Gastrointestinal neuroendocrine tumors: Searching the optimal treatment strategy—A literature review

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Critical Reviews in Oncology/Hematology journal homepage: www.elsevier.com/locate/critrevonc

Gastrointestinal neuroendocrine tumors: Searching the optimal treatment strategy—A literature review Berardi Rossana a,∗ , Rinaldi Silvia a , Torniai Mariangela a , Morgese Francesca a , Partelli Stefano b,1 , Caramanti Miriam a , Onofri Azzurra a , Polenta Vanessa b,1 , Pagliaretta Silvia a , Falconi Massimo b,1 , Cascinu Stefano a,2 a

Medical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I, GM Lancisi, G Salesi, Ancona, Italy Chirurgia del Pancreas, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I, GM Lancisi, G Salesi, Ancona, Italy b

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 P-NETs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1. First approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Localized P-NETs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1.1. 3.1.2. Locally advanced P-NETs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Metastatic P-NETs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1.3. 3.2. Second approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.3. Further approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4. GI-NETs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.1. First approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.1.1. Localized and locally advanced GI-NETs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.1.2. Metastatic GI-NET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.2. Second and further approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Author contribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

a r t i c l e

i n f o

Article history: Received 7 November 2014 Received in revised form 29 March 2015 Accepted 4 November 2015 Keywords: Neuroendocrine tumor Surgery Somatostatin analogs Sunitinib

a b s t r a c t Neuroendocrine tumors of the gastro-entero-pancreatic system (GEP-NETs) are a heterogeneous group of neoplasms, with different malignant potential and behavior. Many treatment options are available. Surgery should be considered for localized tumors and in some selected cases of metastatic disease. Somatostatin analogs, useful for symptoms control in functioning tumors, are also effective to inhibit tumor progression in specific settings. The multi-TKI sunitinib and of the mTOR-inhibitor everolimus are efficacy for metastatic pancreatic NET (P-NET) treatment. Chemotherapy is generally used in symptomatic and progressive NETs. Peptide receptor radionuclide therapy (PRRT) should be recommended after failure of medical therapy. For tumors confined to the liver ablative techniques should be considered. Nevertheless a shared therapeutic sequence for GEP-NET treatment still does not exist. In this

∗ Corresponding author at: Medical Oncology Unit, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria, Ospedali Riuniti Umberto I, GM Lancisi, G Salesi di Ancona, Via Conca, Ancona 71-60126, Italy. Fax: +39 71 5965053. E-mail address: [email protected] (B. Rossana). 1 Actual position: Chirurgia del Pancreas, Ospedale San Raffaele IRCCS, Università Vita e Salute, Milano, Italy. Fax: +39 71 5964440. 2 Actual position: Oncologia Medica, Università delgli studi di Modena e Reggio Emilia. http://dx.doi.org/10.1016/j.critrevonc.2015.11.003 1040-8428/© 2015 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Rossana, B., et al., Gastrointestinal neuroendocrine tumors: Searching the optimal treatment strategy—A literature review. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.11.003

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2 Everolimus Chemotherapy Peptide receptor radionuclide therapy

review, we analyzed available data trying to identify the better treatment strategy and to suggest potential therapeutic algorithms distinguishing P-NETs from gastrointestinal NETs (GI-NETs). © 2015 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Neuroendocrine tumors of the gastro-entero-pancreatic system (GEP-NETs) represent a heterogeneous family of neoplasms arisen from the diffuse endocrine system of gastro-intestinal tract and pancreatic islet cells (Massironi et al., 2008). The most common primary sites are the stomach and the appendix, followed by small intestine, rectum, pancreas, colon and duodenum. The most recent WHO classification (2010) splits up all GEP-NETs into 2 categories with different malignant potential and behavior: well-differentiated neoplasms, called neuroendocrine tumors (NETs), and poorly differentiated neoplasms, currently termed neuroendocrine carcinomas (NECs). NETs usually involve G1 or low grade-tumors (Ki67 <2%) as well as G2 or intermediate grade-tumors (Ki67 3–20%) (Scarpa et al., 2010; Rindi et al., 2012), while NECs are often characterized by a Ki-67 >20%, then chemotherapy still remains the only treatment proposed for advanced stages (Fazio et al., 2013). The increased incidence and prevalence of GEP-NETs in the last four decades (Hassan et al., 2008) have led to rising interest about these tumors with remarkable progresses in their treatment and management (Massironi et al., 2008). Nevertheless treatment of GEP-NET still remains controversial and a shared therapeutic sequence still does not exist. The aim of this review is to identify the first and further better approaches among all available therapeutic options, trying to create an algorithm, sharing pancreatic NETs (P-NETs) from gastrointestinal NETs (GI-NETs). We considered larger retrospective studies and phase II and III trials that significantly improved the outcome of NETs patients, even if only few studies are present in Literature usually conducted on small and heterogeneous sample of patients. 2. Materials and methods The published scientific Literature regarding well-to-moderate differentiated GEP-NETs in peer-review journals was extensively reviewed. We used the MEDLINE and CancerLit databases searching studies on peptide receptor radionuclide therapy, somatostatin analogues, chemotherapeutic and targeted therapies trials between 1982 and 2014. The search was restricted to Englishlanguage publications. The search term included “surgery, peptide receptor radionuclide therapy, somatostatin analogues, octreotide, lanreotide, chemotherapy, targeted therapy, everolimus, sunitinib, multimodality treatment” in association with NETs. Full articles regarding ENETS consensus guidelines, phase II, III trials and some significant retrospective studies were obtained, and references were checked for additional appropriate references. In case of ongoing trials, also abstracts were considered. Where results were reported or updated in more than one publication, only the most recent was used. 3. P-NETs 3.1. First approach P-NETs treatment should be individualized and planned in a multidisciplinary team. Patients’ clinical characteristics, stage, primary tumor type, size and localization are the main criteria to evaluate radical surgery (Bettini et al., 2011).

Surgical strategy was defined according to small retrospective studies due to the lack of prospective clinical trials. 3.1.1. Localized P-NETs 3.1.1.1. Not functioning tumors. Clinical and instrumental followup should be considered in asymptomatic P-NETs with a diameter <2 cm, and without metastasis (Falconi et al., 2010; Gaujoux et al., 2013; Crippa et al., 2007a). Enucleation or pancreatic-sparing-parenchymal-procedures may represent an alternative in case of small neoplasms (Falconi et al., 2010; Crippa et al., 2007b). For tumors >2 cm surgery represents the most important therapeutic option (Falconi et al., 2012). 3.1.1.2. Functioning tumors. For functioning tumors, regardless of the size, surgery represents the most important treatment, after specific medical treatment (Crippa et al., 2012). Larger resectable lesions (>2 cm) should be treated with left pancreatectomy (for distal lesions) or pancreatoduodenectomy (for lesions in the head of the pancreas) with lymph node resection (Partelli et al., 2014). Tumors infiltrating major part of the gland without metastases or multiple tumors in several regions of the gland may require a total pancreaticoduodenectomy to achieve radicalness (Crippa et al., 2011). 3.1.2. Locally advanced P-NETs 3.1.2.1. Resectable tumors. Locally advanced tumors invading contiguous vessels and surrounding organs may benefit from surgery, when feasible (Falconi et al., 2012). 3.1.2.2. Unresectable tumors. Unlike other available non-operative therapies, this approach offers an excellent means of symptomatic palliation and local disease control even if R2 with low perioperative mortality and morbidity, so an aggressive approach might be useful to optimize palliation and survival, when feasible (Teh et al., 2007). 3.1.3. Metastatic P-NETs 3.1.3.1. Resectable liver metastasis. Resection of liver metastases increases survival (five-year survival of 76% compared to a 30–40% in untreated cases), therefore when radical resection is possible, surgery should be done. If liver metastases are few and radical liver resection can be performed, liver involvement does not represent a contraindication to primary resection. Small liver resections can be managed at the same time with pancreatic resection while major liver surgery is usually performed as a two-stage operation in most Centers (Fendrich et al., 2006; Pavel et al., 2012). 3.1.3.2. Unresectable liver metastasis. When radical liver resection is not achievable, cytoreductive hepatic resection should be considered to obtain an important symptoms palliation in patients with severe and poorly controlled endocrinopathy or local symptoms from expanding neoplasms (Steinmuller et al., 2008). Criteria for liver surgery with curative intent are as follows: well-differentiated and resectable liver disease with acceptable morbidity and <5% mortality, absence of right heart insufficiency,

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absence of extra-abdominal metastasis (previously assessed by CT scan and somatostatin receptor scan (SRS)) and absence of diffuse peritoneal carcinomatosis (Steinmuller et al., 2008).

3.1.3.3. Unresectable metastasis. In functioning P-NETs, surgical treatment is not indicated if radicalness canot be reached (Capurso et al., 2011). In case of asymptomatic primary P-NETs with unresectable metastasis, the role of resection still remains controversial. However, some studies suggest that resection of the primary tumor may improve survival; therefore it should be considered when feasible (Capurso et al., 2011). A recent meta-analysis showed a significant longer survival in patients affected by only liver metastasis treated with hepatic resection than all other nonsurgical treatments, therefore surgery, when feasible, represents the first chance (Bacchetti et al., 2013). In other cases, metastasis should be treated with loco-regional therapies. Liver transplantation is not recommended by Milan criteria, due to the insufficient postoperative outcomes (Kulke et al., 2010). When the tumor has spread to multiple organs and curative treatments are not possible, the aim of the therapy is palliation. Somatostatin analogues (SSa) are used to control hormone-related symptoms and to decrease tumor burden both in functionally and non-functionally P-NETs (Baudin et al., 2012). In fact, the CLARINET study showed an anti-proliferative effect of SSa also in medical therapy naïve patients with non-functioning well or moderately differentiated P-NETs (Ki67 <10%) (Caplin et al., 2014) (Table 1). Predictive factors for no-response to SSa are ki67 >5% (Butturini et al., 2006) and distant extra-hepatic metastasis (Panzuto et al., 2006). In these situations chemotherapy should be considered alternatively. Chemotherapy represents a useful treatment option especially for symptomatic patients, progressive disease, with G2 differentiation, and a more aggressive behavior. It also should be considered when the primary objective is tumor load reduction for bulky lesions. However the optimal time for chemotherapy treatment initiation still remains to be define (Vilar et al., 2007; Bajetta et al., 2007; Brixi-Benmansour et al., 2011; Engstrom et al., 1984; Vogl et al., 2009). Few randomized trials about chemotherapy for P-NETs have been published and none compared chemotherapy with best supportive care (Engstrom et al., 1984; Moertel et al., 1980, 1992; Ramanathan et al., 2001a; Kouvaraki et al., 2004; Kulke et al., 2006; Strosberg et al., 2011) (Table 2). Monochemotherapy showed limited response rate (lower than 20%), therefore it can be reserved to pre-treated patients or for patients with a poor performance status. Combination chemotherapy regimens have shown increased activity. The most widely used are alkylating agents (streptozotocin (STZ), dacarbazine, temozolomide), antimetabolites (5-fluorouracil (5FU), capecitabine) and platinum derivatives. STZ/5FU and STZ/doxorubicin remain the gold standard chemotherapy regimens for unresectable P-NETs in most Institutions nowadays (Yao et al., 2011; Pavel et al., 2011). Considering of targeted therapy, as showed by the RADIANT 3 study, naïve patients with P-NETs with a low or an intermediate grade but with progressive disease could benefit from everolimus (Strosberg, 2012). Also continuous administration of sunitinib improved patients’ outcome in advanced stages (Strosberg, 2012). Then, everolimus and/or sunitinib should be considered as first-line therapy only in selected cases as an alternative treatment option considering of their specific toxicities. In particular, metabolic and pulmonary AEs (adverse events) for everolimus and vascular toxicity for sunitinib (Raymond et al., 2011; Jensen et al., 2012).

3

3.2. Second approach Considering of targeted therapy, patients with low- or intermediate-grade P-NETs with disease progression after SSa or chemotherapy should receive everolimus as second line treatment. Benefit is irrespective of age, gender, race, performance status, prior treatment (chemotherapy or SSa) and tumor grade (low- or intermediate). In fact treatment with everolimus confirmed a better tumor response and stabilization when compared with placebo (PR 5% vs. 2%, SD 73% vs. 51%) (Yao et al., 2011; Lombard-Bohas et al., 2015; Ito et al., 2012). Sunitinib exhibits a potent antitumor activity in welldifferentiated P-NETs, and its main indication is as a second- or third-line therapy (Jensen et al., 2012) (Table 3). Concomitant SSa use should be considered (Strosberg, 2012). As a result, either everolimus (active in low or intermediate P-NETs) or sunitinib (used in G1 P-NETs) may be considered for second-line treatment after SSa or chemotherapy or alternatively in naïve patients with progressive disease (Yao et al., 2011; Blumenthal et al., 2012). Ki67 index has been proposed in order to identify patients with high level of cancer cell proliferation who may benefit more from an anti-proliferative treatment such as chemotherapy (Scarpa et al., 2010; Rindi et al., 2012). Chemotherapy should be also considered in well-differentiated NET patients; in fact Bajetta et al. (2007) showed the activity of the CapOx combination in this setting in case of progressive disease after SSa. 3.3. Further approaches If the tumor is confined to the liver and patients are not suitable candidates for surgery, liver metastasis may be treated with different ablative techniques such as radiofrequency ablation, laser ablation, cryotherapy or embolization of the hepatic artery by particles or cytotoxic agents (chemoembolization) with a palliative aim, especially in patients with slow growing functional tumors refractory to medical therapy. They may also be useful to reduce tumor burden and to control tumor progression in non-functioning NETs (García-Carbonero et al., 2011). Radiofrequency ablation (RFA) could be used as a supplementary or as secondary treatment toliver resection in selected cases (diameter <4 cm; <8–10 metastasis in total and metastasis not near to venous and biliary structures). It can be performed either before or during surgery and chemotherapy. It may be also used to convert an unresectable or a borderline resectable disease into a resectable one (Pavel et al., 2012). However, there are no data regarding survival prolongation in patients undergone ablative procedures. Moreover, no data regarding direct comparisons between RFA andother local ablative methods are available (O’Toole et al., 2003). Increased risk of complications occurs in patients undergoing surgery (i.e. bilio-digestive anastomosis should be avoided in this case), while previous chemotherapy treatment does not represent a risk factor for the development of complications (Curley et al., 2004). Trans arterial embolization (TAE) and trans arterial chemoembolization (TACE) may be used in patients with unresectable disseminated hepatic metastasis whose blood supply is from the hepatic arteries. Bland particles are used in TAE, whilst doxorubicin, STZ, mitomycin and 5FU are commonly used in TACE. Clinical responses have been reported in up to 80% of the patients and radiological responses in about 50%. Arterial phase enhancement is a positive predictive factor of tumor response (Vogl et al., 2009; Falconi et al., 1999).

Please cite this article in press as: Rossana, B., et al., Gastrointestinal neuroendocrine tumors: Searching the optimal treatment strategy—A literature review. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.11.003

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4

Table 1 Comparative trials with somatostatin analogs in gastro-entero-pancreatic tumors (GEP-NETs). Trial name, first authors and year

Type of study

Experimental drugs

Patients included

PFS (months)

Type of response with experimental drug (RECIST) or RR

PROMID; Rinke et al. (2009)

Randomized, double-blind, placebo-controlled, multicentre, phase III Prospective, randomized, double-blind, placebo-controlled, multinational study, phase III

Octreotide LAR 30 mg i.m. vs. placebo

85 locally advanced or metastasized G1 or G2, NET of midgut or unknown origin-treatment naïve 204 G1-G2 (ki67 <10%) non-functioning GEP-NETs or unknown origin; no receiving somatostatin analogues, interferon, chemoembolization or chemotherapy with six months prior to study entry

14.3 vs. 6

SD = 66.7%

Not reached vs. 18

SD = 96%

CLARINET; Caplin et al. (2012, 2014)

Lanreotide Autogel 120 mg vs. placebo

PFS: progression free survival; RECIST: response evaluation criteria in solid tumors; RR: response rate; SD: stable disease; OS: overall survival xNET: neuroendocrine tumor.

Embolization is contraindicated in patients with portal-vein thrombosis, liver insufficiency, biliary obstruction or prior Whipple procedure. The presence of portal vein occlusion, ascites hepatic tumor burden >75% of the total liver, are considered relative contraindications (Dominguez et al., 2000). In a retrospective study in patients with P-NETs, chemoembolization showed better results when compared with bland embolization (response: 50% vs. 25%, respectively) (Gupta et al., 2005). Radioembolization or selective internal radiation therapy (SIRT) with 90Y-microspheres are relatively new treatment options for liver metastasis. Radiological tumor response rates are seen in about 60% of cases (Kennedy et al., 2008). Peptide receptor radionuclide therapy (PRRT) can be recommended especially after failure of medical therapy considering of its delayed toxicity (Kwekkeboom et al., 2009). Indications for this treatment also include local and systemic symptom palliation (Ramage et al., 2012). Campana et al. showed that stage of the disease (IV vs. III), proliferation rate (G2 vs. G1) and the previous use of TACE are significant negative factors for progression-free survival in patients treated with PRRT (Campana et al., 2013). The main selection criterion for PRRT is the evidence of a strong radiotracer expression (ideally higher than normal liver tissue) on somatostatin receptor imaging modality (Kwekkeboom et al., 2009). The optimal radionuclide is not still determined. 90Yttrium octreotide (90Y-DOTATOC), 90Y-lanreotide and Lu177-DOTA octreotate have been used therapeutically obtaining tumor stabilization (60%) and partial responses (20%) in GEP-NETs. These results derive only from retrospective or phase II studies, because no randomized phase-III trials are currently available in Literature (Kwekkeboom et al., 2008; Reubi et al., 2000). In these different studies, PRRT shows an increased effectiveness in GEP-NETs compared to other NETs and the majority of patients had progressive disease and no other treatment options (Imhof et al., 2011; Bodei et al., 2003).The main 90Y-DOTATOC treatmentlimiting toxicity is renal and myelotoxicity (Barone et al., 2005). In conclusion, SSa and TT (targeted therapy) should be considered as first line options in the management of G1-G2 advanced P-NETs. The choice of one treatment over the other could reasonably be strictly related to the expected toxicity, to the tolerability of these drugs and to the comorbidity of the patients (Fig. 1) (Ito et al., 2012; Öberg et al., 2012; Ramanathan et al., 2001b).

4. GI-NETs 4.1. First approach 4.1.1. Localized and locally advanced GI-NETs Major of surgical strategy was resulted by small retrospective studies, because of the lack of an adequate number of prospective clinical trials. Patients with localized GI-NETs should be treated with curative surgery after a multidisciplinary evaluation—In gastric NENs, surgery depends on type, size and involvement of submucosa or muscle. Type 1 gastric enterochromaffin-like (ECL) cell carcinoids (ECL-omas) are the most common. In case of tumors <1 cm, a conservative treatment with endoscopic resection or endoscopic surveillance every 6–12 months can be considered. There is no evidence that endoscopic resection is superior to endoscopic surveillance. Tumors whose diameter is ≥1 cm and ≤2 cm, without muscularis propria involvement, should be endoscopically resected. For polyps over 2 cm dimensioned, or invading beyond the submucosa, or if there are positive resection margins, multiple tumors >1 cm, or regional lymph node metastasis, local antrectomy or total gastrostomy should be performed (Delle Fave et al., 2012; Merola et al., 2012). In Type 2 carcinoids, rare and often present with Zollinger–Ellison syndrome, local excision is recommended. Surgical treatment should be evaluated only in presence of multiple tumors, submucosa invasion and to prevent the gastrin-induced stimulation of the ECL-omas (Delle Fave et al., 2012). Type 3 neoplasms, which have an aggressive behavior, should be treated like gastric adenocarcinomas with partial or total gastrectomy and lymph node dissection (Borch et al., 2005). All localized duodenal NETs should be removed. Duodenal NENs <1 cm should be endoscopically excised after endoscopic ultrasound examination. However, NENs of the periampullary region should be treated with local surgical resection plus lymphadenectomy. Surgical resection is the treatment of choice for tumors >2 cm or with lymph node metastasis. Treatment of intermediate size tumors (1–2 cm) is controversial: if no lymph node metastasis are present, endoscopic treatment may be considered (Pavel et al., 2012). In jejunum–ileum NETs, curative surgery should be considered for localized small intestinal neuroendocrine tumors with or without regional lymph node metastasis (García-Carbonero et al., 2011). However, a second localization occurs in up to 30% of cases so a careful exploration and palpation of the abdominal cavity should

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Experimental drugs

Patients included

Moertel et al. (1980)

Randomized, phase II

84 Advanced pNETs

Moertel et al. (1992)

Randomized, phase II

Kouvaraki et al. (2004)

Retrospective study

Streptozocin alone or streptozocin plus fluorouracil. Streptozocin plus doxorubicin versus STZ plus 5-FU vs. chlorozotocin alone Bolus of fluorouracil, doxorubicin and streptozocin

Ramanathan et al. (2001a,b)

Phase II

Dacarbazine

Strosberg et al. (2011)

Retrospective single-center,

Chan et al. (2012)

Phase II trial

Kulke et al. (2006)

Multicenter, phase 2 trial

Ekeblad et al. (2007a,b)

Prospective study

Capecitabine and temozolomide Temozolomide in combination with bevacizumab Temozolomide in combination with thalidomide Temozolomide

50 Advanced pancreatic islet cell tumors, having progressive symptoms or evidence of rapidly advancing disease. 30 Chemo-naïve pancreatic G1 and G2 NET patients 15 pNETs

Koumarianou et al. (2012)

Prospective study

Brizzi et al. (2009)

Phase II trial

Turner et al. (2010)

Retrospective study

Cassier et al. (2009)

Retrospective study

Bajetta et al. (2007)

Retrospective study

Capecitabine and oxaliplatin (XELOX)

Chan et al. (2012)

Prospective study

Temozolomide and Bevacizumab

Walter et al. (2010)

Retrospective study

Bajetta et al. (1998)

Retrospective study

5-fluorouracil, dacarbazine, and epirubicin 5-Fluorouracil, dacarbazine, and epirubicin

Combination treatment with metronomic temozolomide, bevacizumab and long-acting octreotide Continuous 5-fluorouracil infusion plus long acting octreotide 5-fluorouracil, cisplatin and streptozocin Gemcitabine and oxaliplatin

PFS (months)

Type of response with experimental drug (%) (RECIST) or RR (%)

OS (months)

105 Advanced pNETs

20 vs. 6.9 vs. 6.9

RR = 63% vs. 36% in STZ alone arm CR = 33% vs. 12% RR = 69% vs. 45% vs. 30%

84 Advanced pNETs

36

RR = 39%

18

Between 8% and 15% in carcinoid tumors and 33% in pancreatic islet cell tumor.

19.3

18

RP = 70%

92 (2 years)

14.3

RR = 33%

Not reached

RR = 25%

Not reached

TTP= 7

Unknown

TTP= 36 weeks

PR = 14% SD = 53% CR = 7% PR = 57% SD = 21%

TTP = 22,6

RP = 24.1% SD= 69.0%

Not reached

TTP = 9.1

RR = 33%

31.5

7

RP = 17%

23.4

Unknown

RR: 78%

Unknown

11

RR = 15%

33.3

11

RR: 44%

21

Unknown

RR = 30%

Unknown

29 Patients with advanced pNETs or carcinoid tumors. 36 Patients with advanced NETs 15 Advanced NETs

29 Metastatic or locally advanced well-differentiated NETs. 79 Patients with locally advanced or metastatic NETs 20 Patients with metastatic well differentiated NETs after other chemotherapy regiment failure 27 Advanced well differentiated NETs after SSAs progression 34 Patients with locally advanced and metastatic pNETs or carcinoid tumors. 39 Patients with advanced well-differentiated NETs 30 GEP-NETs

Unknown Unknown

26 vs. 17vs. 18

Unknown

PFS: progression free survival; RECIST: response evaluation criteria in solid tumors; RR: response rate; RP: partial response; SD: stable disease; OS: overall survival; NET: neuroendocrine tumor; p-NET: pancreatic neuroendocrine tumor; STZ: streptozocin; 5FU: fluorouracil.

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Table 2 Chemotherapy in gastro-entero-pancreatic tumours (GEP-NETS).

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Type of study

Experimental drugs

Patients included

PFS

Type of response with experimental drug (%) (RECIST) or RR(%)

Yao et al. (2008)

Phase II

30 patients with carcinoid and 30 with pNETs

72 vs. 50 week

RR = 30% vs. 13%

Radiant 1 O’Donnell et al. (2008)

Open-label nonrandomized phase II

Everolimus (5 vs 10 mg) in combination with ocreotide LAR 30 mg Everolimus 10 mg alone or everolimus plus longacting octreotide

Stratum 1: 9.7 months. Stratum 2: 16.7 months.

Stratum 1: PR = 9,6% SD = 67.8% PD = 13.9% Stratum 2: PR = 4,4 % SD = 80% PD = 0%

Radiant 2; Pavel et al. (2010, 2011)

Randomised, multicentric, double-blind, placebo-controlled, phase III Randomized, doubleblinded,multicentric phase III Double-blind, placebo-controlled, randomized phase III trial.

Patient with metastatic pNETs progressive on or after chemotherapy Stratum 1: previous octreotide therapy. Stratum 2: no previous octreotide therapy 429 G1-G2 advanced NETs, documented progressive disease and history of carcinoid symptoms. 410 patients with pNET

Radiant 3; Yao et al. (2010, 2011)

Raymond et al. (2011)

Everolimus 10 mg/die with octreotide LAR 30 mg i.m. vs. placebo with octreotide LAR 30 mg i.m. Everolimus vs. placebo (with crossover at PD after unblinding) Sunitinib 37,5 mg/die vs. placebo

173 advanced and metastatic, G1 pNETs in progression disease within 12 months prior to trial enrollment

OS (months)

16,4 months vs. 11,3 months

11 months vs. 4.6 months

PR = 5% vs. 2% SD = 73% vs. 51%

OS not reached in both the groups.

11.4 vs. 5.5 months

RR = 9.3%

1 year OS = 90% vs. 70%

PFS: progression free survival; RECIST: response evaluation criteria in solid tumors; RR: response rate; RP: partial response; SD: stable disease; PD: progression disease; OS: overall survival; NET: neuroendocrine tumor; p-NET: pancreatic neuroendocrine tumor.

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Table 3 Everolimus and Sunitinib in pancreatic G1-G2 neuroendocrine tumors (pNETs).

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Fig. 1. Algorithm for treatment of pancreatic neuroendocrine tumors (P-NET). This possible treatment algorithm was created based on the results of the clinical studies reported in the text. Starting from tumor stage, this algorithm helps to identify the best therapeutic sequence for each patient, considering previously treatments and site metastases. PRRT: peptide receptor radionuclide therapy; RFA: radiofrequency ablation; SIRT: selective internal radiation therapy; Introduction TACE: trans arterial chemoembolization; TAE: trans arterial embolization.

be undertaken. All patients with small intestinal NETs should be treated peri-operatively with octreotide in order to prevent carcinoid crises (Pape et al., 2012). In appendix NETs <1 cm, well differentiated and without invasion of the meso-appendix or regional lymph node metastasis, appendectomy is curative. A right-sided hemicolectomy is recommended in the following cases: tumors >2 cm in size or localized at the appendix base, infiltrating the mesoappendix, angioinvasion, Ki-67 index >2%,with regional lymph node metastasis. In case of 1–2 cm tumors, there is no consensus for surgical procedure (Plöckinger et al., 2008). Colonic endocrine tumors <2 cm when confined to the submucosa (T1), can be treated with endoscopic resection (Al Natour et al., 2012) if there are no risk factors as a high mitotic rate, muscularis propria invasion, vascular or neural invasion or lymphatic involvement. Lesions that are greater than 2 cm, or have invasion of the muscularis propria at diagnosis, should be treated as adenocarcinomas with segmental colectomy and lymph node dissection Rectal G1 tumors <2 cm and G2 tumors <1 cm without muscular invasion (T1 and T2) can usually be resected endoscopically (Caplin et al., 2012). G2 tumors of 1–2 cm without muscular invasion or lymph node metastasis can be treated with endoscopic submucosal dissec-

tion or transanal endoscopic microsurgery (TEM) (Kinoshita et al., 2007). G2 tumors >2 cm or neoplasms with muscular invasion (T3 and T4) or lymph node metastasis should undergo low anterior or abdomino-perineal resection. No adjuvant therapy is recommended in completely resected, well differentiated, localized NETs (García-Carbonero et al., 2011).

4.1.2. Metastatic GI-NET In metastatic gastric and midgut-NETs surgery should be considered as the first choice when it is possible to obtain R0 resection with removal of the primary tumor, lymph node and distant metastasis (Ahmed et al., 2009). However in midgut NETs the resection of the primary and regional lymph node metastasis without resection of distant metastasis should be considered because it induces an increase of overall survival (up to 8–10 years vs. 4–5 years) and may prevent later development of bowel obstruction (Pape et al., 2012). In gastric and colorectal neoplasms with distant metastasis, there is no evidence that primary tumor resection, in cases of unresectable metastasis, is prognostically favorable. Nevertheless, palliative surgery should be indicated to prevent intestinal obstruction, bleeding or ischemic complications due to

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Fig. 2. Algorithm for treatment of gastrointestinal neuroendocrine tumors (GI-NET). This possible treatment algorithm was created based on the results of the clinical studies reported in the text. Starting from tumor stage, this algorithm helps to identify the best therapeutic sequence for each patient, considering previously treatments and site metastases. PRRT: peptide receptor radionuclide therapy; RFA: radiofrequency ablation; SIRT: selective internal radiation therapy; Introduction TACE: trans arterial chemoembolization; TAE: trans arterial Embolization.

tumor mass or to relieve symptoms in hormonal syndrome refractory to medical therapy (Ekeblad et al., 2007a). As previously described for P-NETs, if the tumor is confined to the liver, as first approach liver metastasis should be treated with loco-regional therapies, and surgery, when possible (Bacchetti et al., 2013). In patients with bi-lobar liver metastasis without extra-hepatic disease, total tumor hepatectomy with liver transplantation can be considered with curative intent, or in order to palliate from lifethreatening hormonal disturbances (Pfitzmann et al., 2007). This option could be considered especially for young patients (<50 years) with WHO performance status 0, non-resectable metastasis confined to the liver, G1 and G2 small intestinal NETs, severe uncontrolled endocrine symptoms (Le Treut et al., 2008). Medical treatment choice depends on grade of differentiation and site of the primary tumor. In G1 and G2 gastric type 3 NETs patients, chemotherapy could be a treatment option instead for G1 and G2 other GI-NETs, chemotherapy is usually not recommended as first line (Pape et al., 2012), because well-differentiated carcinoid tumors appear to be significantly more resistant to cytotoxic chemotherapy (Ramage et al., 2012).

In non-functioning midgut metastatic and slowly progressive G1 NETs, with expression of somatostatin receptors, SSa represent the better first-line treatment option. It should be considered also in naïve patients without a prior observation period of spontaneous tumor growth behavior, as SSa seem to exercise anti-proliferative function (Le Treut et al., 2008). The indication of using SSa as first-line derives mainly from two studies: PROMID and CLARINET trials (Caplin et al., 2014; Rinke et al., 2009). The PROMID study showed a significant benefit with octreotide LAR therapy in metastatic well-differentiated NETs of the midgut with low hepatic tumor load. However in patients with hepatic tumor burden >10%, time to progression in the octreotide-LAR arm was almost double than in the control arm. Furthermore octreotide LAR was effective both in functional and non-functional NETs (Rinke et al., 2009). The PROMID trial unfortunately does not clarify if it is advantageous to wait until tumor progression or to treat at initial diagnosis, if an early treatment determine benefit on OS and finally if these data can be extrapolated to patients with G2 NETs. Then two options remain:

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1 octreotide LAR use for controlling tumor growth in functioning as well as non-functioning well-differentiated midgut NETs; 2 ‘wait and see’ strategy for a few months after initial diagnosis of a well-differentiated asymptomatic NETs in order to assess tumor growth speed. CLARINET study instead showed the anti-proliferative effect of SSa in all non-functioning well or moderately differentiated GEPNETs (Ki67 <10%) (Caplin et al., 2014) (Table 1). In conclusion SSa should represent the first line for G1 and G2 GI-NETs (Fig. 2).

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able options in order to better select the patients who could benefit from different treatment options. In fact a better understanding of the molecular pathways involved in the NETs carcinogenesis, might predict the efficacy of each therapeutic approach. Furthermore, research on identifying the best strategy involving the available options would be beneficial. Conflict of interest All authors disclose no financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work.

4.2. Second and further approaches Author contribution Even if midgut tumors seem not benefit from chemotherapy, this treatment should be considered in well-differentiated pretreated NET patients with progressive disease. Chemotherapy could be also associated with SSa considering of some phase II trials (Brizzi et al., 2009; Berruti et al., 2014; Bajetta et al., 1998; Walter et al., 2010; Chan et al., 2012; Cassier et al., 2009; Turner et al., 2010; Koumarianou et al., 2012; Ekeblad et al., 2007b) (Table 2). Conversely, everolimus plus octreotide LAR treatment seemed to demonstrate significant benefits and improve outcomes for patients with advanced colorectal NETs with progressive disease compared with placebo plus octreotide LAR treatment in a posthoc analysis of RADIANT-2 study (Castellano et al., 2013) (Table 3). However these preliminary findings support additional investigations of everolimus plus octreotide LAR in those patients. In order to get further information on the anti-proliferative role of everolimus as a single agent, in non-functioning welldifferentiated non-pancreatic tumors, we should wait the results of RADIANT 4 trial. As previously described for P-NETs, if the tumor is confined to liver and surgery could not be considered, liver metastasis may be treated with different ablative techniques such as RFA, laser ablation, cryotherapy, TAE and TACE. In particular, a retrospective study showed that bland embolization seemed superior to chemoembolization in patients with small intestinal NETs (response: 81% vs. 44%, respectively) (Gupta et al., 2005). These treatments generally have a palliative aim in patients with slow growing functional tumors, refractory to medical therapy, but they may also be useful to reduce tumor burden and control tumor progression in non-functioning tumors (García-Carbonero et al., 2011). Again, as told for P-NETs, PRRT could be recommended in GINETs with evidence of high radiotracer expression in somatostatin receptor imaging modality (Ahmed et al., 2009). Tumor responses are more frequent in rectal NETs, instead midgut NETs show less responses. However, when PRRT produced a clinical benefit in symptomatic midgut NETs, it was possible to observe an improvement on survival (Bushnell et al., 2010). As aforementioned for P-NETs, PFS of patients treated with PRRT is worse in metastatic stage of the disease, G2 and previous TACE (Campana et al., 2013). All G2 patients should be managed by a multidisciplinary team to identify those patients who may benefit from chemotherapy as first line treatment (García-Carbonero et al., 2011). 5. Conclusions In summary, given the rarity of GEP-NETs, there is a lack of a real standard approach, although multimodality treatment demonstrated to obtain the best results in survival in this setting. Nevertheless, therapeutic sequence is still controversial. To date research efforts are focused on translational studies on the avail-

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Biography Rossana Berardi MD is a Consultant Medical Oncologist and Senior Lecturer at University Hospital. She is also the Responsible of the Trial Unit at Dept of Oncology, Università Politecnica Marche, Italy. Dr Berardi usually deals with about 35 GCP trials/year with new drugs mainly in lung and GI cancer. She also treats significant numbers of neuroendocrine tumors. Dr Berardi is Assistant Professor in Medical Oncology at Università Politecnica Marche, Ancona, Italy. She is Member and national representative of the Lecturer in Medical Oncology of the Academic Medical Oncology Committee, she is Member of the “Education” Working Group of the Italian Association of Medical Oncology and she is Member of the “ESMO/ASCO Global Curriculum for Training in Medical Oncology Working Group” of the European Society for Medical Oncology. Dr Berardi has been awarded many grants and prizes (among the others, several ASCO and ESMO travel grants and merit awards). She has authored more than 100 manuscripts in peer-reviewed journals and she has been a speaker at national and international meetings. Dr Berardi has been selected as an expert evaluator in several boards of examiners (i.e. European Community, Italian University Ministry).

Please cite this article in press as: Rossana, B., et al., Gastrointestinal neuroendocrine tumors: Searching the optimal treatment strategy—A literature review. Crit Rev Oncol/Hematol (2015), http://dx.doi.org/10.1016/j.critrevonc.2015.11.003