Abstracthowever, there is no algorithm to determine the optimum sequence of therapies. Approved treatments for pNETs include somatostatin analogues (SSAs), streptozocin-based chemotherapy and targeted therapies such as everolimus and sunitinib. Unapproved therapies include systemic peptide receptor-targeted radiotherapy (PRRT), temozolomide-based chemotherapy, liver resection, liver transplantation, hepatic artery embolisation with or without chemotherapy and selective internal radiation therapy (SIRT). An individualised approach to the treatment of pNETs is described. Firstly, it is necessary to decide whether it is appropriate to treat at all. For those with symptoms, it is necessary to define the treatment goal: symptomatic or oncological control. Symptoms may direct treatment decisions; for example in patients with hypogycaemia, everolimus would be the most effective therapy. In high-volume disease where tumour reduction is the highest priority, streptozocin-based chemotherapy would be a more appropriate choice. For patients with disease progression and a moderate-to-high tumour volume, targeted therapy is the preferred choice. Following the failure of first-line therapies, second-line options include other targeted agents and cytotoxic chemotherapy. PRRT is recommended only after failure of prior therapy. Treatment decisions of pNETs should be made in a patient-oriented manner and on a case-by-case basis.
Pancreatic neuroendocrine tumour, pNET, everolimus, sunitinib, RADIANT-1, RADIANT-3, somatostatin analogues, streptozocin-based chemotherapy
James C Yao has acted as Consultant for Ipsen, Novartis and Pfizer, and has received research funding from Novartis. Alexandria T Phan has received research funding from Ipsen, Novartis and Lexicon.
August 09, 2012
James Yao, The University of Texas, MD Anderson Cancer Center, Houston, Texas, US. E: firstname.lastname@example.org
The publication of this article was funded by Novartis. The views and opinions expressed are those of the authors and not necessarily those of Novartis.
Pancreatic neuroendocrine tumours (pNETs), also known as islet cell tumours, arise from the pancreatic islet of Langerhans and can be divided into functioning and non-functioning tumours based on whether they are associated with hormonal syndromes caused by excess hormone or peptide secretion. Functioning pNETs can be responsible for a variety of clinical syndromes: Zollinger-Ellison syndrome is caused by gastrinomas (tumours that oversecrete gastrin), insulinomas are pNETs that overproduce insulin or proinsulin and glucagonomas overproduce glucagon and enteroglucagon. Other hormonal syndrome tumour types include: vasoactive intestinal peptide-producing tumours (VIPomas), pancreatic polypeptidomas (PPomas), and somatostatinomas.1
pNETs account for only 1.3 % of all pancreatic cancer.2 Estimates of incidence vary but the most recent published data suggest an annual incidence of 1-3 per million individuals, per year.3–6 Data from 1,185 cases of pNETs from the surveillance, epidemiology and end results (SEER) database was used to further examine the epidemiology of this tumour type. Distribution of cancer stage for pNETs at diagnosis included 14 % localised, 23 % regional and 54 % distant or metastatic.2 The median survival rate for patients with localised pNETs was not reached, however, the 5-year survival rate was 79 %.6 in patients with regional stage disease, the median survival was 111 months and the five-year survival rate was 62 %. These numbers were further reduced in patients with distant metastatic disease, with a median survival rate of 27 months and a five-year survival rate of 27 %.
Although the majority of pNETs occur sporadically, pNETs can arise inassociation with several hereditary cancer syndromes. Approximately 10 % may be connected with multiple endocrine neoplasia type 1 (MEN1),7 an autosomal dominant inherited disorder characterised by mutations in the menin tumour suppressor gene and development of tumours of the pancreas, parathyroid and pituitary. In addition to MEN1, other genetic cancer syndromes associated with pNETs include: von Hippel-Lindau (vHL) disease, tuberous sclerosis and neurofibromatosis. A recent study determined the exomic sequences of ten non-familial pNETs to explore the genetic basis of sporadic disease.8 The commonly mutated genes were then screened against an additional 58 pNETs and it was determined that, within the 68 pNETs analysed, 43 % had alterations in DAXX (death-domain associated protein) or ATRX (alpha thalassemia/mental retardationsyndrome X-linked) which encode subunits of a transcription/chromatin remodelling complex. A total of 44 % contained mutations in MEN1, the menin tumour suppressor gene and 14 % had mutations affecting genes within the mammalian target of rapamycin (mTOR) pathway.
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