Selecting patients for cytotoxic therapies in gastroenteropancreatic neuroendocrine tumours

Best Practice & Research Clinical Gastroenterology 26 (2012) 843–854

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Best Practice & Research Clinical Gastroenterology

11

Selecting patients for cytotoxic therapies in gastroenteropancreatic neuroendocrine tumours F.P. Costa a, *, B. Gumz a, B. Pasche b a

Centro de Oncologia, Hospital Sírio Libanês, Rua Dona Adma Jafet 90, São Paulo, SP, CEP 01308-050, Brazil Division of Hematology/Oncology, Department of Medicine, The University of Alabama at Birmingham, 1802 6th Avenue South, NP 2566, Birmingham, AL 35294-3300, USA b

a b s t r a c t Keywords: Gastroenteropancreatic Neuroendocrine tumour Carcinoid Pancreatic Chemotherapy

Gastroenteropancreatic neuroendocrine tumours (GEP-NET) have heterogenic clinical presentations. The majority of GEP-NET tumours have an indolent behaviour, but patients will eventually develop symptoms of tumour progression or hormone secretion that may require systemic medical interventions. Cytotoxic chemotherapy has been tested in GEP-NETs since the 80s, but treatment recommendations are controversial in many instances. Patient selection is mandatory for optimal use of chemotherapy. Important prognostic factors such as primary tumour site, tumour differentiation, tumour staging and proliferation index have been identified and validated in retrospective and prospective series. The combination of those factors and the natural history of GEP-NET provide valuable information with respect to treatment planning. In this report we provide treatment recommendations to improve systemic therapy in patients with advanced GEP-NETs based on a comprehensive review of the literature. Ó 2013 Elsevier Ltd. All rights reserved.

Introduction Neuroendocrine tumour, historically perceived as an exceedingly rare neoplasm, has recently been shown to be more common than previously suspected. In the US SEER Registry from 2000 to 2004, the age-adjusted incidence was 5.0 per 100.000 [1]. Because these tumours derive from neuroendocrine

* Corresponding author: Tel: þ55 113155 0686; fax: þ55 113155 0250. E-mail address: [email protected] (F.P. Costa). 1521-6918/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpg.2012.12.001

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cell compartments, they can arise in diverse anatomic locations. Nearly 60% of neuroendocrine tumours arise along the intestine and 15% arise in other gastro-pancreatic regions where those tumours occur less frequently such as oesophagus, stomach, appendix, colon and rectal. Close to 25% of neuroendocrine tumours arise within the bronchopulmonary system [1,2]. Those tumours and other nongastrointestinal track tumours will be not be discussed in this report. Gastroenteropancreatic neuroendocrine tumours (GEP-NET) are classically associated with the secretion of hormones or vasoactive peptides into the systemic circulation. Although the majority of clinical manifestations of GEP-NET often are either subtle or clinically silent, approximately 10–30% of patients have symptoms resulting from bioactive mediators secreted by these tumours [2]. These tumours are classified as ‘functional’ and those clinical characteristics depend on the tumour site and type of hormones secreted. In the intestine, functional tumours produce the carcinoid syndrome, mediated by serotonin secretion [3]. In pancreatic tumours the functional symptoms are related to the type of hormone secreted: gastrin, glucagon, insulin, vasoactive intestinal peptide, somatostatin or combination of them [4]. Because the pathophysiology and outcome of GEP-NETs differ substantially from gastrointestinal adenocarcinomas, clinicians must consider GEP-NET biology to select the appropriate therapy (Table 1) [1,2,4–9]. While systemic chemotherapy constitutes the backbone treatment strategy for advanced adenocarcinomas in the gastrointestinal tract, this is not the case for their neuroendocrine counterparts. Since the 80s several systemic chemotherapy regimens have been studied and are available for the treatment of patients with indolent and aggressive GEP-NET [8,10,11]. Indication for chemotherapy use is mainly restricted to the palliative setting. Active single chemotherapeutic agents include dacarbazine, streptozocin, platinum compounds, doxorubicin, etoposide, fluorouracil, ifosfamide, irinotecan, taxanes, and temozolomide. Various combinations of chemotherapy agents have been investigated along the years and demonstrated higher response rates but at the price of higher toxicity. The data supporting doublet or triplet regimens are based on small phase II and phase III trials. The studies didn’t stratify patients with advanced GEP-NET by known prognostic characteristic. Hence, clear indications for the optimal use of systemic chemotherapy are lacking and formal recommendations are still based on expert opinions [9,12–16]. For this reason, no individual treatment schema has been defined as a standard option due to insufficient data on activity and toxicity.

Table 1 Clinical presentation of GEP-NET. Tumour

Functional symptoms

Metastases

Behaviour

OS (month) In metastatic patients

Small intestine

Diarrhoea, flushing, tachycardia, bronchospasm (carcinoid syndrome)

Frequent

Indolent disease

56

Hypoglycemia, sweating, weakness, nausea

<5–12% (61% pb)

30

Necrotizing migratory erythema, cachexia, diabetes, deep vein thrombosis Profound secretory diarrhoea, electrolyte disturbance

<5% (56% pb)

60–90%

Life-threatening symptoms; Indolent disease Life-threatening symptoms; Indolent disease Life-threatening symptoms, indolent disease More aggressive

74

45–78% 54% Rare Frequent

Indolent Indolent Indolent More aggressive

40% (5y OS)* 24 27 5

Rare

Indolent

22

Pancreatic Insulinoma

Glucagonoma

VIPoma

Gastrinoma Somatostatinomas Non-functioning Appendix Colon Rectal

Acid hypersecretion, abdominal pain, diarrhoea Steatorrhoea, diabetes, cholelithiasis Mass effect Asymtomatic Diarrhoea, flushing, tachycardia, bronchospasm (carcinoid syndrome) Mass effect

<10% (47% pb)

72

60

* There is no clear data for median survival since somatostatinomas are rare tumours. pb: population based data.

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Selecting patients for chemotherapy The multidisciplinary approach is a central tenet for the treatment of GEP-NET patients. The decision making process is multifactorial and has been constantly influenced by new developments in the field. Surgical procedures or local regional treatment strategies should be always favoured, even in patients with metastatic disease [17–20]. Systemic chemotherapy is frequently reserved for palliative purposes, since its use in the adjuvant or pre-operative setting is anecdotal [21]. Considering that the majority of studies of chemotherapy in neuroendocrine tumours were performed more than 10 years ago, the available data needs to be carefully analysed. The majority of patients with GET-NET have indolent disease [1,2]. The primary physician should consider the actual clinical situation the patient is facing, but also the sequence of treatments. A ‘watch-and-wait’ strategy is important to better understand the natural history of the patient [22]. Tumour progression by standard imaging studies, worsening of functional or constitutive symptoms are often documented prior to systemic cytotoxic treatment initiation. The exception to this rule is a patient with aggressive disease in which immediate treatment initiation should be recommended [23]. GEP-NET is a heterogeneous neoplasm, which presents with a wide spectrum of clinical presentations [1,2,4]. Accurate understanding of the patient prognosis is needed in order to define the best systemic treatment strategy. In this report we discuss the selection and indication of systemic cytotoxic chemotherapy based on the available literature.

Practice points The fundamental aspects associated with prognosis should be taken in consideration when chemotherapy is being considered:    

Primary tumour location Tumour differentiation and grade Tumour stage Proliferation index

Primary tumour location In the 1960s, Williams et al. classified NET based on embryologic derivation, distinguishing between foregut (bronchial, stomach, pancreatic, duodenal), midgut (jejunal, ileal, cecal, appendiceal), and hindgut (distal colon and rectal) [24]. Most of the older studies in GEP-NET called ‘carcinoid’ the tumours originated from the midgut. That nomenclature is based on the work of Oberndorfer, who first used the word karzinoide in 1907 to distinguish these indolent neoplasms, which he believed were benign, from malignant adenocarcinomas [2]. The midgut tumours, or ‘carcinoids’, are well-differentiated and indolent tumours in at least 85% of the cases [25]. Despite a large number of small trials testing different regimens of single- or multi-chemotherapy agents, differences are invariably negligible and associated with substantial diminution in quality of life due to drug toxicity (Table 2) [26–42]. In many cases the adverse events associated with these regimes usually exceed the efficacy of the agents. The response rates for single agent therapy were not significant better than any of the drug combination regimens. Most studies with a meaningful number of patients (above 40 patients) reported response rates under 10%. In a recent retrospective review form Uppsala University the median survival from 603 midgut tumours was 8.4 years [17]. However, chemotherapy trials in midgut tumours lack information about progression status. Similarly, there is no progression-free survival (PFS) information available in almost

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Table 2 Chemotherapy data for ‘carcinoid’ NET. Regimen

Patients

Objective response (%)

PFS (m)

OS (m)

First author

FU þ Strepto Dox FU CDDP FU þ Strepto Ciclop þ Strepto Strepto FU þ Strepto Dox þ Strepto þ INF DTIC FU þ Strepto þ Ciclop þ Dox FU þ DTIC þ Epi FU þ DTIC þ Epi Temoz þ Thalidomide Gemcitabine Docetaxel Paclitaxel FU þ DTIC þ Epi FU þ DTIC FU þ Strepto FU þ Strepto Valproic acid

86 86 19 15 118

22 21 26 7 33 26 3.2 6.4 0 16 31 10 25 7 0 8 7 17 11 16 15.9 12.5

7.75 6.5 Nr Nr Nr Nr Nr Nr Nr Nr Nr Nr Nr Nr Nr Nr Nr Nr Nr Nr Nr Nr

16 12 Nr Nr Nr Nr 7.5 18 Nr 20 10.8 Nr Nr Nr Nr Nr Nr Nr Nr 24.3 15.7 Nr

Engstrom (1984)

7 24 11 63 56 20 12 14 9 12 14 6 9 249 5

Moertel (1979) Moertel (1986) Moertel (1979) Oberg (1987) Janson (1992) Bukowski (1994) Bukowski (1987) Di Bartolomeo (1995) Walter (2010) Kulke (2006) Kulke (2004) Kulke (2004) Ansell (2001) Bajetta (1998) Ollivier (1998) Sun (2005) Mohammed (2011)

PFS: progression-free survival; OS: overall survival; Nr: not reported; Chloroz: chlorozotocin; FU: fluorouracil; Strepto: streptozotocin; Dox: doxorubicin; Ciclop: ciclophosfamide; CDDP: cisplatin; Temoz: temozolomide; Thalido: thalidomide; Epi: epirubicin.

all studies. The PFS reported by Engstrom et al. was obtained by current suboptimal tumour evaluation, performed in the 80s [26]. Most of the chemotherapy trials are uncontrolled, and the few controlled trials do not compare the intervention with best supportive care. Finally, objective response evaluation in indolent GEP-NETs is difficult to assess using traditional measures of efficacy in clinical trials. The information available today does not show convincing benefit. It is clear that systemic chemotherapy should not be recommended as an option in welldifferentiated, indolent neoplasms originated from the jejunum, ileum, cecum, and appendix. Low grade tumours from the stomach and rectum are also included in this list. Instead, other systemic and targeted therapies should be favoured [43,44]. In contrast to midgut tumours, pancreatic tumours originating in the foregut, are partially sensitive to systemic therapy, especially to alkylating agents (Table 3) [8,28,35,37–39,45–53]. Those tumours are more aggressive in comparison with tumours arising from the small intestine. Pancreatic neoplasms are well-differentiated and low grade in 64% of the cases, 27% are intermediate grade and 8% are poorly differentiated [25]. Studies have shown that response rates ranging from 35 to 70% can be achieved using different chemotherapy regimens (Table 3). Treatment duration with chemotherapy in pancreatic NET ranged from 3.8 to 13.6 months, which is consistent with the results observed in other solid tumours. Published reports provide a strong rationale for the use of two compounds: streptozotocin and temozolomide. Streptozocin selectively targets pancreatic islet cells and has been approved for this indication in US and Europe. Most of the data from phase II and III trials show that pancreatic NET responds to a number of chemotherapeutic agents. Doxorubicin and fluorouracil are commonly administered in combination with streptozotocin. However, streptozotocin combinations have higher toxicity and are not accessible in all regions, which limits its use worldwide [12]. Temozolomide is an oral alkylating agent. Like dacarbazine, temozolomide is converted to the active alkylating agent MTIC through a spontaneous chemical conversion process. It has shown significant response rates from 34% to 70% with manageable toxicity profile in first line therapy [35,52]. Retrospective data demonstrate tumour stabilization in 38% of patients in second or third

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Table 3 Chemotherapy data for pancreatic NET. Regimen

Patients

Objective response (%)

PFS (m)

OS (m)

First author

Chlorozotocin Chloroz þ FU FU þ Strepto Dox þ Strepto Dox þ Strepto Dox þ Strepto DTIC FU þ Strepto þ CDDP Temoz þ Thalido Temoz þ Bev Strepto þ Dox þ FU FU þ DTIC þ Epi Temoz þ X Temoz Temoz þ Cape Paclitaxel Genitabine Topotecan

33 44 33 36 16 16 50 49 11 17 84 28 53 12 30 10 7 8

30 36 45 69 6 6 34 38 45 24 39 28.5 34 8 70 10 0 0

17* 11 14* 18* 3.9 18 Nr Nr Nr 8.6 18 10 13.6 Nr 18 3.2 Nr 2.9

18.0 25 16.8 26.4 20.2 Nr 19.3 Nr Nr Nr 37 Nr 35.3 Nr Nr 26 11.5 26.6

Moertel (1992) Bukowski (1992) Moertel (1992) Moertel (1992) McCollum (2004) Cheng (1999) Ramanathan (2001) Turner (2010) Kulke (2006) Kulke (2006) Kouvaraki (2004) Bajetta (1998) Kulke (2009) Ekeblad (2007) Strosberg (2011) Ansell (2001) Kulke (2004) Ansell (2004)

PFS: progression-free survival; OS: overall survival; Nr: not reported; Chloroz: chlorozotocin; FU: fluorouracil; Strepto: streptozotocin; Dox: doxorubicin; CDDP: cisplatin; Temoz: temozolomide; Thalido: thalidomide; Bev: bevacizumab; Ever: everolimus; Epi: epirubicin; X: combination of different drugs; Cape: capecitabine.

line [54]. In a recent publication from Strosberg et al., an objective radiographic response rate of 70% was observed among 30 patients with metastatic pancreatic NETs treated with first line capecitabine and temozolomide [52]. The median progression-free survival was 18 months and the median duration of radiographic response was 20 months. This data also supports the role of drug combination and capecitabine, an oral prodrug for 5-FU, appears to be well tolerated in combination with temozolomide. The precise mechanism of synergism is uncertain; however, it requires that temozolomide be administered after exposure of neuroendocrine tumour cells to capecitabine [55]. One potential rationale for synergy is depletion of the DNA repair enzyme O6 methylguanine DNA methyltransferase (MGMT) by capecitabine, thereby potentiating the effect of temozolomide [56]. Systemic chemotherapy is a valuable treatment option for patients with pancreatic NET and should be considered in patients with symptoms or progressive disease, mainly in those with more aggressive behaviour or when tumour response is necessary for bulky lesions. Newer chemotherapy regimens are currently tested using less toxic compounds such as oxaliplatin and irinotecan [57–61]. While there is no optimal regimen, chemotherapy regimens with acceptable toxicity profiles should be considered. In patients with more indolent pancreatic NET, especially given the demonstrated efficacy of targeted agents such as everolimus and sunitinib, the optimal time for chemotherapy treatment initiation remains to be defined [62–64]. Whether chemotherapy should be considered as first line therapy in patients with low grade disease, even after documented tumour progression, remains a topic of discussion [6,9,13,21]. Certainly other targeted agents have their place in this setting and should also be considered [43].

Practice points  The benefit of chemotherapy varies according to primary tumour site.  Midgut tumours do not benefit from systemic chemotherapy.  Pancreatic NETs are responsive to systemic chemotherapy and cytotoxic drug should be considered.

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Research agenda  Define the role and timing of initiation of systemic chemotherapy in patients with pancreatic NET in the era of approved medical targeted therapies.  Define treatment duration and the value for maintenance therapy after achieving best response.  Develop new effective and less toxic chemotherapy regimens.

Tumour differentiation and grade Tumour characteristic are a central consideration for treatment decisions of GEP-NETs [19]. In a comprehensive survival analysis performed by Yao et al. the median overall survival of 35,097 cases with NETs was 75 months. When survival was analysed by histological tumour grade, the median survival duration in patients with grade 1 (G1) and G2 was 124 and 64 months, respectively. In patients with G3 tumours the median survival duration was only 10 months. Patients with ‘carcinoid’ tumours and pancreatic NETs classified with G1 tumours had a median survival of 129 months. This was significantly better than patients with G3 tumours (p ¼ 0.001) [1]. Another significant predictor of outcome was the presence of adenocarcinoma features in mixed-histology NETs, which was associated with poor prognosis [1]. In the 2010 World Health Organization (WHO) GI classification the nomenclature for NET changed, replacing the definition of the 3 classes of well-differentiated endocrine tumour, well-differentiated endocrine carcinoma and poorly differentiated carcinoma. The ENETS (European Neuroendocrine tumour Society) grading and TNM staging systems are now complementary tools with a new four class system adopted by the WHO for endocrine tumours of the lung and GEP-NETS (Table 4) [21,65,66]. In the new classification, poorly differentiated gastrointestinal tumours are called neuroendocrine carcinomas (NEC G3), which account for 35–55% of all extra-pulmonary NEC, mainly located in the oesophagus, stomach, pancreas and colon. The ENETS and NANETS (North American Neuroendocrine tumour Society) guidelines advocate the use of platinum-based chemotherapy combined with etoposide for treating patients with NEC, similarly to the treatment of small cell lung cancer [67,68]. There are only few studies defining the activity, treatment duration and survival of this combination in extra-pulmonary NEC (Table 5) [23,69–73]. GEP-NEC encompasses two histopathological entities: small-cell NEC (SCNEC) and large-cell NEC (LCNEC) [74,75]. Even though those entities are different tumours as assessed by microscopy and immuno-histochemistry, their prognosis and survival appears to be the same [76,77]. There are also no differences in response rate and survival according to subtype morphology and both entities should be treated the same way, i.e. platinum-based systemic chemotherapy [23,68,78]. For G1 and G2 tumours, the indication of chemotherapy is less clear. In the G1 tumours the majority of experts agree that other forms of systemic therapy such as somatostatin analogues, medical targeted therapies or Peptide Receptor Radionuclide Therapy (PRRT), seem more appropriate [15,16,44]. In midgut tumours, the indication of somatostatin analogues in G1 tumours has been defined in a phase III trial [79]. The data for somatostatin analogues in pancreatic NET G1 is not yet available but medical targeted therapies such as everolimus and sunitinib have demonstrated efficacy in phase III trials in pancreatic NET G1 and G2 [62–64]. Table 4 Nomenclature and classification of neuroendocrine tumours. NET grading system

Lung classification

ENETS/WHO Classification

Well differentiated, low grade (grade 1) Well differentiated, intermediate grade (grade 2) Poorly differentiated, high grade (grade 3)

Carcinoid tumour Atypical carcinoid

Neuroendocrine tumour, grade 1 Neuroendocrine tumour, grade 2

Small-cell carcinoma Large-cell neuroendocrine Carcinoma

Neuroendocrine carcinoma, grade 3 small-cell Neuroendocrine carcinoma, grade 3 large-cell

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Practice points    

Tumour grading is paramount for selecting patients who should receive chemotherapy. Chemotherapy should be avoided in patients with NET G1 in most cases. In NET G2 first-line chemotherapy is controversial. Patients with NEC G3 tumours should always receive treatment with platinum-based systemic chemotherapy.

Research agenda  Determine the optimal sequence of treatments in NET G1 and G2 patients.  Define the value of temozolomide-based regimens in aggressive NETs.

Table 5 Chemotherapy in extra-pulmonary NEC. Regimen

Patients

Objective response (%)

PFS (m)

OS (m)

First author

CDDP þ Eto CDDP þ Eto CDDP þ Eto Carbo þ Eto þ Pacli CDDP þ Eto Carbo þ Eto Carbo þ Eto þ Vinc CDDP þ Eto or CAV

18 41 4 78 129 67 28 51

67 42 67 53 31 31 44 33–37

8 9.2 Nr Nr 4 4 4 Nr

16 15 Nr 14.5 12 11 10 9.2–19.6

Moertel (1991) Mitry (1999) Fjallskog (2001) Hainworth (2006) Sorbye (2012)

Brenner (2004)

PFS: progression-free survival; OS: overall survival; Nr: not reported; CDDP: cisplatin; Eto: etoposide; Pacli: paclitaxel; Vinc: vincristine; CAV: cyclophosphamide, doxorubicin and either vincristine or etoposide.

Tumour stage Staging has prognostic implications in gastrointestinal malignancies. This is also true for GEP-NET but with distinct implications. In an analysis of 28,515 cases from the SEER database, Yao et al. observed a strong correlation between primary tumour site and staging (Table 6) [1]. The presence of distant disease at diagnosis had a significant negative impact on overall survival (p < 0.001) [1]. In the Uppsala University midgut series, mesenteric lymph-node metastases were discovered in 528 (88%) patients at diagnosis. Laparotomy detected locoregional disease in 93% of the patients and clinical staging detected regional metastasis in 57% of the cases. Distant hepatic metastases were found in 61% of patients and extra-abdominal metastases were uncommon (4%) [17]. Even though advanced staging was associated with worse prognosis in this retrospective series (p < 0.001), the 5-year overall survival for stage IV patients was 57% and 86% for stage III patients. Surprisingly, patients with documented peritoneal carcinomatosis and with >10 liver metastases had a 5-year overall survival of 52% and 50%, respectively [17]. In pancreatic NET, there is also an association between tumour staging and worse outcome (p ¼ 0.001) [4]. In the SEER registry data that included 1310 patients with pancreatic NET, the 5-year survival for local, regional and distant disease was 71%, 55% and 23% [4]. It is evident that tumour staging and its impact on prognosis reflect the differences in natural history of GEP-NET. Tumours with more favourable behaviour tend to do better even in more advanced stages. So, tumour staging alone should not be used as surrogate for cytotoxic therapy, especially in G1 GEP-NETs. Besides the primary tumour site, histological grade also is strongly associated with disease stage (p < 0.001) [1]. Patients with well-differentiated G1 tumours are diagnosed with synchronic metastatic involvement in 21%. This rate increases to 30% and 50% in G2 and G3 tumours, respectively [1].

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Table 6 Staging differences by GEP-NET tumour site and impact on survival [1]. Tumour staging

Median survival

Tumour site

Localized (%)

Regional (%)

Distant (%)

Localized (m)

Regional (m)

Distant (m)

Stomach Duodenum Small intestine Cecum Appendix Colon Rectum Pancreas

76 81 29 14 60 45 92 14

9 10 41 42 28 23 4 22

15 9 30 44 12 32 5 64

154 101 111 135 >360 261 290 136

71 101 105 107 >360 36 90 77

13 57 56 41 27 5 22 24

Tumour staging information might be very relevant in the management of NET G2 and poorly differentiated carcinoma (NEC G3) tumours. In a large multicentric Italian prospective series of pancreatic NET, 297 patients were analysed and 251 (84.5%) underwent surgical resection after diagnosis [5,18]. A total of 134 patients had well-differentiated carcinoma (NET G2) and 23 patients (7.7%) had poorly differentiated carcinoma (NEC G3). Regional or distant metastases were detected in 41% of all patients, but in 94.1% and 100% of patients with NET G2 and NEC G3 patients, respectively. Complete surgical resection was less frequent for patients with NET G2 and NEC G3 than for patients with NET G1 (45.8% vs. 97.8%, p < 0.001) and palliative resection was performed in 17.1% and 13% of patients with NET G2 and NEC G3 disease, respectively. Liver resection was also performed in NET G2 and NEC G3 in 15.6% and 21.4 %. Unfortunately, no survival data is available [5]. In a retrospective series of 193 patients with GEP-NET from Princess Margaret Hospital, the 5-year survival was 67.9% for ‘carcinoid’ patients and 59.1% for pancreatic NET who underwent surgical resection. On the other hand, among patients with high-grade tumours (NEC G3) there were no survivors 5 years after surgical resection [80]. In a small series reported by Sellner et al., the survival data after complete surgical resection at 1-, 3-, and 5-year for well-differentiated tumours pancreatic NET patients was 100%, 100%, and 86%, respectively [81]. On the other hand, patients with poorly differentiated carcinomas (NEC G3) had a much worse survival, 38%, 0%, and 0%, respectively (p ¼ 0.0009). The role of debulking surgery in the treatment of GEP-NET G2 and G3 is clearly not defined and the available data failed to show any survival advantage after primary tumour resection in the presence of metastases. Thus, in patients with more aggressive disease, such as NET G2 and NEC G3, tumour staging is crucial, especially in patients in whom potentially curative or palliative resection is considered. Those patients should be managed by a multidisciplinary team and cytotoxic chemotherapy should be favoured as the initial therapy. The value of complete surgical resection in patients with documented response to chemotherapy is not yet defined.

Practice points  NET G1 patients with advanced stage may still have good prognosis and chemotherapy is usually not recommended.  Careful staging is mandatory in NET G2 and NEC G3 patients and systemic chemotherapy should be considered as first line treatment in advanced stages.  Surgical treatment is unlikely to be beneficial in patients with NET G2 and NEC G3, but should be considered whenever possible in NET G1 patients.

Research agenda  Determine the value of pre-operative chemotherapy in NET G2 patients.

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Proliferating index It is common knowledge in the medical oncology community that slow-growing tumours seldom respond to traditional cytotoxic chemotherapy. The simple explanation is that cytotoxic drugs preferentially aim cells that are rapidly dividing. So, clinical determination of tumour proliferation indices, such as the number of mitoses per high power field or the percentage of cells expressing Ki-67 is logical. Higher indices of proliferation (Ki-67 > 20%) are associated with significantly higher responses to chemotherapy, whereas tumours with very low indices of proliferation (Ki-67 < 2%) tend not to respond [10]. As earlier discussed it is now commonly accepted that there is virtually no role for cytotoxics in well-differentiated ‘carcinoid’ tumours. Cytotoxic chemotherapy has a prominent role in the treatment of more aggressive NETs and unequivocally in the treatment of poorly differentiated carcinoma. But is there an ideal Ki-67 index that should trigger chemotherapy? The Ki-67 protein is a proliferation antigen, which is present in G1, S, G2, and M phases of the cell cycle. Quiescent or resting cells in the G0 phase of the cell cycle do not express the Ki-67 antigen [82]. There is a strong correlation between Ki-67 and mitotic index, so both could be used in daily practice [83]. Both Ki-67 proliferation index and mitotic index are assessed by scanning stained slides to determine the area of maximum staining intensity or mitotic figures. The number of positive cells in a total of 2000–4000 should be examined and counted in ten or more representative high-power fields (HPF) [66,83,84]. In the 2010 WHO classification, the proliferation index is now included in the NET classification (Table 7) [83,84]. That stratification is simple and reproducible, but it may not represent the full spectrum of disease. In the NET G2, the range of Ki-67 between 3% and <20% is wide and may include different patient populations. The same applies to NEC G3, in which Ki-67 index ranges between 20% and 100%. In a phase III study of sunitinib in patients with pancreatic NET G1 and G2 conducted by Raymond et al. [64] 92% of the patients had NET G2. Sunitinib improved progression-free survival as compared with placebo among patients with a Ki-67 index of 5% or less, with a trend towards a benefit among the few patients with a Ki-67 index of more than 5%. In the Nordic retrospective study of patients with GEP-NET NEC G3 reported by Sorbye et al. [23], patients with Ki-67 < 55% had a significantly longer survival compared with patients with higher Ki-67 levels (14 versus 10 months, p < 0.05). Thirty months after chemotherapy initiation, 23% of patients with a Ki-67 < 55% were alive compared with only 7% when Ki-67  55% (P < 0.001). There are other limitations to the use of proliferative index in GEP-NETs for selecting treatment strategies [10]. Most of the series available were retrospective, based on surgically resected patients. They did not use current NET classification for grading and staging and used the primary tumour as the main source of histological material. Also, due to tumour heterogeneity, the proliferation index may not represent all sites of disease within the same patient. Understanding those limitations, common sense would advise use of chemotherapy in higher proliferative tumours. While there is no ideal cut-off number, consideration for chemotherapy in patients with a Ki-67 value > 5% seems reasonable.

Practice points  Proliferation index should be used in the selection of patients for chemotherapy.  The ideal proliferation index cut-off value for chemotherapy is not yet defined.

Research agenda  Refinement of the classification based on proliferation analysis to better select patient suitable for systemic treatment.

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Table 7 Proliferation index and tumour differentiation. Tumor differentiation

Mitotic count (/10HPF)

Ki-67 (%)

Neuroendocrine tumor, grade 1 Neuroendocrine tumor, grade 2 Neuroendocrine carcinoma, grade 3

<2 2–20 >20

2 3–20 >20

Summary GEP-NET is a heterogeneous neoplasm, which presents with a wide spectrum of clinical presentations. A multidisciplinary approach is important for the treatment of patients with GEP-NET. Systemic chemotherapy is frequently reserved for palliative purposes, since its use in the adjuvant or pre-operative setting is anecdotal. Considering that the majority of studies of chemotherapy in neuroendocrine tumours were performed more than 10 years ago, one should consider different factors such as primary tumour location, tumour differentiation, tumour staging and proliferative index in order to optimize the modality and sequence of patients’ treatments. Even though there are clear indications for the optimal use of systemic chemotherapy, in many situations there is no evidence-based recommendations and treatment decisions are still based on expert opinions. Conflict of interest None. References [1] Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. Journal of Clinical Oncology 2008;26:3063–72. [2] Modlin IM, Lye KD, Kidd MA. 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003;97:934–59. [3] Janson ET, Oberg K. Long-term management of the carcinoid syndrome. Treatment with octreotide alone and in combination with alpha-interferon. Acta Oncologica 1993;32:225–9. [4] Yao JC, Eisner MP, Leary C, et al. Population-based study of islet cell carcinoma. Annals of Surgical Oncology 2007;14: 3492–500. [5] Zerbi A, Falconi M, Rindi G, et al. Clinicopathological features of pancreatic endocrine tumors: a prospective multicenter study in Italy of 297 sporadic cases. The American Journal of Gastroenterology. 2010;105:1421–9. [6] Ehehalt F, Saeger HD, Schmidt CM, Grutzmann R. Neuroendocrine tumors of the pancreas. The Oncologist 2009;14: 456–67. [7] Hirshberg B, Cochran C, Skarulis MC, et al. Malignant insulinoma: spectrum of unusual clinical features. Cancer 2005;104: 264–72. [8] Kulke MH, Bendell J, Kvols L, Picus J, Pommier R, Yao J. Evolving diagnostic and treatment strategies for pancreatic neuroendocrine tumors. Journal of Hematology & Oncology 2011;4:29. [9] Ganetsky A, Bhatt V. Gastroenteropancreatic neuroendocrine tumors: update on therapeutics. The Annals of Pharmacotherapy 2012;46:851–62. [10] Vilar E, Salazar R, Perez-Garcia J, Cortes J, Oberg K, Tabernero J. Chemotherapy and role of the proliferation marker Ki-67 in digestive neuroendocrine tumors. Endocrine-related Cancer 2007;14:221–32. [11] Basu B, Sirohi B, Corrie P. Systemic therapy for neuroendocrine tumours of gastroenteropancreatic origin. Endocrinerelated Cancer 2010;17:R75–90. [12] Costa F, Domenichini E, Garavito G, et al. Management of neuroendocrine tumors: a meeting of experts from Latin America. Neuroendocrinology 2008;88:235–42. [13] Strosberg JR, Cheema A, Kvols LK. A review of systemic and liver-directed therapies for metastatic neuroendocrine tumors of the gastroenteropancreatic tract. Cancer Control: Journal of the Moffitt Cancer Center. 2011;18:127–37. [14] Lawrence B, Gustafsson BI, Kidd M, Modlin I. New pharmacologic therapies for gastroenteropancreatic neuroendocrine tumors. Gastroenterology Clinics of North America. 2010;39:615–28. [15] Paulson AS, Bergsland EK. Systemic therapy for advanced carcinoid tumors: where do we go from here? Journal of the National Comprehensive Cancer Network. 2012;10:785–93. [16] Poncet G, Faucheron JL, Walter T. Recent trends in the treatment of well-differentiated endocrine carcinoma of the small bowel. World Journal of Gastroenterology 2010;16:1696–706. [17] Norlen O, Stalberg P, Oberg K, et al. Long-term results of surgery for small intestinal neuroendocrine tumors at a tertiary referral center. World Journal of Surgery 2012;36:1419–31. [18] Zerbi A, Capitanio V, Boninsegna L, et al. Surgical treatment of pancreatic endocrine tumours in Italy: results of a prospective multicentre study of 262 cases. Langenbeck’s Archives of Surgery/Deutsche Gesellschaft Fur Chirurgie 2011;396: 313–21.

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