Proactive multi-modality treatment of Pancreatic Neuroendocrine Tumours (PNETs): Potential survival benefits
Introduction
The incidence of pancreatic neuroendocrine tumours has been steadily increasing in the recent years [1]. This has partly been attributed to the rise in the identification of incidental neuroendocrine tumours by better diagnostic imaging but also an increase in awareness of the disease [2]. Compared to other gastrointestinal and bronchial neuroendocrine tumours (NETs), PNETs carry a relatively poor prognosis [3,4]. Functioning PNETs are generally diagnosed early due to the presence of endocrine syndromes. However, the more common non-functioning PNETs tend to present late due to lack of symptoms early in the disease [4]. Around half of the patients with PNETs present with liver metastases [1,2]. Furthermore, the majority of patients will develop liver metastases during the course of their disease [7]. Overall survival of 24–34 months have been reported in patients with liver metastases without treatment [8,9]. Even in the presence of distant metastases, grade of a tumour plays a significant role in predicting survival [10]. However, recent studies demonstrate an improvement in 5-year median survival of up to 59–88% with hepatic resection in selected patients with liver metastases[4,11,12]. This large variation in 5-year survival is attributed largely to the heterogeneity of PNET [10,12] but also reflects non-conformity in management strategies.
Surgery is the mainstay of curative treatment and a key modality in the cytoreduction of PNETs. Locoregional liver directed therapy is also usefully employed in the treatment of PNETs: trans-arterial chemo-embolisation (TACE), transarterial embolisation (TAE), radiofrequency ablation (RFA) or microwave ablation (MWA), selective internal radiation therapy (SIRT) and cryotherapy. Systemic therapies offer other treatment options: cytotoxic chemotherapy, biological therapy (Everolimus/Sunitinib), somatostatin receptor inhibition (SSRI), and peptide receptor radiotherapy (PRRT). The choice of modality is guided by the site of disease, Ki67 index, somatostatin receptor status, clinician and patient choice amongst other factors [7,19]. There is little by way of randomised controlled studies to guide management, particularly the order in which treatment is given.
Our multidisciplinary team has a proactive management philosophy. We define treatment as proactive because it is employed at the time of diagnosis, rather than being reserved for when symptoms occur or there is radiological disease progression. In this paper, we report our short and long-term outcomes of this approach in a large cohort of patients with both early and advanced disease.
Section snippets
Methods
We reviewed a prospectively collected database of all patients referred with PNETs in a tertiary referral centre (Southampton University Hospitals NHS Trust) between January 2000 and December 2014. The centre receives referrals from 13 hospitals across the South of England. All patients were included in the analysis whether they received active treatment with either curative or palliative intent or no active treatment. The study was retrospectively registered on August 2017 (registration number
Results
From the NET database of which 127 (29.7%) patients with a diagnosis of PNET were identified. A total of 21 patients were excluded from analysis: 17 had incomplete clinical data or no histology/Ki67 index, 2 were lost to follow up and 2 patients treated elsewhere. An increase in the number of referrals to the NET service year on year was observed but the overall proportion with PNETs remained the same.
106 patients with histologically proven PNETs were analysed. Median follow up was 67 months
Discussion
In this study, we report the outcome of a large cohort of patients presenting with PNETS who were treated with a proactive management strategy. The survival for all stages of disease were 92.5%, and 62% at 1, and 5 years respectively. This data compares very favourably with historical data from USA, Norway and UK, which reports 5-year survival of 17–43% [22]. Like this data, our cohort includes all patients including those who did not have treatment. Indeed, the outcomes we see in our stage 4
Acknowledgements
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. The authors declare no conflict of interests.
References (50)
- et al.
Multimodal management of neuroendocrine liver metastases
Hpb
(2010) - et al.
Endocrine tumours of the pancreas
Best Pract Res Clin Gastroenterol
(2005) Prognostic factors at diagnosis and value of WHO classification in a mono-institutional series of 180 non-functioning pancreatic endocrine tumours
Ann Oncol
(2008)- et al.
Pancreatic endocrine tumour: a 22-year clinico-pathological experience with morphological, immunohistochemical observation and a review of the literature
Eur J Surg Oncol
(1997) Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor
Surgery
(2011)- et al.
Aggressive surgery for metastatic liver neuroendocrine tumors
Surgery
(2003) Resection of the primary pancreatic neuroendocrine tumor in patients with unresectable liver metastases: possible indications for a multimodal approach
Surgery
(2014)Long-term survival after surgical management of neuroendocrine hepatic metastases
HPB
(2010)Bevacizumab plus capecitabine in patients with progressive advanced well-differentiated neuroendocrine tumors of the gastro-intestinal (GI-NETs) tract (BETTER trial) – a phase II non-randomised trial
Eur J Canc
(2014)Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study
Lancet
(2016)
Assessing the role of primary tumour resection in patients with synchronous unresectable liver metastases from pancreatic neuroendocrine tumour of the body and tail. A propensity score survival evaluation
Eur J Surg Oncol
Treatment parameters and outcome in 680 treatments of internal radiation with resin 90Y-microspheres for unresectable hepatic tumors
Int J Radiat Oncol
Implementation of enhanced recovery programme after pancreatoduodenectomy: a single-centre UK pilot study
Pancreatology
Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States
JAMA Oncol
Therapy of metastatic pancreatic neuroendocrine tumors (pNETs): recent insights and advances
J Gastroenterol
Update on pancreatic neuroendocrine tumors
Gland Surg
One hundred years after “Carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States
J Clin Oncol
Survival and prognostic factor analysis in patients with metastatic pancreatic endocrine carcinomas
Pancreas
Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis
Ann Surg Oncol
Surgical management of advanced pancreatic neuroendocrine tumors: short-term and long-term results from an international multi-institutional study
Ann Surg Oncol
AJCC cancer staging handbook. Cancer
ENETS consensus guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary
Neuroendocrinology
Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study
J Clin Oncol
Sunitinib malate for the treatment of pancreatic neuroendocrine tumors
N Engl J Med
Cited by (3)
Combined medical therapy, nuclear medicine therapy and other therapies in metastatic neuroendocrine tumor
2022, Nuclear Medicine and Molecular Imaging: Volume 1-4The role of oncologic resection and enucleation for small pancreatic neuroendocrine tumors
2021, HPBCitation Excerpt :The treatment of pancreatic neuroendocrine tumors (PNETs) varies with regards to size, function, and lymph node involvement.1
Prognostic factors in patients with surgical resection of pancreatic neuroendocrine tumours
2018, Acta Endocrinologica