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ANTICANCER RESEARCH 32: 4193-4200 (2012)

Review New Perspectives in the Treatment of Neuroendocrine Tumours

EMILIO BAJETTA1, LAURA CATENA1, MONICA VALENTE1, NADIA BIANCO1, FERNANDA BELLOMO1 and EMILIO BOMBARDIERI2

1Institute of Oncology – Policlinico of Monza, Monza, Italy; 2National Institute of Milan, Italy

Abstract. The treatment of neuroendocrine tumours (NETs) mitoses/10HPF and Ki-67 of 3-20%), NEC (neuroendocrine is mainly based on their biological characteristics of carcinoma) G3 (>20 mitoses/10HPF and Ki-67 >20%), with aggressiveness and functional features. Radical surgery is a high grade of malignancy and a poor prognosis; mixed the sole effective approach. In other types of well- adenoneuroendocrine carcinoma; hyperplastic and differentiated tumours, hormonal is the treatment of paraneoplastic lesions (1). The classification of lung tumours choice, as well as is the treatment of choice is still based on the article by Travis (2) who recognized the for aggressive diseases. Recent advances in the field of following four categories: typical carcinoid, atypical targeted have expanded options for NETs, carcinoid, small-cell lung cancer (SCLC) and large-cell particularly of pancreatic neuroendocrine tumours. The neuroendocrine carcinoma. Typical carcinoids are generally radiotherapy option in NETs is based on less aggressive than atypical carcinoids, which are less radiopharmaceuticals targeting receptors over-expressed by aggressive than small-cell carcinoma (poorly-differentiated these diseases and acting on the cell metabolism. NETs). The treatment of NETs is mainly based on their biological characteristics of aggressiveness and functional On account of their natural history, clinical evolution and features, such as symptoms and endocrine markers. When tumour biology, neuroendocrine tumours (NETs) represent a feasible, radical surgery remains the sole effective approach, very heterogeneous group of neoplasms. With the purpose of whereas in other cases hormonal treatment is the treatment categorizing the different prognostic variables such as site of choice for G1 and G2 NETs and lung carcinoid, as well as and size of primary tumour, histological grading, chemotherapy for progressive disease and aggressive NETs. proliferative index and release of biologically active Incidence of NETs has been estimated to be about substances, several classification models have been proposed. 2/100,000 cases per year. The stratification of the incidence Up to now, none of these classifications appears completely rates according to age has identified two peaks: the first in comprehensive from the prognostic point of view, because the age ranging from 15 to 25 years, and the second one only a correct evaluation of the different clinico-pathological between 65 and 75 years (2, 3). signs is truly predictive of the natural history of the disease. The stage of disease at diagnosis represents one of the However, the most comprehensive classification is that of the most important prognostic factors, as the best 5-year survival World Health Organization (WHO), issued in 2010 that rate is observed for the presence of localized disease (93%), indicates clinical and biological features of NETs. It divides as compared to 20%-30% for advanced disease. Other gastroenteropancreatic (GEP) NETs into the following survival-related prognostic factors are the site of the primary categories: NET G1 with a good prognosis (<2 tumour, tumour grading, number and site of metastases, mitoses/10HPF and Ki-67 <3%), NET G2 (2-20 presence of tumour syndrome and expression of receptors for somatostatin analogues. In the presence of advanced disease, the most favorable prognostic variables lie in a low-proliferative index and in a Correspondence to: Emilio Bajetta, Istituto di Oncologia, Policlinico good level of cell differentiation of appendicular and ileal di Monza, Via C. Amati, 111 Monza (MB) Italy. Tel: +39 origin (4-8). 0392810661/662/663, Fax: +39 0392810331, e-mail: emilio.bajetta@ policlinicodimonza.it The aim of the present article is to underline the importance of definitively-differentiated therapeutic Key Words: Neuroendocrine tumors, treatment, carcinoid, review. approaches for therapies of NETs, and the continuous

0250-7005/2012 $2.00+.40 4193 ANTICANCER RESEARCH 32: 4193-4200 (2012) attempts aiming at improving therapy through targeted stage NETs, such as , , 5- research of the understanding of tumour biology. , , and . Recently, some new chemotherapeutic agents have become available, Somatostatin Analogues such as , , , and . Taking into account the lack of clinical The biological activity of natural somatostatin is based on studies in this setting, there are currently no indications for the inhibition of hormone secretion, in the suppression of the chemotherapy in adjuvant or neoadjuvant treatment. The release of insulin-like growth factors, in the negative control available clinical results strongly vary on the basis of the of , and in the enhancement of apoptotic utilized agents and on the prognostic characteristics of NETs. processes in the tumour tissue. Physiologically, somatostatin In particular, the variable most likely predictive of is a potent secretion inhibitor of several hormones derived responsiveness is a very high proliferative index (>15%) (5). from the hypophysis, pancreas and gastrointestinal tract (growth hormone, insulin, gastrin, cholecystokinin, etc.); in Well-differentiated GEP-NETs. Single-agent chemotherapy addition, it regulates different cell activities such as growth, with streptozotocin yielded a tumor response rate of 36-42%, gastro-intestinal motility and fluid secretion (9). but these early studies can be criticized with respect to the All these activities are mediated by the interaction of rough methods of interpreting morphological responses. somatostatin with a series of five receptors (SSTRs), encoded Other monotherapies, including chlorotozotocin, by five different genes belonging to the class of receptors doxorubicin, 5-FU and dacarbazine have been used, but were linked to transmembrane G-proteins, able to inhibit cAMP (9). criticized due either to the high toxicity rate or lack of Therapeutic activity is achieved through the interaction objective response. Monotherapy strategies have been with two out of five SSTRs and, more precisely, with universally replaced by combination chemotherapy protocols. subtypes 2 and 5 for which there is the highest affinity (9). As can be seen in Table I (4), many combinations have been Octreotide and lanreotide are the two somatostatin used, with streptozotocin, 5-FU and making- analogues exploitable by injection. They proved highly up the cornerstone of the tested regimens. In well- effective in the symptomatic treatment of NETs, being able differentiated pancreatic endocrine tumors the results to control the symptoms related to carcinoid syndrome in up obtained by Moertel et al. using streptozotocin and to 90% of cases. Reduction of tumour biochemical markers doxorubicin, so far, have not yet been improved, with a 69% is reached in up to 70% of cases (8, 10-13). objective response rate and a median survival of 26 months; A recent randomized phase III study (PROMID study) these results should be compared with an objective response (14) has demonstrated that in patients with advanced midgut rate of 45% for 5-FU and streptozotocin. The same group NETs, octreotide LAR compared to placebo induces an had previously obtained better results with 5-FU in advantage in terms of progression-free survival (14.3 months combination with streptozotocin in a phase III trial, in vs. 6.0 months, p=0.000072). comparison with streptozotocin monotherapy (6-7). While no An analogue named SOM 230 (pasireotide), able to bind group has managed to achieve the same response rates, four out of five receptors (all except SSTR4) is presently objective responses of 36-55% have been established using under clinical development. On account of this characteristic, streptozotocin plus doxorubicin, with the exception of one SOM 230 is potentially more effective as compared to the study where a response rate of 6% was reported in a group of analogues presently available, since it may also be active in 16 patients. The authors questioned the reliability of Moertel tumours unresponsive to somatostatin analogues, which does et al.’s earlier studies, especially their methods of measuring not bind subtypes 2 and 5. Clinical trials are ongoing to assess responses. However, three recent studies have reported good the true efficacy of SOM 230 in different types of NETs (9). response rates using well-defined criteria for recruitment and On the whole, all somatostatin analogues have a good safety evaluation. Strosberg et al. reported that the combination of profile even in cases of long-term treatment. Adverse events capecitabine and temozolomide is associated with a high and occurring in 25-50% of cases usually are mild to moderate in durable response rate in metastatic endocrine carcinomas of severity and do not require treatment discontinuation, being the pancreas, superior to those observed with streptozotocin- most frequently represented by development of gallbladder based regimens (26). As for well-differentiated GEP tumors stones, pain at the site of injection, abdominal colic, flatulence, of the pancreas, single-agent regimens have been largely , asthenia and reduced tolerance to glucose. disappointing in GEP tumors of midgut origin, with objective response rates of <25% and response durations rarely Chemotherapy exceeding three months. In 1979 Moertel et al. combined 5- FU with streptozotocin for midgut carcinoids, yielding a Several chemotherapy agents have been employed either as response rate of 33%. Later studies using the same single-agent or in combination in the treatment of advanced combination have failed to reproduce these results (Table I).

4194 Bajetta et al: Treatment of Neuroendocrine Tumors (Review)

Table I. Chemotherapy of well-differentiated gastroenteropancreatic neuroendocrine tumours.

References Type of Regimen No. of Objective Response Median tumour patients response (%) duration (months) survival (months)

Moertel et al., Carcinoid 5-FU+ 47 33 - - 1979 ref. 5 STZ+5-FU 42 33 - - Moertel et al. Pancreatic STZ 42 36 17 17 1980 ref. 6 STZ+5-FU 42 63 17 26 Engrstom et al. Carcinoid STZ+5-FU 80 22 8 16 1984 ref. 7 DOX 81 21 6.5 12 Frame et al. Carcinoid DOX+STZ 33 40 - 11 1988 ref. 15 Eriksson et al. Pancreatic DOX+STZ 25 36 22 - 1990 ref. 16 Moertel et al. Pancreatic DOX+STZ+5-FU 36 69 18 26 1992 ref. 17 STZ 33 45 14 18 Bukowski et al. Carcinoid DOX+STZ+5-FU+ 56 31 - - 1992 ref. 18 cyclophosphamide STZ+5-FU+ 9 22 - 10.2 cyclophosphamide Di Bartolomeo et al. Carcinoid DOX+DTIC+5-FU 20 10 - 5 1995 ref. 19 Bajetta et al. Carcinoid +5-FU-DTIC 15 27 10 - 1998 ref. 20 Cheng et al. Pancreatic DOX+STZ 16 6 18 - 1999 ref. 21 McCollum et al. Pancreatic DOX+STZ 16 6 3.9 20.2 2004 ref. 22 Kouvaraki et al. Pancratic DOX+STZ+5-FU 84 39 9.3 40 2004 ref. 23 Su net al. Carcinoid DOX+5-FU 25 15.9 4.5 15.7 2005 ref. 24 STZ+5-FU 27 16 5.3 24.3 Strosberg et al. Pancreatic TMZ-Capecitabine 30 70 18 - 2011 ref. 26

(Modified by Caplin M. et al. 2006, ref.4).

Therefore, other drug combinations have also been cisplatin plus etoposide regimen is indicated; however examined, but apart from a 40% objective response rate for XELOX (capecitabine and oxaliplatin) or FOLFOX (5-FU, patients with midgut carcinoids treated with doxorubicin and lederfolin and oxaliplatin) chemotherapy regimens (15) or streptozotocin in a phase II study, no other reliable cytotoxic even the combination of CDDP with a molecular-targeted regimen has been found for patients with advanced or therapy, can be considered as backup. New options are metastatic disease of midgut origin (15-27). required for the treatment of these patients (28-36).

Poorly-differentiated GEP-NETs. Standard treatment of Thoracic NETs. NETs of the thorax include both bronchial patients with advanced poorly-differentiated GEP tumors has and thymic NETs. No adjuvant chemotherapy or largely been based on protocols containing etoposide and chemoradiation is recommended for well-differentiated cisplatin (Table II); such patients are rarely sensitive to tumors. G1/G2 bronchial NETs are generally less responsive combination therapies with streptozotocin, dacarbazine and to chemotherapy than SCLC. However, platinum-based 5-FU. Other studies were conducted with cyclophosphamide, regimen may be considered and have reported activity in dacarbazine and , recording an unsatisfactory patients with more aggressive/intermediate-grade tumors. response duration. A study involving the combination of The use of various chemotherapeutic agents (doxorubicin, 5- 5-FU, epirubicin and dacarbazine, had a lower response rate FU, dacarbazine, cisplatin, etoposide, streptozotocin and compared to the regimen of cisplatin and etoposide. While ) in the treatment of lung carcinoids has yielded tumor response rates are often good (42-65%), the duration minimal (20-30%), mostly short-lasting results, and an of response rarely exceeds 10 months and median survival is effective chemotherapeutic regimen for unresectable disease in the order of 15 months. The guidelines state that a is still lacking. Combination for carcinoids

4195 ANTICANCER RESEARCH 32: 4193-4200 (2012)

Table II. Chemotherapy in poorly-differentiated neuroendocrine tumours.

References Regimen No. of Objective Response Median survival patients response (%) duration (months) (months)

Moertel et al. 1991 ref. 28 VP16+CDDP 18 67 8 19 Seitz et al. 1995 ref. 29 Vp16+CDDP 11 54 - - Mitry et al. 1999 ref. 30 VP16+CDDP 41 42 9 15 Bajetta et al. 1998 ref 20 5FU+Epiribicin+DTIC 15 27 10 - Fjallsskog et al. 2001 ref. 31 VP16+CDDP 36 47 9 - Bajetta et al. 2007 ref. 32 XELOX 38 63 8.5 23.5

(Modified by Caplin M et al. 2006, ref.4) are usually platinum and streptozocin-based. Due to the low sunitinib has been evaluated in phase II and III studies in response rates for chemotherapy in BP-carcinoids combined patients with pancreatic NETs. In a randomized, double- with serious side effects, the indication to use currently blinded, multinational, phase III trial, continuous treatment available chemotherapeutic regimens is limited (25). Results with oral sunitinib at 37.5 mg/day significantly prolonged the from a published phase II trial suggest antitumor activity median progression-free survival time (primary end-point) by with single-agent temozolamide for well-differentiated NETs approximately two-fold relative to placebo, in adults with (26). In small studies, large-cell NETs have been shown to locally-advanced and/or metastatic, well-differentiated have a low and partial response rate to preoperative or pancreatic NETs. Sunitinib was also associated with a postoperative chemotherapy but therapy prolongs survival in significantly greater objective tumour response rate than lower-stage disease (27, 28). The standard-of-care for placebo, although limited data from an updated analysis limited-stage SCLC includes early thoracic radiotherapy demonstrated no significant difference between the treatment combined with cisplatin and etoposide. Extensive-stage groups, in terms of median overall survival. On account of disease is usually treated with chemotherapy with etoposide the drug-related side effects, of the difficulty to identify the and a platinum compound, considered as the reference optimal duration of treatment and of the slow-growing feature treatment for inoperable poorly-differentiated NETs (23). of NETs, further investigations are needed to clarify the possible role of sunitinib in this disease (42, 43). The New Drugs m-TOR pathway inhibitors. Clinical investigations aiming at Monoclonal antibodies – bevacizumab. Bevacizumab evaluating the efficacy of everolimus (RAD001), both as (Avastin®) is a humanized murine monoclonal antibody single-agent and in combination with octreotide LAR, in directed against Vascular Endothelial Growth Factor (VEGF), patients with advanced NETs have achieved interesting utilized in the treatment of several neoplasms with results. An international, multicenter, phase II study antiangiogenic purposes. A randomized phase II study has (RADIANT1), carried out in a significantly representative demonstrated that in patients with advanced carcinoids population of 115 patients with pancreatic NETs has bevacizumab (15 mg/kg q 3 w) compared to interferon-2β confirmed the efficacy of RAD001, employed as single-agent has an advantage in terms of progression-free survival. and in combination with octreotide, in terms of disease Another randomized phase II trial carried out in patients with control. The preliminary results of the RADIANT2 study in advanced carcinoids on treatment with octreotide and with patients with GEP and lung NETs with carcinoid syndrome progressive disease showed a benefit of bevacizumab over have not reached the primary end-point (PFS). Instead, the IFN-α in terms of objective responses and progression-free RADIANT3 study confirms the efficacy of RAD001, survival (37-41). compared to placebo, in pancreatic NETs (44-46). In conclusion, following recent efficacy data, the therapeutic Tyrosine kinase inhibitors (TKIs). Sunitinib malate (SU- algorithm, particularly in pancreatic NETs should include the 11248, Sutent®) is a selective inhibitor of some tyrosine use of biological drugs, such as sunitinib and RAD001, after kinases (TKI), such as Vascular Endothelial Growth Factor failure of somatostatin analogues. Receptor (VRGFR)1, 2 and 3, Platelet-Derived Growth Factor There are currently several studies underway to assess Receptor (PDGFR), c-KIT and REarranged during efficacy and safety of some other new molecules. Transfection (RET) gene. It exerts a dual antitumour activity Cabozantinib is a potent dual inhibitor of the MNNG HOS either as or as antiproliferative agent Transforming gene (MET) and VEGF pathways, designed to through a direct effect on tumour cells. The clinical activity of block MET-driven tumor escape. It is under investigation in

4196 Bajetta et al: Treatment of Neuroendocrine Tumors (Review)

Table III. Radiotherapy of neuroendocrine tumours.

References Radiopharmaceutical No. of patients Clinical benefit (%)

Valkema et al. 2002 ref. 48 111DTPA-octreotide 26 66 Otte et al. 2002 ref. 49 90Y-DOTATOC 29 96 Bodei et al. 2003 ref. 50 90Y-DOTATOC 141 76 Kwekkebom et al. 2003 ref. 53 177Lu-DOTATATE 310 46 Imhof et al. 2011 ref. 51 90Y-DOTATOC 1109 34

pancreatic neuroendocrine tumor in a phase II study. (Trial the substitution of phenylalaline at position 3 with a tyrosine- n˚: NCT01466036) residue produced Tyr3-octreotide (TOC). This increased the Panzem (2-methoxyestradiol, 2ME2) nanocrystal dispersion affinity for SSTR2. Replacing the C-terminal threoninol with (NCD) is derived from estrogen and works by suppressing threonine resulted in the synthesis of Tyr3-octreotate (TATE), tumour growth and blocking the formation of new blood which has been shown to have much higher affinity for vessels that feed tumours. It is administered orally with SSTR2 when compared to octreotide. Many other analogues recombinant human monoclonal antibody against VEGF have been developed, by substituting chemical groups with (bevacizumab) which is administered intravenously, to patients the aim of enhancing the affinity of the analogues for the with locally-advanced or metastatic carcinoid (Trial n˚: receptors. Among them, one of the most recent is Nal3- NCT00328497). octreotide (NOC), obtained by substituting a naphtyl-alanine Axitinib is a small-molecule TKI. It inhibits multiple in position 3. An important part of these radiopharmaceuticals targets, including VEGFR1, 2, 3, PDGFR, and cKIT is the radioisotope which is bound to pepdide through the (CD117). A phase II study will assess efficacy and safety of chelator diethylentriaminepenta-acetic-acid (DTPA) or tetra- this drug in carcinoids (Trial n˚: NCT01435122). azacyclododecanetetra-acetic-acid (DOTA). EPO 906 is a potent member of a new class of The most relevant radiopharmaceuticals that should be -stabilizing cytotoxic agents, known as cited for peptide receptor radionuclide therapy (PRRT) are . A phase II study will examine if EPO906, given (Table III): 111In- pentetreotide (Octrescan®), 90Y, DOTA by intravenous infusion, is effective in shrinking tumors and (Tyr3) TOC, 177Lu-DOTA (Tyr3) TATE. preventing the growth of cells (Trial n˚: NCT00050349). Valkema et al. treated 26 patients with GEP NETs Pansierotide LAR is a somatostatin analogue that binds for tumours with high doses of 111In-DTPA octreotide, receiving each of the five known SSTRs. A randomized, multicenter, a total cumulative dose of more than 20 GBq. The results phase III study is comparing the efficacy of pasierotide LAR were: 8% partial response (PR), 58% stable disease (SD). In and octreotide LAR in patients whose disease-related other studies patients were treated with high cumulative symptoms are inadequately controlled by currently available activities (up to 36.6 GBq) and 17% of them had PR, with somatostatin analogues (Trial n˚: NCT00690430). 58% SD. In all studies, the most common toxicity was bone Vatalanib is an oral tyrosine kinase inhibitor targeting marrow suppression (48). VEGFR1, 2, and 3. In a phase II trial vatalanib together with Therapy with 90Y-DOTATOC was performed by Otte et al. octreotide are being studied to understand if they work in who treated 29 patients with GEP-NETs using a dose- treating patients with progressive neuroendocrine tumors escalating scheme of four or more cycles of 90Y-DOTATOC, (47). (Trial n˚: NCT00627198) up to a cumulative dose of 6.120±1.347 MBq/m2. The results were: 24 patients had SD, two had PR and three had Radiotherapy of NETs progressive disease (PD). (49). Bodei et al. published data of a phase I study in 21 patients with GEP NETs. Cumulative The treatment of NETs with radiopharmaceuticals is possible total doses given in two cycles ranged from 5.9-11.1 GBq. The today, both for radiopharmaceuticals targeting receptors results were: 29% PR, with a median duration of response of overexpressed by these tumours and also with 9 months. The same group evaluated the objective response of radiopharmaceuticals acting on the cell metabolism. Different 141 patients with various types of NETs, treated with doses receptors have been investigated as a target of the higher than 7.4 GBq of 90Y-DOTATOC (cumulative activity: radioisotope, however, so far the SSTRs seem to be the best 7.4-26.4 GBq) divided into 2-16 cycles. An overall clinical option. The radiopharmaceuticals targeting SSTRs are based benefit (CR+PR+SD) was observed in 76% of patients (50). on three components: a peptide, a chelator and a radionuclide. The most important study of the use of 90Y-DOTATOC is The first somatostatin analogue synthesized was octreotide; a phase II study by Imhof et al., who investigated the

4197 ANTICANCER RESEARCH 32: 4193-4200 (2012) efficacy, survival and toxicity of such therapies in 1,109 performed by a radioisotope with low-energy and short range patients. Out of these patients, 378 (34.1%) experienced (177Lu) followed by a radioisotope with higher energy and morphological responses; 172 (15.5%), biochemical wide range (90Y). The results of a randomized study by responses; and 329 (29.7%), clinical responses. During a Villard et al. on 486 patients with advanced GEP-NETs median follow-up of 23 months, 491 patients (44.3%) died. yielded an improvement of survival for patients treated with Longer survival was correlated with each: morphological the combination (5.51 vs. 3.96 Gy) with comparable rates of (hazard ratio (HR)=0.46; 95% Confidence Interval toxicities (55). (CI)=0.38-0.56; median survival, 44.7 vs. 18.3 months; In conclusion, radiolabelled somatostatin analogues have a p<0.001), biochemical (HR= 0.75; 95% CI=0.59-0.96; 35.3 good efficacy as therapeutic agents for PRRT in NETs vs. 25.7 months; p=0.023), and clinical response (HR=0.68; (tumour reduction, improvement of quality of life, biochemical 95% CI=0.56-0.82; 36.8 vs. 23.5 months; p<0.001). Overall, response). Only a small number of serious adverse effects 142 patients (12.8%) developed grade 3 to 4 transient occurred and only in those patients who had previous haematological toxicities, and 103 patients (9.2%) chemotherapy. experienced grade 4 to 5 permanent renal toxicity. Multivariable regression revealed that tumoral uptake in the Conclusion initial imaging study was predictive of overall survival (HR=0.45; 95% CI=0.29-0.69; p<0.001), whereas the initial The high biological and clinical heterogeneity of NETs kidney uptake was predictive for severe renal toxicity require a multimodal therapeutic approach to be taken. The (HR=1.59; 95% CI=1.17-2.17; p=0.003). (51) The therapeutic options available nowadays are extremely advantages of using 177Lu DOTA-TATE have the best different and must be related according to the natural history tumour/kidney, spleen and liver uptake ratio which allows of the disease. The biology of NETs can justify several higher tumour-absorbed doses without major effects on the therapeutic approaches which can include simple surveillance dose-limiting organs, the longer residency time of 177Lu of indolent and asymptomatic disease, biological therapy, DOTA-TATE in tumours and the gamma emission of 177Lu chemotherapy or integrated approaches such as the use of (52). Most of the studies using 177Lu-DOTA-TATE have radioisotopes. The best therapeutic decision must be taken in been performed by Kwekkeboom et al. who propose 177Lu relation to all the prognostic characteristics of the disease. octreotate as the radiolabeled somatostatin of choice when performing PRRT. In 2003 they assessed the effects of Conflicts of Interest 177Lu-DOTA-TATE in 34 patients with GEP tumours. The results were: 3% CR, 35% PR, 41% SD and 21% PD. The Authors have no conflicts of interest to be declared. Following this study they treated 131 patients with GEP tumours with a cumulative dose of 22.2-29.6 GBq of 177-Lu Acknowledgements DOTA-TATE: 3 (2%) obtained a CR, 32 (26%) a PR, 44 The Authors thank the Italian Trials in Medical Oncology (I.T.M.O.) (35%) had SD and 22 (18%) developed PD. In a more Group for editorial support. extensive study by the same group the efficacy of 177Lu- DOTA-TATE was evaluated in 310 patients and toxicity was References evaluated in 510 patients, each receiving a cumulative radiation dose of 27.8-29.6 GBq in four treatment cycles 1 Bosman FT, Carneiro F, Hruban R and Theise ND: WHO with 6-10-week intervals between each cycle. Complete Classification of Tumours of the Digestive System. IARC: Lyon, response was seen in 2 %, PR in 28% and a MR in 16% of 2010. patients. 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N Engl J Med 364(6): 514- 523, 2011. 46 Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O’Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA and Wiedenmann B: Daily oral everolimus activity in patients with metastatic pancreatic Received June 4, 2012 neuroendocrine tumors after failure of cytotoxic chemotherapy: Revised August 2, 2012 a phase II trial. J Clin Oncol 28(1): 69-76, 2010. Accepted August 3, 2012

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