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REVIEW |
Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
(Correspondence should be addressed to P Corrie; Email: pippa.corrie{at}addenbrookes.nhs.uk)
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Abstract |
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Introduction |
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2% of all malignant tumours diagnosed in the western world. They can arise from neuroendocrine cells anywhere in the body and form a spectrum of cancers that vary in their biology, clinical behaviour, response to treatment and ultimate outcome. Oberndofer first described the carcinoid (or ‘karzinoide’) tumour in 1907, distinguishing them from other cancer types because of their slow growing nature (Obendorfer 1907). However, it emerged that some tumours with similar histological characteristics were less indolent, and these were separated from the rest of the carcinoids, arising in the vicinity of the pancreas and thus falling into the group now identified as pancreatic endocrine tumours (islet cell tumours). Other tumours in this diverse group are NETs of unknown primary, adrenal gland tumours, poorly differentiated anaplastic small cell tumours and NETs that comprise the multiple endocrine neoplasia type I and II syndromes. The purpose of this review is to summarise the role of systemic treatments in the management of NETs occurring in the gastrointestinal tract and pancreas (GEP NETs), which are the most common sites for NETs to occur. NETs are frequently characterised by their ability to produce peptides that can cause specific hormonal syndromes. The symptoms of carcinoid syndrome occur when the peptide, serotonin, is secreted by the primary tumour, or more usually, from liver metastases and enters the general circulation from the enterohepatic circulation. Classic symptoms include flushing, diarrhoea and bronchospasm. Less frequent but more catastrophic events include right-sided valvular heart defects, or carcinoid crisis, when large volumes of circulating vasoactive peptides generate a host of symptoms ranging from facial swelling, tachycardia and palpitations to life-threatening vasogenic shock. Since Oberndofer's first description, it has become apparent that NETs can produce a wide variety of peptides including serotonin metabolites, prostaglandins and kinins.
Endocrine tumours arising from the pancreas, also known as islet cell tumours, may produce diverse symptoms as a result of the secretion of glucagon, insulin, gastrin, corticosteroids (ACTH) or vasoactive intestinal peptide. Thus, gastrinomas can result in stomach ulcers and pain, with diarrhoea and fat malabsorption. Insulinomas produce fasting hypoglycaemia with neurological symptoms such as ataxia, confusion, weakness headache and visual symptoms. Glucagonomas can cause weight loss as a result of hyperglycaemia, with poorly healing sores and mucosal inflammation. The excess corticosteroids produced as a result of ACTH-producing tumours can cause typical Cushingoid facies, including abnormal fat distribution, reduced muscle mass, hypertrichosis, thin skin and increased risk of infection from the immunosuppressive effects of corticosteroids, as well as increased blood pressure and mental disturbances. VIPomas that release vasoactive intestinal peptide can result in flushing as well as numerous gastrointestinal symptoms including nausea and vomiting, diarrhoea, in addition to constitutional symptoms such as lethargy and weakness. In contrast to the specific symptoms generated by secretory (or ‘functional’) tumours, non-secretory (or ‘non-functional’) tumours may produce morbidity from tumour bulk and physical location.
In general, NETs are associated with a relatively inert behaviour compared with other more common epithelial cancers. However, there is a tendency to become more aggressive over time, and most patients will ultimately die of their disease. The majority of NETs (excepting insulinomas which are often benign) are malignant, and frequent sites of metastasis are lymph nodes, and liver, with less common dissemination to bone, lung and brain. The overall prognosis of NET patients differs widely according to extent of disease, histological grade and site of the primary tumour. In patients with localised NETs, the 5-year survival rates after surgery range between 60 and 90% (Modlin et al. 2003). However, due to the indolent growth patterns of these tumours, most patients present after their disease has begun to spread, largely because of the non-specific nature of their symptoms (Grama et al. 1992, Shebani et al. 1999). In patients with regional lymph node involvement, 5-year survival rates after surgery are between 50 and 75%, while for patients with distant metastases not amenable to surgery, around 25–40% of patients will still be alive 5 years from diagnosis (Modlin et al. 2003).
Histopathological classification of this complex group of tumours has proven to be extremely difficult. Until recently there was no internationally approved tumour-node-metastasis (TNM) staging system for NETs, and they were staged according to their organ of origin and whether they were functional or not. Traditionally NETs have been classified according to their embryonic origin into foregut (thymus, respiratory tract, oesophageal, stomach, pancreatic, duodenal and ovarian), midgut (jejunal, ileum, appendiceal, caecal, ascending colon and from Meckel's diverticulum) and hindgut (transverse, descending and sigmoid colon) tumours. The World Health Organization (WHO) 2000 classification defined GEP NETs in a prognosis-oriented manner, taking into account not only the size of tumour, its location and presence of metastases, but also the histological grade, presence of vascular or perineural invasion, hormone production and rate of proliferation (Solcia et al. 2000, Heitz et al. 2004). This distinguished NETs as either being well- or poorly differentiated with presence of mitoses and Ki-67 staining assists the pathologist in judging the benign or aggressive nature of the tumour (Solcia et al. 2000, Bajetta et al. 2005, Vilar et al. 2007). When classified according to these characteristics, well-differentiated tumours are likely to remain indolent for many years, while poorly differentiated tumours behave more like adenocarcinomas, with much shorter life expectancy (Klöppel et al. 2004, Artale et al. 2005, Bajetta et al. 2005, Panzuto et al. 2005). Thus, even in the presence of metastases, patients with well-differentiated NETs have a good prognosis, with life expectancy measured in years. Other prognostic indicators have been proposed and validated to varying extents. In the largest review of NET patients published to date (35 825 cases), Yao et al. (2008b) performed a multivariate analysis of patients with well- to moderately differentiated NETs for predictors of outcome. Statistically significant predictors were disease stage, primary tumour site, histological grade, sex, race, age and year of diagnosis.
In 2005 and 2006, the European Neuroendocrine Tumour Society (ENETS) proposed TNM systems for NETs of foregut (including pancreatic), midgut and hindgut origins at Consensus Conferences in Rome (Rindi et al. 2006, 2007). These staging systems included a proposal for grading, in which proliferative indices were incorporated (Grade I: <2 mitosis per 10 high-power fields (HPF) and/or Ki-67<2%; Grade II: 2–20 mitosis per 10 HPF and/or Ki-67 index 3–20%; Grade III: >21 mitosis per HPF and/or Ki-67 index >20%). The prognostic relevance of the TNM staging and grading system of foregut tumours was validated in a retrospective analysis of 202 patients from a German referral centre suggesting that the new classification system could allow prognostic stratification of GEP NETs in clinical practice and research (Pape et al. 2008). Further validation of the TNM classification for midgut and hindgut NETs by clinicopathological studies is awaited. Both the WHO and ENETS systems offer considerable value in current clinical practice.
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Treatment options for NET patients |
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Knowledge about the tumour biology of these rare tumours is now expanding, and a host of novel small molecule drugs targeting pathways known to be up-regulated in NETs are increasing the repertoire of systemic therapeutic strategies which could potentially improve outcomes. There is therefore an imperative to ensure proper evaluation of such new treatments. Collaborative national and international research networks partnering academic and commercial enterprise is beginning to provide a platform from which a solid evidence base can be generated to allow more informed treatment decision making in the near future.
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Surgery |
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Orthotopic liver transplantation is also considered an option for patients with hepatic metastatic NETs who have symptoms that are difficult to control with other therapies. Use of transplantation is in debate, however, since 62% disease-free survival at 1 year and 23% at 5 years following transplantation suggest that the short supply of livers may be more gainfully employed for conditions with better post-transplant outcomes, where 5-year survival rates in excess of 70% are observed (Neuberger 1999, Ramage et al. 2005).
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Loco-regional strategies |
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Targeted radiotherapy |
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Targeted systemic therapy |
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Several groups have reported anti-proliferative actions from somatostatin analogues, possibly by induction of apoptosis (Imam et al. 1997, Ducreux et al. 2000, Aparicio et al. 2001), although significant tumour shrinkage has been reported to occur in <5% of cases (Oberg 2001). The question whether somatostatin analogues therefore should be used in an attempt to control tumour growth and dissemination has proved controversial. However, this year the early results of the PROMID trial were released and suggest they may indeed have true antitumour activity (Rinke et al. 2009). This double-blind trial randomised the patients with metastatic well-differentiated midgut NETs to receive either monthly octreotide LAR (30 mg) or placebo injections. Although it was planned to enter 162 patients, an interim analysis of the first 85 patients revealed that octreotide LAR significantly lengthened time to tumour progression (the primary end point of the study) compared with those receiving placebo (14.3 vs 6 months). Although there was no survival benefit in the treatment arm, a possible explanation for this was due to the low number of observable deaths. Octreotide LAR was effective in patients with both functional and non-functional NETs (over 60% of the patients had non-functioning tumours), while those with the lowest liver tumour burden (<10%) experienced the greatest benefit. This is the first trial to report a convincing disease stabilisation and will no doubt impact on standard clinical management of well-differentiated NETs in the very near future.
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Systemic treatments: guided by tumour characteristics |
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The foregut tumours (excluding those of thymic and bronchial origin), particularly the pancreatic NETs are most likely to respond to conventional cytotoxic chemotherapy. Midgut tumours appear often to be low proliferating tumours, and cytotoxic chemotherapy has only resulted in responses of short duration in <10% of patients. Therefore, in slow growing tumours, there is an interest to evaluate treatment modalities with mechanisms of action other than cell cycle arrest. Immune modulation using interferon-
(IFN) administered s.c. at doses ranging 3–9 million units given 3–7 days a week has been shown to produce RRs up to 50%, measured by biochemical criteria, with durable reduction in tumour growth in up to 15% of patients and symptomatic improvement seen in 40–70% of patients (Oberg et al. 1983). Somatostatin analogues have been used in conjunction with IFN, and long-term survival gains have been suggested (Ducreux et al. 2000, Filosso et al. 2000, Faiss et al. 2003). However, the benefits of IFN have not definitively been shown to outweigh its toxicity so as yet, IFN is not generally adopted as routine treatment for NETs.
So-called ‘borderline tumours’ with histological evidence of a well-differentiated phenotype but moderately raised Ki-67 of 2–15% present management dilemmas that may be clarified by future correlative studies assessing proliferation indices with treatment outcomes (Solcia et al. 2000, O'Toole & Ruszniewski 2006). In the following sections, the evidence base for treating GEP NETs with systemic chemotherapy is summarised, drawing distinction between NETs of the gastrointestinal tract (well-differentiated foregut, midgut and hindgut carcinoids), the pancreatic endocrine and anaplastic subtypes, since they appear to follow different clinical paths in terms of aggressiveness and response to cytotoxic agents.
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Cytotoxic chemotherapy: when to implement it and how to assess it |
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Conventionally, response to chemotherapy is defined as a measurable reduction in tumour size, using internationally agreed criteria, such as the response evaluation criteria in solid tumours criteria (Therasse et al. 2000). However, NET patients may derive clinically significant symptom relief and biochemical reduction in hormonal secretion despite never showing objective tumour shrinkage (Hatton & Reed 1997). Thus, response evaluation in NET studies may be either measurable change in tumour size, biochemical response or both. Whichever outcome measure is utilised, it is important to balance these potential benefits against the side effects associated with cytotoxic agents. Changes in health-related quality of life as a result of treatment need also to be assessed in order to optimise management of this diverse group of patients (Cella 1995, Kaltsas et al. 2001b). The best validated tool for measuring patient quality of life is the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C-30 instrument. This general health questionnaire is the basis upon which NET patient-specific instruments such as EORTC QLQ-GINET21 have been developed (Davies et al. 2006).
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Single agent chemotherapy for NETs |
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While most chemotherapy trials have focused on pancreatic NETs as being the potentially chemosensitive population, a recent phase II study conducted in the UK addressed whether there is a role for single agent fluoropyrimidine chemotherapy (using capecitabine) in non-pancreatic metastatic NETs. Of 19 patients recruited, 2 had a biochemical response, while 11 patients had stable disease. Time to progression was 5.3 months and overall survival was 23.7 months (Talbot & Medley, personal communication December 2009). Even so, taken together, these data suggest that single-agent chemotherapy for NETs limited benefit (Oberg 1993, 1999). Thus, single-agent cytotoxics are rarely employed in the management of these tumours.
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Combination chemotherapy for NETs |
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The original NET chemotherapy regimens designed by Moertel incorporated i.v. 5FU bolus injections and were associated with considerable severe drug-related toxicity, in particular, myelosuppression. From studies primarily in colorectal cancer, 5FU administered as a continuous infusion is better tolerated and achieves higher RRs compared with bolus administration (Van Cutsem et al. 2001). A retrospective review of 15 patients treated with STZ combined with infusional 5FU (Gonzalez et al. 2003) suggested equivalence in terms of response (53% objective response), but improved patient tolerance compared with the standard bolus 5FU-containing regimens described by Moertel et al. (1980, 1992). A more intensive regimen combining 5FU, STZ and cisplatin was developed at the Royal Free Hospital, London, and their review of 35 patients with pancreatic NETs treated with this regimen reported acceptable toxicity and a RR of 34% (Sarkar et al. 2004).
Other combination chemotherapy regimens have been shown to achieve equivalent or better RRs in phase II studies. Capecitabine combined with oxaliplatin achieved a 30% objective RR, 20% biochemical RR and 50% symptomatic RR in 27 patients with well-differentiated NETs (Bajetta et al. 2007). Temozolomide combined with the anti-angiogenic and immunomodulatory agent, thalidomide, has achieved RR of 45% (Kulke et al. 2006a). Temozolomide has been reported to show in vitro synergy with capecitabine resulting in increased apoptosis of neuroendocrine cell lines, and this combination has raised interest from recent reports that an impressive RR of 71% has been observed in pancreatic NETs (Fine et al. 2005, Strosberg et al. 2008).
Chemotherapy regimens incorporating triplet chemotherapy combinations such as DTIC, 5FU plus epirubicin, or carboplatin, gemcitabine plus irinotecan have so far not yielded significantly better results, but have been associated with unacceptable side effects (Di Bartolomeo et al. 1995, Bajetta et al. 1998, Ollivier et al. 1998, de Lima Lopes et al. 2007). Combining chemotherapy with IFN has been tried, but has not yielded any major benefits (Oberg et al. 1994). Given the paucity of randomised trial data other than the ECOG trials described here, STZ/5FU and STZ/Dox remain the gold standard chemotherapy regimens for unresectable pancreatics NETs in most institutions today.
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Cytotoxic treatment for anaplastic NETs |
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Newer chemotherapy combinations tested in this group include irinotecan plus cisplatin (Kulke et al. 2006b) and paclitaxel, carboplatin plus etoposide (Hainsworth et al. 2006). Indirect comparisons suggest that neither regimen is superior to standard platinum/etoposide regimens, but toxicity is problematic. The overall prognosis remains poor in this group of patients, with a 2-year survival between 20 and 33%, so there is a pressing need for identification of new therapeutic strategies.
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Current chemotherapy trials |
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Novel molecular targeted therapy |
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and β and insulin-like growth factor 1 (IGF1). Of the growth factor receptors that show increased expression, namely epidermal growth factor receptor (EGFR), PDGF receptor, IGF1 receptor and stem cell factor receptor (KIT), a number of receptors possess tyrosine kinase (TK) activity. Two key treatment strategies have been successfully implemented to date. Firstly, monoclonal antibodies (mAbs) targeting a specific ligand or receptor provide specificity against the target and are usually administered as an infusion, intermittently, every few weeks. Secondly, small molecule TK inhibitors (TKIs) are selective rather than specific to one or more TKs and can be taken orally on a daily basis (Fig. 1).
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arm. Trials are ongoing, combining bevacizumab with different chemotherapy combinations: 5FU plus oxaliplatin, capecitabine plus oxaliplatin or 5FU plus STZ in various NET patient groups (see Table 3). A new mAb, cixutumumab (IMC-A12), directed against the human type I IGF receptor (IGF1R), is now being studied in NET patients, as a significant proportion of NETs express IGF and it has been reported that high levels of IGF1R expression is associated with rapid tumour growth, increased aggressiveness and lower likelihood of cure in gastrinoma (Furukawa et al. 2005). Sorafenib, originally developed as a BRAF kinase inhibitor, is known to inhibit kinase activity associated with VEGFR 2, FLT3, PDGFR and FGF receptor-1 (FGFR1). Inhibition of multiple signalling pathways might be expected to be advantageous to achieving effective antitumour activity. However, early data from a phase II trial evaluating sorafenib in 93 NET patients (51 carcinoid and 42 pancreatic islet cell) reported objective RRs in only 7% of carcinoids and 11% of pancreatic NETs (Hobday et al. 2007). This agent is currently being tested in combination with other agents such as everolimus and chemotherapy (see Table 3) in early phase trials, an attempt to improve efficacy.
Another multi-targeted TKI, sunitinib, with activity against VEGFR 1, 2, and 3, PDGFR and β, KIT and RET, has shown impressive efficacy in advanced renal cell cancer, and it now plays a well-established role in the management of this chemoresistant tumour (Motzer et al. 2007). Rather disappointingly, sunitinib produced only low RRs (17% of pancreatic NET patients and 2% of carcinoid tumours) in a phase II study of 109 patients with advanced NETs (Kulke et al. 2008). Interestingly, however, the median time to tumour progression was 10.2 and 7.7 months for patients with carcinoid and pancreatic endocrine tumours respectively, suggesting a clinical benefit in terms of disease stabilisation. The clinical efficacy of sunitinib for these tumours was substantiated in a recently reported phase III randomised double blind trial that compared sunitinib against placebo in patients with progressive, well-differentiated malignant pancreatic islet cell tumours (Raymond et al. 2009). Sunitinib resulted in a substantial improvement in median progression free survival (PFS) of 11.1 vs 5.5 months, with a hazard ratio of 0.4 in favour of sunitinib.
These data reflect the fact that TKIs may exert cytostatic effect as opposed to cytotoxic effects on tumours and emphasise the need to review the choice of end points for evaluating these agents in clinical trials. The concept of ‘disease control’ is becoming more widely accepted, whereby stable disease (as opposed to tumour shrinkage) is considered to be a positive response to treatment. Imatinib, another small molecule inhibitor of several TKs, including Bcr-Abl, PDGFR and β and KIT, showed encouraging preclinical data inhibiting NET activity in vitro, and it has now been studied in a phase II trial of 27 advanced NET patients, where despite only 1 partial response being reported, 17 cases showed disease stabilisation (Lankat-Buttgereit et al. 2005, Yao 2007). The anti-angiogenic TKI, pazopanib, which inhibits VEGFR 1, 2 and 3, c-kit and PDGFR, is currently being evaluated in a phase II study in patients with low- or intermediate-grade advanced NETs, underlining the ongoing interest in studying efficacy of TKIs in this disease.
The proto-oncogene Akt is overexpressed in some NETs and its downstream targets include the mammalian target of rapamycin (mTOR). This is a threonine kinase that has been implicated in NET growth via its activity on signalling pathways. In addition, mTOR-containing complexes (mTORCs) are important for hypoxia-inducible factor (HIF) synthesis and therefore mTOR inhibitors could potentially show effects on the key molecules of angiogenic signalling, the HIF proteins. The mTOR inhibitor everolimus (RAD001) has been demonstrated to abrogate NET cell line proliferation and promotes apoptosis in vitro (Zitzmann et al. 2007). Everolimus and another mTOR inhibitor temsirolimus have now been evaluated in phase II studies in NET patients with promising early results (O'Donnell & Ratain 2007). Everolimus has also been evaluated in combination with depot octreotide in a phase II study (US-52) of 60 NETs patient, with partial responses observed in 5 of 30 (17%) carcinoid patients and 8 of 30 (27%) patients with pancreatic NETs (Yao et al. 2008a). A biochemical RR of 70% was noted in the 37 patients with elevated chromogranin levels.
The results of the RADIANT-1 phase II study, evaluating everolimus either alone or in combination with Sandostatin LAR in patients with advanced pancreatic NET progressing on chemotherapy, were presented this year at the 11th World Congress on Gastrointestinal Cancer, Barcelona (Yao et al. 2010). This study enrolled patients who were resistant to prior cytotoxic chemotherapy and stratified them into two groups receiving either everolimus monotherapy if they had received prior somatostatin analogues, or combination of everolimus/Sandostatin LAR therapy. The addition of the somatostatin analogue resulted in a higher rate of disease control (tumour shrinkage plus stable disease) 84.4% compared with 77%, and improved median PFS by 7 months (16.7 vs 9.7 months). Everolimus is now being studied in combination with chemotherapy, for example temozolomide, and with other targeted agents such as sorafenib and the anti-EGFR TKI erlotinib, and data on these novel combinations are eagerly awaited.
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Conclusions |
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Clearly, there is a great need to improve treatment for inoperable NET patients. Better understanding of the biology of these rare and complex tumours is already beginning to drive development of novel biological therapies which show some early promise. Introduction of targeted systemic therapies, whether alone or concomitantly with cytotoxic agents, should raise the therapeutic index, maximising benefit while minimising chance of harm. It is essential for new treatment strategies to be evaluated in the context of well-designed clinical trials, which can be achieved with the good will of clinicians, scientists and Pharma to generate multinational collaborations focussing on improving outcomes associated with an orphan disease.
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Declaration of interest |
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Funding |
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References |
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Abstract
Introduction