozotocin regimen to IFN in 64 patients with various types of carcinoid tumours, and confirmed that this chemotherapy regimen was not efficacious with only 1 patient (3%) in the chemotherapy

Table 4 Effects of chemotherapy in well-differentiated neuroendocrine tumours: results of recent studies (1999 2011). First author (Ref), year Chemotherapy n and type PD (%) at inclusion Chemotherapy-naïve (%) OR (%) SD (%) Outcome (months) Cheng [49], 1999 STZ doxo 16 P-NETs 88 6 56 Duration 18+ McCollum [50], 2004 STZ doxo 16 P-NETs 88 6 38 PFS 4 Delaunoit [47], 2004 STZ doxo 45 P-NETs 76 36 25 Duration 20 Kouvaraki [48], 2004 STZ doxo 5FU 84 P-NETs 100 39 50 Duration 9, PFS 18 Fjällskog [51], 2008 STZ doxo 30 P-NETs 100 40 57 Duration 9 (liposomal) Dahan [39], 2009 STZ doxo 32 carc 100 87 3 56 PFS 6 Turner [52], 2010 STZ doxo cisplatin 79 various NETs including 47 P-NETs 67 Sun [58], 2005 STZ 5FU 88 carc 100 16 15 PFS 5 Sun [58], 2005 5FU doxo 88 carc 100 16 15 PFS 5 Sun [58], 2005 Dacarbazin 91 carc 16 8 PFS 4 Ramanathan [106], 2001 Dacarbazin 50 P-NETs 44 34 Duration 10 Bajetta [107], 2002 5FU dacarbazin 82 various NETs 100 24 40 TTP 21 epirubicin Ekeblad [55], 2007 Temozolomide 36 various NETs 6 14 53 TTP 7 Maire [24], 2009 Temozolomide 21 various NETs 100 29 5 81 TTP 9 Kulke [54], 2009 Walter [56], 2010 Strosberg [53], 2011 Bajetta [108], 2007 Cassier [109], 2009 Temozolomidebased therapies a 5FU dacarbazin epirubicin Capecitabin temozolomide Capecitabin oxaliplatin Gemcitabin oxaliplatin 53 pnets 44 carc 100 33 38 51 51 TTP 9 34 2 PFS 14 PFS 10 16 P-NETs16 carc 74 54 58 25 37 69 Duration 19Duration 5 30 P-NETs 67 100 70 27 PFS 18 27 various NETs 100 100 30 48 Duration 12, TTP 20 20 various NETs 100 10 17 67 PFS 7 Ducreux [110], 2006 Folfiri 20 various NETs 85 20 5 75 PFS 5 Brixi-Benmansour [57], 2011 Folfiri 20 P-NETs 100 100 5 75 PFS 9 Hentic [45], 2010 Etoposide cisplatin 14 various NETs b 14 36 n: number of patients, STZ: streptozotocine, Doxo: doxorubicin, 5FU: 5 fluorouracil, Folfiri: 5-fluorouracil, leucovorin and irinotecan, carc: carcinoid tumours, P-NETs: pancreatic neuroendocrine tumours, : not available, PD: progressive disease, OR: objective response, SD: stable disease, TTP: time to tumour progression, PFS: progression free survival, Duration: duration of OR, Various NETs: various types of NETs. a Alone or associated with thalidomide, bevacizumab or xeloda. b With Ki67 15%. T. Walter et al. / Digestive and Liver Disease 44 (2012) 95 105 99

100 T. Walter et al. / Digestive and Liver Disease 44 (2012) 95 105 arm experiencing a partial response [40]. In contrast, there was a trend in favour of IFN therapy with a median PFS of 14.1 months as compared to 5.5 months in the chemotherapy arm [40]. Another randomized study showed low objective response rates and stabilization rates with the combination streptozotocindoxorubicin and streptozotocin-5fu, respectively 16% and 15% [59]. However, some of the previously cited chemotherapy studies suggested that clinically significant results could be obtained in some patients with GI-NETs, although less impressive compared to those of in patients with P-NETs, especially with the association 5-fluorouracil, dacarbazin, and epirubicin [57] or the association of streptozotocin, doxorubicin, and cisplatin [53]. This should be confirmed in controlled studies. 4.5. Angiogenesis inhibitors and others new targeted therapies Most well-differentiated GEPNETs are highly vascularised with high expression of pro-angiogenic molecules, such as the vascular endothelial growth factor (VEGF) [60], along with overexpression of certain tyrosine kinase receptors, such as the epidermal growth factor receptor (EGFR), the insulin growth factor receptor, and their downstream signalling pathway components (PI3K-AKTmTOR). Molecular targeted therapies present a promising approach for the treatment of GEPNETs. Currently, there are a number of new drugs undergoing evaluation (Tables 2 and 5). They could be divided into three groups as follows: (i) drugs targeting VEGF, such as the VEGF monoclonal antibody bevacizumab and a more recent related compound, VEGF-trap; (ii) small molecules that inhibit the intracellular tyrosine kinase domain of the VEGF receptor or other growth factor receptors, such as sunitinib, sorafenib, and pazopanib and (iii) other compounds inhibiting different signalling-pathway components such as the EGFR, insulin-like growth factor 1 receptor, phosphoinositide-3-kinase, RAC-alpha serine/threonine-protein kinase (AKT), and the mammalian target of rapamycin (mtor). 4.5.1. Bevacizumab The first published trial of bevacizumab in NETs was performed in 44 patients with advanced carcinoid tumours. Patients were randomly assigned to treatment with bevacizumab or pegylated- IFN [61]. At week 18, the progression-free survival rate (which was not the primary aim) was 95% in the group receiving bevacizumab versus only 67% in the group receiving pegylated-ifn. A rapid reduction in blood tumour perfusion measured by functional computed tomography scan was demonstrated in the bevacizumab-treated patient. Based on the promising results in this first study, a confirmatory randomized phase III trial is ongoing, comparing octreotide-bevacizumab with octreotide-ifn in advanced carcinoid tumours, with progression-free survival as the primary endpoint (www.clinicaltrials.gov). The experience with bevacizumab in other solid tumours such as colorectal cancer has shown that its addition to chemotherapy can significantly improve outcomes, whereas the clinical activity of the drug as a single agent is irrelevant. Different combinations of bevacizumab with temozolomide [14], capecitabine-oxaliplatine [62], or 2- methoxyestradiol [63] are ongoing or recently reported (Table 5 and www.clinicaltrials.gov). However, it is difficult to evaluate if the addition of bevacizumab has really improved the outcome of the treated patients compared with those who would have just received chemotherapy. Therefore, it is too early to use bevacizumab except in clinical trials, especially because the role of VEGF may be different in GEPNETs than in other malignancies [64]. Other anti-angiogenic agents (endostatine, thalidomide) have been tested in phase II trials (Table 5), but their development has been currently stopped because of their toxicity (thalidomide) and/or their lack of efficacy [65 67]. 4.5.2. Multikinase inhibitors Three multikinase inhibitors (sunitinib, sorafenib, and pazopanib) have been tested in phase II trials for advanced GEPNETs (Table 5), with close results in term of efficacy: very low objective response rates were observed (0 7%), always lower in GI-NETs than in P-NETs; stable disease was frequent (70 83%), and the median PFS ranged from 7.7 to 12.7 months [68 70]. In 2011, Raymond et al. reported a phase III randomized, placebocontrolled, double blind study, demonstrating the efficacy of sunitinib (activity against VEGFR-1 to 3, PDGFR, FLT-3, c-kit and RET) (37.5 mg per day) in patients with advanced P-NETs [71]. The study was discontinued before the first planned interim analysis after the enrolment of 171 patients and the observation of 81 PFS events. There was a 2.2-fold prolongation in median PFS in the sunitinib group versus placebo group (Table 2). The significant difference between the two arms in overall survival has not been confirmed in a further analysis [72]. Most common adverse events (AEs) were diarrhea, nausea, asthenia and vomiting; grade 3/4 AEs included neutropenia (12%), hypertension (1), hand-foot syndrome (6%) and leucopenia (6%). No other phase III data are available for any other multikinase inhibitor in GI-NETs, and no comparison has been done with streptozotocin-based therapy or other chemotherapy in P-NETs. 4.5.3. mtor inhibitors The third approach in news drugs has focused on inhibiting different signalling-pathway components. The best example is represented by mammalian target of rapamycin (mtor), which is an intracellular serine/threonine kinase that acts as a central regulator of multiple signalling pathways (IGF-I, EGF, VEGF) that participates in the regulation of apoptosis, angiogenesis, proliferation and cell growth through modulation of cell cycle progression [73]. Two rapamycin derivatives have been evaluated in GEP- NETs: temsirolimus [74] and everolimus [75 77]. The results of phase II studies are reported in Table 5. Two large phase III placebo-controlled randomized trials recently reported the efficacy of everolimus in patients with advanced P-NETs (RADIANT-3) and GI-NETs (RADIANT-2) (Table 2). In the RADIANT-3 study, everolimus significantly increased PFS (11.0 months) as compared to placebo (4.6 months) with a 65% reduction in the risk of disease progression (Table 2) [77]. This superiority was observed in all subgroups of patients. No difference in terms of overall survival was observed (cross-over in case of progression in the placebo arm). The RADIANT-2 study compared everolimus-octreotide with placebooctreotide in patients with advanced GI-NETs [78]. Although the study failed to reach its primary endpoint (PFS by central review), the moderate increase in median PFS in the everolimus group versus placebo group is considered clinically significant because the difference in PFS was statistically significant by local investigator review (Table 2). More than 1,000 people have been now treated in trials by everolimus [75 78]: most AEs were Grade 1 or 2, although Grade 3/4 AEs did occur; hematologic events, diarrhea, stomatitis, and hyperglycemia were the most prevalent (ranging from 3% to 7%). Other studies testing everolimus in combination with pasireotide, sorafenib or bevacizumab are ongoing (www.clinicaltrials.gov). 5. Conclusion and algorithms of treatment in patients with advanced NETs Much advancement in treatment options have been observed over recent years. Although there is no randomised comparison between most of these treatments, guidelines and management

T. Walter et al. / Digestive and Liver Disease 44 (2012) 95 105 101 Fig. 1. Management algorithm for patients with (a) advanced neuroendocrine tumours (NETs) of the gastrointestinal tract, (b) or with advanced pancreatic NETs. Abbreviations: mtor: mammalian target of rapamycin; PPI: proton pump inhibitor; RFA: radiofrequency ablation; TAE: transarterial embolization.

102 T. Walter et al. / Digestive and Liver Disease 44 (2012) 95 105 Table 5 Main phase II trials in advanced neuroendocrine tumours testing novel targeted therapies. Author Experimental drugs n and type OR (%) SD (%) PFS (months) Bevacizumab Yao [60], 2008 Bevacizumab versus Pegylated interferon 22 carc 22 carc 18% 5% 77% 68% 95% at 4 months 67% Kunz [61], 2008 Capecitabine-oxaliplatine + bevacizumab 12 NETs 18% 63% 14.1 Kulke [14], 2006 Temozolomide + bevacizumab 12 carc 17 P-NETs 24% Kulke [62], 2011 2-Methoxyestradiol + bevacizumab 28 carc 96% 11.3 Multikinase inhibitors Kulke [67], 2008 Sunitinib 41 carc 66 P-NETs 2% 17% 83% 68% TTP = 10.2 TTP = 7.7 Hobday [68], 2007 Sorafenib 50 carc 43 P-NETs 7% 11% 4 at 6 months 6 Phan [69], 2010 Pazopanib 20 carc 30 P-NETs 19% mtor inhibitors Duran [73], 2006 Temsirolimus 21 carc a 5% 15 P-NETs a 7% Yao [74], 2008 Everolimus 30 carc 17% 30 P-NETs 27% Yao [75], 2010 Everolimus 115 P-NETs a 1 Everolimus + octreotide 45 P-NETs a 4% LAR Other angiogenesis inhibitors Varker [64], 2008 Thalidomide 12 carc 4 P-NETs Kulke [66], 2006 Temozolomide + thalidomide 14 carc 7% 11 P-NETs 45% Kulke [65], 2006 Endostatine 22 carc 20 P-NETs 7 69% 57% 6 8 6 68% 8 75% 5 12.7 11.7 6.0 10.6 14.5 11.5 9.7 16.7 Not reached n: number of patients, OR: objective response, SD: stable disease, PFS: progression-free survival, TTP: time to progression, carc: carcinoid tumours, P-NETs: pancreatic neuroendocrine tumours, : not available. a Patients with disease progression at inclusion. 7.6 5.8 algorithms have been proposed by the ENETS, [17,79 81], the NCCN [26], the NANETS [27,82,83], the European Society for Medical Oncology (ESMO) [84], and the French Thesaurus National de Cancérologie Digestive (www.tncd.org). Personal algorithms for GI-NETs and P-NETs are detailed in Fig. 1a and b. Management of all patients with NETs must be discussed in multidisciplinary rounds including the surgeon, interventional radiologist, pathologist, gastroenterologist and oncologist in order to propose therapies adapted to each individual. In France since 2009, regional multidisciplinary rounds have been gradually developed specifically to focus on the treatment of NETs as a last resort for difficult cases (www.sfendocrino.org/article/257/renaten). Resection or destruction of all liver metastases associated with the primary tumour and associated lymph nodes is the goal. In patients with midgut NETs, resection of the primary tumour with mesenteric lymph nodes is recommended by most of the experts, even in the presence of unresectable liver metastases, to avoid local complications [26,27,79]. The treatment of the carcinoid syndrome is primarily based on SSA. Since the publication of the PROMID study, SSA may be also considered for asymptomatic patients with midgut advanced NETs, at least with progressive tumours. In these patients, SSA effect seems limited to those with low hepatic burden and low proliferation index. Liver-directed therapy and surgical debulking are indicated in selected patients with GI-NETs and symptomatic and/or progressive disease; new techniques of embolization exist and need to be better evaluated. TAE/TACE are probably the most effective therapies in GI-NETs with predominant liver metastases with high response rates. GI-NETs are usually chemoresistant and few antineoplastic treatments currently exist. Interferon is used in second-line treatment for functioning GI-NETs, it might have an anti-tumoral effect. The impact of everolimus on PFS is low but is considered clinically significant. It should be limited to patients in whom other therapies are not indicated, especially TAE/TACE. PRRT showed promising activity especially with lutetium agents, but further studies comparing its efficacy with other treatments are warranted. In patients with advanced P-NETs (Fig. 1b), the anti-tumoral effect of SSA for non-functional P-NETs with low grade and low progression, although probable based on open studies, has not yet been proven. The first line treatment in progressive disease remains chemotherapy with drugs such as dacarbazin, temozolomide or oxaliplatin, challenging streptozotocin-based chemotherapies. Chemotherapy can induce high response rates that might allow the secondary surgical resection of the tumours. Targeted therapies, such as everolimus and sunitinib significantly increased PFS but gave low objective response rates. The comparison between chemotherapy and targeted therapy in first line systemic treatment is urgently warranted. Finally, including patients with GEPNETs in prospective studies testing new agents or therapeutic strategies is primordial; these studies ought to include translational research in order to elucidate the mechanisms of adaptive resistance of these new drugs available in the treatment of GEPNETs. Conflicts of interest statement T. Walter contributed for consulting fees Novartis, Ipsen, Roche. H. Brixi-Benmansour contributed for fees and invitations to meetings: Ipsen, Novartis. C. Lombard-Bohas contributed as consultant: Novartis, Keocyt, Roche; also contributed for fees: Novartis, Ipsen, Amgen. G. Cadiot contributed as consultant: Ipsen, Novartis; contributed for fees: Ipsen, Novartis, Pfizer, and invitations to meetings: Ipsen, Novartis; also contributed as principal investigator of FFCD 0302 study (NCT00416767) partially funded by Pfizer.

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