Gastrointestinal Cancer

Gastroenteropancreatic Well-Differentiated Grade 3 Neuroendocrine Tumors: Review and Position Statement ROMAIN CORIAT,a,c THOMAS WALTER,d,e BENOˆIT TERRIS,b,c ANNE COUVELARD,f,h PHILIPPE RUSZNIEWSKIg,h Departments of aGastroenterology and bPathology, Cochin Teaching Hospital, Assistance Publique–Hˆopitaux de Paris, Paris, France; c ´ Facult´e de Medecine, Universit´e Paris Descartes, Sorbonne Paris Cit´e, Paris, France; dHospices Civils de Lyon, Hˆopital Edouard Herriot, Service d’Oncologie Digestive, Lyon, France; eUniversit´e Claude Bernard Lyon 1, Universit´e de Lyon, Lyon, France; fDepartment of Pathology, Bichat Hospital, Assistance Publique–Hˆopitaux de Paris, De´ partements Hospitalo Universitaires, Paris, France; gUniversit´e Paris ´ Paris, France; hDepartment of Gastroenterology and Pancreatology, Beaujon Hospital, Assistance Diderot, Sorbonne Paris Cite, ´ Publique–Hˆopitaux de Paris, Departements Hospitalo Universitaires, Clichy, France Disclosures of potential conflicts of interest may be found at the end of this article.

Key Words. Well-differentiated x Grade 3 x Neuroendocrine tumor x WHO classification x Chemotherapy x Targeted therapy

ABSTRACT In 2010, the World Health Organization (WHO) classification of neuroendocrine neoplasms was reviewed and validated the crucial role of the proliferative rate. According to the WHO classification 2010, gastroenteropancreatic neuroendocrine neoplasms are classified as well-differentiated neuroendocrine tumors (NETs) of grade 1 or 2 in up to 84%, or poorly differentiated neuroendocrine carcinomas in 6%–8%. Neuroendocrine carcinomas are of grade G. Recently, a proportion of neuroendocrine tumors presenting a number of mitoses or a Ki-67 index higher than 20% and a well-differentiated morphology have been identified, calling for a new category, well-differentiated grade 3 NET (NET G-3). Studies that have reported the characteristics of neuroendocrine neoplasms

have identified more well-differentiated NET G-3 than neuroendocrine carcinomas. The main localizations of NET G-3 are the pancreas, stomach, and colon. Treatment for NET G-3 is not standardized and is balanced between G-1/2 neuroendocrine tumor and neuroendocrine carcinoma treatments. In nonmetastatic neuroendocrine tumors, the European and American guidelines recommended a surgical resection for localized neuroendocrine neoplasm, irrespective of the tumor grading. In NET G-3, chemotherapy is the benchmark if the main treatment goal is reduction of the tumor mass, particularly if it would allow a secondary surgery. In the present work, we review the epidemiology and make recommendations for the management of NET G-3. The Oncologist 2016;21:1191–1199

Implications for Practice: Neuroendocrine tumors presenting a number of mitoses or a Ki-67 index higher than 20% and a welldifferentiated morphology have been identified and named well-differentiated grade 3 neuroendocrine tumors (NET G-3). The main localizations of NET G-3 are the pancreas, stomach, and colon.The prognosis is worse than that for NET G-2. In nonmetastatic NET G-3, surgery appeared to be the first option. The chemotherapy regimen in pancreatic NET G-3 should be in line with that implemented in NET G-1/2 when the Ki-67 index is below 55% and should be in line with that implemented for neuroendocrine carcinoma when Ki-67 is above 55%.

INTRODUCTION Gastroenteropancreatic neuroendocrine neoplasms (NENs) are rare tumors defined by the expression of specific diagnostic biomarkers [1–3]. Cell differentiation is a major prognostic marker of neuroendocrine neoplasms [4, 5]. Indeed, regardless of the stage or the location of the primary tumor, it has been highlighted [3] that well-differentiated lesions have a better prognosis than poorly differentiated ones [4, 6–8]. In 2010, the World Health Organization (WHO) classification of neuroendocrine neoplasms was reviewed and validated

the crucial role of the proliferative rate [9–14]. The WHO Classification 2010 defined three groups of tumors, according to the combination of the morphological characteristics and the mitotic index as well as the Ki-67 index [15]: grades 1 and 2 corresponded to well-differentiated neuroendocrine tumors (NETs), whereas grade 3 corresponded to poorly differentiated lesions called neuroendocrine carcinomas (NECs) (Table 1). Initially, it was assumed that no NET with a mitotic or a Ki-67 index above 20% could exist.

Correspondence: Romain Coriat, M.D., Ph.D., Gastroenterology and Endoscopy Unit, Universit´e Paris Descartes, Assistance Publique–Hˆopitaux de Paris, 27 Rue du Faubourg Saint Jacques, 75014 Paris, France. Telephone: 33 (0) 1 58 41 19 52; E-Mail: [email protected] Received November 23, 2015; accepted for publication March 21, 2016; published Online First on July 8, 2016. ©AlphaMed Press 1083-7159/2016/$20.00/ 0 http://dx.doi.org/10.1634/theoncologist.2015-0476

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Table 1. The “modified” World Health Organization 2010 classification of NENs of the digestive system Tumor type and grade NET Grade 1 (NET G-1) Grade 2 (NET G-2) NEN Grade 3 (NET G-3)a (well-differentiated NET) Grade 3 (NEC)b

Mitotic index (per 10 HPF) ,2 2–20

Ki-67 index (%) #2 3–20

.20

.20

.0

.20

a

Category not described in the WHO classification. b Large or small cell type. Abbreviations: HPF, high-power fields; NEC, neuroendocrine carcinoma; NEN, neuroendocrine neoplasm; NET, neuroendocrine tumor. Source: Modified from Rindi et al. [15].

According to the 2010 WHO classification, gastroenteropancreatic NENs are classified as NET G-1 or G-2 in up to 84% of cases or NEC in 6%–8% [16, 17]. Mitoses .20 per highpower field (HPF) or a Ki-67 index .20% are identified in grade 3 tumors. Recently, a proportion of NET presenting a high proliferation, either mitoses or Ki-67 index cutoff above 20% and a well-differentiated morphology, have been identified, thereby calling for a new category, well-differentiated grade 3 NET (NET G-3). NET G-3 has been estimated between 5.6% and 8% of gastroenteropancreatic NENs [16, 18]. This category appeared as a distinct entity from NECs because of their better overall survival [16, 18]. NET G-3 suffered from a lack of guidelines or consensus-based recommendations. We herein stress the histopathological identification, frequency, treatment, and outcome of NET G-3.

HISTOPATHOLOGICAL CHARACTERISTICS OF THE NET G-3 The majority of gastroenteropancreatic NENs are classified in the well-differentiated category because they retain the organoid architecture typical of neuroendocrine organs and have a relatively low proliferative rate. It is stated that all gastroenteropancreatic NETs—with the exception of the pancreatic microadenomas and minute, gastrin-driven type 1 neuroendocrine tumors in the stomach—are potentially malignant neoplasms. Different classifications have been used to distinguish pure neuroendocrine tumors from mixed endocrineexocrine tumors, and to distinguish within pure neuroendocrine tumors different categories according to their behavior (welldifferentiated NETs with benign behavior, well-differentiated NETs with uncertain behavior, well-differentiated NETs with malignant behavior, and poorly differentiated endocrine carcinomas with high-grade malignant behavior) [19, 20]. These classifications were based on their site of origin, size, gross and/or microscopic tumor extension, vascular invasion, and/or proliferative activity (Ki-67 index), as well as their syndromatic clinical/functioning features. The prognostic assessment of gastroenteropancreatic NENs has improved significantly since the introduction of the European Neuroendocrine Tumor Society (ENETS) and the WHO 2010 staging and grading systems [21]. The unifying grading scheme is based solely on the proliferative rate (mitoses and the Ki-67 index), permitting classification of all

gastroenteropancreatic NENs as follows: low-grade, or G-1 (mitoses #2/10 HPF and Ki-67 index #2%); intermediategrade, or G-2 (mitoses 2–20/10 HPF or Ki-67 index 3%–20%); and high-grade, or G-3 (mitoses .20/HPF or Ki-67 index .20%) (Table 1). The WHO recommends that mitoses and the Ki-67 index should be counted in 50 high-power fields and 500–2,000 cells in the highest labeling regions, respectively. According to this system, a distinction can be made between well-differentiated gastroenteropancreatic NETs (low-grade G-1 and intermediate-grade G-2), the most frequent form, and poorly differentiated gastroenteropancreatic NECs (highgrade G-3) that include small- and large-cell NECs. Microscopically, well-differentiated NETs are composed of monotonous regular cells presenting round or oval nuclei with “salt and pepper” chromatin and eosinophilic granular cytoplasm. The tumor nests are arranged in trabecular, insular, or sheet-like patterns (Fig. 1A, 1B). In some cases, important nuclear pleomorphisms may be encountered, but are not associated with tumor aggressiveness (Fig. 1B). Poorly differentiated NECs show highly proliferative atypical cells that are organized in diffuse sheets with little nesting (Fig. 1C). Apoptotic bodies and necrosis are usually observed, whereas the Ki-67 index is usually .50% (Fig. 1D). However, it has now become clear that the G-3 group is heterogeneous, comprising, in addition to poorly differentiated NECs, tumors that retain the cytoarchitectural features of well-differentiated gastroenteropancreatic NETs, despite a mitoses/Ki-67 count above 20% (Fig. 1E, 1F). NETs of the G-3 group seemed not to be as aggressive as classic poorly differentiated NECs, but showed a worse outcome than the G-2 group [18, 22]. The prognosis is considered as intermediate between NET G-2 and NEC.Thus, it recently appeared of clinical interest that pathologists distinguished them both from NECs by their well-differentiated pattern and their lower mitosis/ Ki-67 count, which usually ranges from 20% to 50%, but also from G-1/2 NET. In some cases, the morphological distinction with NECs (i.e., the distinction between well and poorly differentiated NENs) remained problematic in case of important tumoral heterogeneity, with limited areas showing less differentiated patterns and/or necrosis. Recently, it has been shown that sporadic NETs and NECs occurring in the pancreas are genetically different [23]. Whereas inactivating mutations in DAXX and ATRX were exclusively found in NETs, abnormal immunolabeling for p53 and the Rb/p16 pathways was, conversely, detected in virtually all NECs (Table 2). Some of these molecular alterations may help pathologists to separate morphologically NEC from NET, in addition to morphological cellular characteristics. An accurate pathological assessment of the proliferation index appears critical to rigorously identify highly proliferative NET G-3. Determination of the Ki-67 index has become a critical element in NET disease management. Discussions remain regarding the lack of uniformity and reproducibility between the different methods used, such as “eyeballing,” manual counting, or digital image analysis. Despite good agreement for tumors showing a very low (,1%) or high (.70%) index, because of the marked interobserver and intraobserver variability, the eyeballing estimation did not appear to be reliable. This was particularly observed around the cutoffs for grading a tumor as G-2 (2%–5% range) or G-3 (15% to .20%) [24]. Compared with the image analysis

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metastasis, from the lung in particular, also need to be distinguished from gastroenteropancreatic NEC. This remains a problem because these tumors are often diagnosed at a multimetastatic stage, and the diagnosis made sometimes requires the use of a microbiopsy performed under endoscopic ultrasound. Furthermore, in contrast to NET, TTF1 and CDX2 are not reliable markers to establish the site of origin of a metastatic NEC. Differential diagnosis with an acinar cell carcinoma is even more problematic and requires the use of a panel of immunohistochemical stains, including both neuroendocrine and acinar markers (trypsin, chymotrypsin, and Bcl10) [31]. This distinction is particularly difficult for mixed acinar-neuroendocrine carcinomas [32].

INCIDENCE OF NET G-3 AND TUMOR PRESENTATION Figure 1. Neuroendocrine neoplasms showing different histologic grades based on 2010 WHO criteria. (A, B): Two cases illustrate low-grade (G-1) NETs with regular nuclei (A) and marked nuclear pleomorphism (B), which can lead to misdiagnosis as a high-grade malignancy. (C, D): Pancreatic NET of high-grade (G-3) showing a Ki-67 index at 45%. (E, F): Pancreatic small-cell NEC showing small atypical cells with necrosis foci and a Ki-67.70%. (A–C, E): H&E staining; original magnification, 3200. (D, F): Immunohistochemical staining for Ki-67; original magnification, 3200. Abbreviations: NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor.

method, eye observation/counting tended to overestimate the Ki-67 index [24–26]. Thus, in practice, the “acceptable gold standard” for determining the Ki-67 index remained the manual counting of a sufficient number of cells (.500), through the microscope or more confidently on a printed version of a captured screenshot as demonstrated by some authors [27]. Besides the problems of quantification, other factors, such as the fixative process, the staining technique, or the antibody used, may potentially affect the reproducibility of Ki-67 values. Underestimated grading has also been demonstrated when histological analysis is performed by endoscopic ultrasoundguided fine-needle aspiration [28, 29].

Differential Diagnosis Most well-differentiated NETs (G-1 and G-2) are recognizable without difficulty by pathologists. It is very unusual that an expert pathologist does not confirm an initial diagnosis. Based on the 2010 WHO classification, morphology has, for the most part, unfortunately been disregarded.The lackof NET G-3 in the current classification could lead to classifying a tumor as a poorly differentiated G-3, mainly because of a high proliferative index, instead of a well-differentiated G-3 [30]. Overdiagnosis can be observed for tumors with a Ki-67 index .20%, showing a marked nuclear pleomorphism or a crushed artifact, particularly on biopsies. However, it is clear that in rare cases, a gray zone persists for pathologists to distinguish NECs from highly proliferative NET G-3. Some authors underline the need to revise criteria concerning G-3 tumors. Revision should put emphasis on differentiation, modification of the Ki-67 cutoff value (50% instead of 20%), and integration of molecular characteristics that could allow a better distinction between these two types of proliferative tumors. Mixed tumors and

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The incidence of gastroenteropancreatic NENs is rising, probably because of the increasing quality and quantity of computed tomography imaging [1, 33]. Epidemiologic data on NEN G-3 (NEC 1 NET G-3) are scarce. Some studies have only reported NECs with a small-cell morphology [34, 35], whereas in contrast with lung NECs, large-cell NECs are more common than small-cell NECs in the gastroenteropancreatic area [36, 37]. Among gastroenteropancreatic NENs, 7%–21% are poorly differentiated (NEC) [1, 17, 35], but no data on G-3 tumors were available in these studies. Some studies reported a frequency of 9%–16% of gastroenteropancreatic NEN G-3 [17, 38, 39]. Studies, which have reported both characteristics, have always found more NET G-3 than NEC: 9.1% versus 6.7% in the Austrian study [17] and 13.5% versus 9% in the Pronet study [39]. Therefore, we can speculate that the NET G-3 incidence is probably underestimated. For instance, we can expect some NET G-3 in the NORDIC NEC study [36], especially from the pancreas, because (a) no pathological review was performed in this population of 305 patients selected on Ki-67 .20% to confirm whether all tumors were poorly differentiated or not and (b) patients with pancreatic tumors had higher rates of positive somatostatin receptor scintigraphy (SRS) (46%), lower rates of Ki-67 (70% with Ki-67 ,55%), and longer overall survival. These factors are more frequent in NET G-3 than in NEC. Very few data comparing NET G-3 and NEC are available. This was the goal of only four recent studies [16, 18, 37, 39]. Therefore, it is difficult to get an idea of the true distribution between NET G-3 and NEC, but NET G-3 would represent approximately one third of NEN G-3.The only prospective data come from the Pronet study, a 1-year prospective, epidemiologic study to assess the characteristics of newly diagnosed NEN, including a review of their diagnostic pathology. This study reported 778 patients with gastroenteropancreatic NEN, including 104 (13.5%) NEN G-3. From the 104 NEN G-3, the proportions of NEC, NET G-3, and mixed adenoneuroendocrine carcinoma were 69% (n 5 72), 20% (n 5 21), and 11% (n 5 11), respectively [39]. Another prospective national cohort, which focused on NEC (NET G-3 excluded) with a pathological review by the French national referent pathological network (TENpath), gathered interesting data on characteristics, prognosis, and treatments of NEC without comparisons with NET G-3 [40]. The paucity of available data on presentation of NET G-3 warrants particular caution regarding their distribution (Table 3) ©AlphaMed Press 2016

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Table 2. Differential immunolabeling and molecular alterations of pancreatic NET and NECs Features

NET

NECs

Morphology Differentiation Extensive Cytoplasm Eosinophilic Apoptosis 2/1 Necrosis 2/1 Positive tumors by immunohistochemistry (%) Ki-67 ,55 (median for NET G-3 ∼35) p53 0–3 Rb 0 p16 0 Bcl2 18 Phospho-mTOR 27 Molecular alterations (%) DAXX 9–25 ATRX 18–36 PTEN 7 MEN1 44 Genes in mTOR pathway 15

Poor (or “limited”) (small or large cells) Basophilic 11 111 20–100 (median ∼70) 90–100 60–89 11–50 50–100 67–80 0 0 — — —

Abbreviations: —, no data; mTOR, mammalian target of rapamycin; NECs, neuroendocrine carcinomas; NET, neuroendocrine tumor. Source: Adapted from Yachida et al. [23] and Jiao et al. [41].

[18, 41]. Further studies are required to evaluate the prognosis and the characteristics of these patients. NET G-3 are mainly located in the stomach, pancreas, and colon/ rectum (Table 2). Clinicians should be aware of the possibility of NET G-3 instead of NEC when a tumor is localized in the pancreas or in the stomach, justifying the reanalysis of the initial histopathological specimen. Similarly, secretory syndrome, positive SRS, Ki-67 index between 20% and 40% and low amount of necrosis should suggest a NET G-3 rather than a NEC. NET G-3 appeared nonfunctioning in more than 75% of cases. A positive 18-fluorodeoxyglucose PET/CT did not appear to be able to distinguish NET G-3 from NEC. In the NET G-3 group, the overall survival was longer than in NEC (NET G-3, 41–99 months; NEC, 11–17 months) [16, 18, 37].

Clinicians should be aware of the possibility of NET G-3 instead of NEC when a tumor is localized in the pancreas or in the stomach, justifying the reanalysis of the initial histopathological specimen.

TREATMENT OPTIONS

NET G-1/2, surgery is recommended as the first option in nonmetastatic NET G-3 patients [43, 44]. In pancreatic tumors, the standard treatment is surgical resection with a 5% mortality—and a 50% morbidity—rate according to the type of surgery [45, 46].The ENETS guidelines suggest that a “wait-and-see” approach might be preferred for asymptomatic patients in case of G-1, ,2 cm tumors. Considering the lack of data, a similar approach cannot be recommended in NET G-3. Ingastrictumors, a cancersurgery iswarranted. Antrectomy, indicated in selected type 1 gastric NET patients to avoid gastrin stimulation, is not recommended in NET G-3 [47, 48]. In colonic and rectal tumors, NET G-3 should be treated with appropriate cancer surgery combined with lymph node resection [49]. Surgical management of metastatic NET is controversial. The overall prognosis of these tumors is mainly based on growth of liver metastasis, cell differentiation, and Ki-67 index. In NET G-1/2, liver surgery can be a valid option. In pancreatic NET G-3, a similar overall survival of patients with NET G-2 and G-3 has been recently reported (67.8 and 54.1 months, respectively), significantly higher than in NEC (11 months) [18]. Therefore, from a surgical point of view, metastatic NET G-3 should be considered as NET G-2.

Surgery In nonmetastatic tumors, the ENETS and U.S. guidelines recommend a surgical resection for localized NEN, irrespective of tumor grading [42–44]. Based on the treatment paradigm for limited-stage small-cell lung cancer, neoadjuvant chemotherapy and radiation can be considered in many gastroenteropancreatic NEC patients, particularly when surgical resection is difficult [43, 44]. No data exist on the efficacy of such an approach in NET G-3 patients. As for well-differentiated

Nonsurgical Approach in Nonmetastatic NET G-3 In well-differentiated NET G-1/2, no data favor the administration of adjuvant chemotherapy. In NEC, there are no studies examining adjuvant postoperative treatments. Nevertheless, their aggressive behavior and high rate of recurrence have led experts to consider adjuvant treatment, using platinum-based combinations as in small-cell lung tumors [44]. In NET G-3, no data suggest a benefit of such an adjuvant therapy. In addition,

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Table 3. Characteristics of patients with grade 3 neuroendocrine neoplasm in studies comparing NET G-3 and NEC Characteristic No. of patients, n (%) Distribution of patients (%) Age (median) Primary tumor location (%) Esophagus Stomach Pancreas Colon-rectum Small-bowel Functional tumors (%) Genetic syndrome Stage IV (%) Percentage of elevated plasma marker (CgA, NSE) CgA (%) NSE (%) Uptake on 18-FDG PET/CT (%) Uptake on somatostatin receptor scintigraphy (%) Ki-67 (median, %) Mitotic index Necrosis (%) Surgery of primary tumor (%) Overall survival in months from diagnosis

NET G-3 a,b,c,d

NEC

89 (23) 18–32a,b,d 52–56a,d

298 (77)a,b,c,d 68–79a,b,d 55–64a,d

0a,b 8–24a,b 33–65a,b,c 8–29a,b 0–5a,b 14–25a,c 0–5c,d 62–100a,c,d CgA . NSEc 42c 25c 25–75a,c 88–92a,c 21–40a,b,c,d 8–17c,d 42c 60–83a,c 41–99a,c,d

5–8a,e 7–8a,e 13–25a,c,e 24–32a,e 3–5a,e 0–6a,c,d,e 0c,d,e 44–75a,c,d NSE . CgAc 31c 50c 19–89a,c,e 40–50a,c 30–80a,b,c,d,e 75–76c,e 14–36a,c,e 11–17a,b,c,d,e

a

Heetfeld et al. [37]: 37 NET G-3 and 167 NEC (204 NET G-3). Scoazec et al. [39]: 21 NET G-3 and 72 NEC (104 NET G-3 with 11 adenocarcinoid). c V´elayoudom-C´ephise et al. [16]: 12 NET G-3 and 16 NEC (28 NET G-3). d Basturk et al. [18]: 19 NET G-3 and 43 NEC (62 pancreatic NEN G-3). e Walter et al. [40]: 294 NEC. Abbreviations: 18-FDG, 18-fluorodeoxyglucose; CgA, chromogranin A; CT, computed tomography; NEC, neuroendocrine carcinoma; NET G-3, well-differentiated grade 3 neuroendocrine tumor; NSE, neuron-specific enolase; PET, positron emission tomography. b

it has been recently ascertained that a platinum-based therapy was less effective in metastatic NET G-3 than in NEC [16, 37]. Differentiation might be considered as a more important parameter than the Ki-67 proliferation index in clinical practice [42, 49–51]. The Ki-67 level in NEC is mainly above 60%. Based on experts considerations and from the NORDIC NEC study (Ki-67 with a cutoff for response found at 55%), we proposed a Ki-67 cutoff between 50% and 60% as the minimum level that should be considered satisfactory to propose platinum based chemotherapy (Fig. 2). Therefore, it appears reasonable to manage NET G-3 and NET G-1/2 patients similarly, without adjuvant therapy although there is a higher risk of recurrence [37].

Nonsurgical Approach in Metastatic NET G-3 Chemotherapy In pancreatic well-differentiated NET, chemotherapy is the benchmark if the main treatment goal is the reduction of the tumor mass, particularly if it would allow secondary surgery. A long time ago, streptozotocin plus doxorubicin was shown to be superior to streptozotocin plus 5-fluorouracil, both in terms of tumor regression rate (69% versus 45%; p 5 .005) and length of time to tumor progression (median: 20 months versus 6.9 months; p 5 .001) [52]. However, in view of renal toxicity of

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streptozotocin and cardiac toxicity of doxorubicin, different chemotherapy regimens have been investigated and may be recommended as a first-line option. Altimari et al. identified a 50% efficacy of dacarbazine in patients with nonresectable intra-abdominal NET [53]. In line with this report, Bajetta et al. showed a 30% response rate with a doublet of dacarbazine and 5-fluorouracil (LV5FU2-dacarbazine) in a cohort of 30 patients [54]. Strosberg et al. identified a major response rate (radiologic objective response: 70%; stable disease: 20%) using capecitabine from days 1 to 14 in addition to temozolomide from day 10 to 14 [12]. In the BETTER trial, chemotherapy-na¨ıve pancreatic NET G-1/2 patients were exposed to a bevacizumab-5-fluorouracil-streptozotocin association and experienced a significant disease control rate (56% of partial responses and 44% of stabilizations) [55]. Irinotecan in addition to 5-fluorouracil (FOLFIRI) has also been considered as an option in second-line pancreatic NET. This regimen was associated with an 80% disease control rate but without objective tumor response [56]. In pancreatic NEC, the association of cisplatin to etoposide appeared as the first chemotherapy option [7, 57]. Recently, Nakano et al. presented another platinum-based regimen with irinotecan and cisplatin and experienced a 50% overall response rate [58]. Similarly to pancreatic NET, FOLFIRI regimen has been evaluated as showing 37% overall response rate in second-line [59]. In a ©AlphaMed Press 2016

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Figure 2. Proposed algorithm for patients with advanced neuroendocrine tumors regarding the tumor grade. p,Cutoff score proposed based on experts’ considerations and from the NORDIC NEC study (Ki-67 with a cutoff for response found at 55%) as the minimum level that should be considered satisfactory to propose platinum-based chemotherapy. Abbreviations: 5-FU, 5-fluorouracil; NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; PRRT, peptide receptor radionuclide therapy.

study including both NEC and NET (32% and 68%, respectively) treated with capecitabine-oxaliplatin, Bajetta et al. identified a discrepancy in tumor control rates in these two groups (30% and 78%, respectively) [60].This lack of response in NEC impacted overall survival (5 versus 40 months). We would therefore consider that the chemotherapy regimen in pancreatic NET G-3 should be in line with that implemented in NET G-1/2 rather than in NEC (Fig. 2). In line with this, a randomized NET G-3 trial has started to evaluate two chemotherapy regimens, temozolomide plus capecitabine or cisplatin plus etoposide, and mandates tissue collection for analysis of differentiation, Ki-67, and molecular analyses (e.g., p53, DAXX, and ATRX) (https://clinicaltrials.gov; NCT02595424). In nonpancreatic NET, no randomized study identified a standard of care. Interferon is mainly proposed in cases of persistent secretory syndrome despite the somatostatin analogs [61, 62]. Interferon did not provide any significant benefit in terms of progression-free survival versus 5-fluorouracil plus streptozotocin (14.1 versus 5.5 months; hazard ratio 5 0.75 [0.41–1.36]) [62]. Interferon-a (3 million IU, three times per week) was used, whereas other forms seem better-tolerated and possibly as effective [63]. Considering the lack of validated chemotherapy, some experts in line with well-differentiated NET recommended dacarbazine [53] with or without 5-fluorouracil (LV5FU2dacarbazine) [64] or temozolomide [65]. An alternative could be the combination of capecitabine and temozolomide [12]. Cassier et al., using a platinum-based chemotherapy (gemcitabine and oxaliplatin regimen), suggested some efficacy in pretreated non-pancreatic-NET G-1/2 patients with an 84% overall response rate [66]. Nevertheless, physicians should keep in mind that the response rates to

alkylant agents are very low in nonpancreatic NET, possibly due to a strong expression of O(6)-methylguanine DNA methyltransferase [67, 68]. The best results of a chemotherapy regimen were obtained in a nonrandomized phase II study of naive patients with nonpancreatic NET [69]. In patients receiving a capecitabine-bevacizumab combination, the response rate was reported as 18%, the overall disease control rate was 88%, and the progression-free survival was approximately 23 months [69]. These results require confirmation. In nonpancreatic NET G-3, no chemotherapy regimen should be considered as a standard of first-line care, considering the very small amount of data available.

In nonpancreatic NET G-3, no chemotherapy regimen should be considered as a standard of first-line care, considering the very small amount of data available.

Targeted Therapies In pancreatic NET G-1/2, two randomized phase III studies demonstrated the efficacy of a targeted therapy, either an mammalian target of rapamycin (mTOR) inhibitor [9] (everolimus) or a tyrosine kinase inhibitor [14] (sunitinib). The ENETS guidelines recommend targeted therapies in second-line and their use in first-line when chemotherapy is not appropriate [70]. In pancreatic NEC, there is no validation of a targeted therapy (except bevacizumab; see above). In nonpancreatic NET G-1/2, an mTOR inhibitor (everolimus) has been evaluated. In the Radiant 2 study, everolimus plus octreotide, compared with placebo plus octreotide, tends

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Coriat, Walter, Terris et al. to demonstrate some efficacy [71]. Everolimus improved progression-free survival in patients with advanced NET associated with the carcinoid syndrome. The median progression-free survival by central review was 16.4 months in the treated group versus 11.3 months in the placebo group (hazard ratio 0.77, 95% CI 0.59–1.00; onesided log-rank test p 5 .026). These data were significantly confirmed by the Radiant 4 trial, which reported that everolimus was associated with a 52% reduction in the estimated risk of progression or death in nonpancreatic NET G-1/2 (hazard ratio [HR] 0.48 [95% CI (0.35–0.67], p , .00001) [72]. Today, there are no data to propose a mTOR inhibitor or a tyrosine kinase inhibitor as first-line treatment in NET G-3. NETs express a high density of somatostatin (SST) receptors involved in the antiproliferative effects of somatostatin analogs. In the Promid study, long-acting octreotide significantly lengthened time to tumor progression compared with placebo in patients with metastatic nonpancreatic (midgut) NET [73]. After 6 months of treatment, stable disease was observed in 67% of treated patients versus 37% in nontreated. Interestingly, the most favorable effect was observed in patients with low hepatic tumor load. The Clarinet study confirmed the efficacy of somatostatin analog, lanreotide in nonpancreatic NET G-1/2, and identified a benefit in pancreatic NET G-1/2 [74]. Lanreotide was associated with a significantly prolonged progression-free survival among patients with metastatic NET G-1/2 (Ki-67 , 10%). Patients with well-differentiated metastatic NET, Ki-67 proliferation index up to 5%, stable disease before treatment, and low-to-moderate hepatic tumor involvement (,25%) have been associated with tumor control during lanreotide treatment [75]. As more precise understanding of NET cell biology evolves, more accurate identification of individual tumors SST receptor (SSTR) profile will probably facilitate a more precise delineation of SST analog treatments [74–76]. Nevertheless, because of the lack of data in NET G-3, the use of somatostatin analogs might be restricted to low hepatic tumor involvement and stable disease. The use of somatostatin analogs in NET G-3 should be only considered with a close monitoring and may be after confirmation of SSTR expression on SST imaging.

Chemoembolization Presence of liver metastases secondary to NET of pancreatic and nonpancreatic origin has been shown to be a major factor in the alteration of both quality of life and prognosis [77]. Hepatic artery embolization or chemoembolization, as well as radioembolization, have been shown to have good clinical, biochemical, and morphological responses when liver burden does not permit ablative therapies [78]. Similar efficacy of hepatic arterial embolization versus chemoembolization in the treatment of liver metastases from well-differentiated nonpancreatic NET in a prospective study has been identified [79]. These data do not favor the hypothesis of an additive efficacy of arterial chemotherapy versus embolization alone. To date, no randomized study has sought to compare the efficacy of either embolization or chemoembolization in NET G-3. The choice of management depends on liver burden, metastases pattern, origin of the primary tumor, tumor differentiation,

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and tumor proliferative activity. In the presence of extrahepatic metastases, especially bone, a systemic treatment is preferred.

Peptide Receptor Radionuclide Therapy Peptide receptor radionuclide therapy (PRRT) is an effective form of treatment for patients with metastatic NET. However, delivering sufficient radiation dose to the tumor to result in a high percentage of long-term tumor remissions remains challenging because of the limits imposed on administered activity levels by radiation damage to normal tissues. Sabet et al. identified a specific efficacy of peptide receptor radionuclide therapy with 177Lu-octreotate in advanced nonpancreatic NET [80]. PRRT was well tolerated and very effective in well-differentiated midgut NET. Disease control rate was similar in patients with a ,2% Ki-67 and 3%–20% Ki-67 NET, 97% and 87%, respectively (p 5 .36) [80]. The treatment with 177Lu-DOTA0-Tyr3-Octreotate plus best supportive care (30 mg Octreotide long-acting repeatable [LAR]) was compared with high-dose (60 mg) Octreotide LAR in patients with inoperable, progressive somatostatin receptor-positive, well-differentiated NET G-1/2 of the small bowel and confirmed its efficacy (median overall survival: not reached, 8.4 months; hazard ratio [95% CI]: 0.21 [0.129– 0.338]; p , .0001) [81]. To date, no data exist that would justify PRRT in NET G-3.

CONCLUSION The identification of NET G-3 is the cornerstone of an adapted therapy. This entity does exist and represents up to 6% of NET. Prognosis and response rate seem to be close to welldifferentiated NET G-1/2 with a worse overall survival. It seems that the cell differentiation should be first taken in consideration when discussing the therapeutic options. To date, cell differentiation, mitoses, and Ki-67 index must be known before treatment choice. The identification of a biological marker would guide the physicians to the best therapy. Our recommendations for management are based on extrapolations of the literature, which has scant data on this particular subset of patients, warranting future studies further focusing on the clinical differences and molecular underpinnings in these patients.

AUTHOR CONTRIBUTIONS Conception/Design: Romain Coriat, Philippe Ruszniewski Provision of study material or patients: Romain Coriat, Thomas Walter Collection and/or assembly of data: Romain Coriat, Thomas Walter, Benoˆıt Terris Data analysis and interpretation: Romain Coriat,Thomas Walter, Benoˆıt Terris, Anne Couvelard, Philippe Ruszniewski Manuscript writing: Romain Coriat, Thomas Walter, Benoˆıt Terris, Anne Couvelard, Philippe Ruszniewski Final approval of manuscript: Romain Coriat, Thomas Walter, Benoˆıt Terris, Anne Couvelard, Philippe Ruszniewski

DISCLOSURES Romain Coriat: Merck, Novartis, Pfizer, Celgene, Roche (C/A); Thomas Walter: Novartis, Ipsen, Celgene (C/A); Anne Couvelard: Ipsen (SAB); Philippe Ruszniewski: Ipsen, Novartis, Keocyt (C/A), Ipsen, Novartis (RF, H). The other author indicated no financial relationships. (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/ inventor/patent holder; (SAB) Scientific advisory board

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