Identifying Prognostic Factors for Well-Differentiated Metastatic Pancreatic Neuroendocrine Tumours: A Retrospective International Multicentre Cohort Study

Abstract

Pancreatic neuroendocrine tumours (pNETs) represent rare neoplasms of all NETs often presenting without functional activity. Many sporadic non-functioning pNET patients are already metastatic at the time of diagnosis, and the therapeutic approach to such patients is mostly palliative. In this international, multicentre, retrospective cohort study, we assessed the prognostic value of a set of anthropometric, clinical, biochemical, radiological and pathological parameters at baseline and the impact of the therapeutic strategies on the survival of patients with sporadic grade 1/2, stage IV, non-functioning pNETs. Three hundred and twelve consecutive patients diagnosed between 1993 and 2010 were included. The median overall survival (OS) was 6.6 years and survival at 5 and 10 years was 62 and 34% respectively. On univariate analysis, Eastern Cooperative Oncology Group (ECOG) status ≥2, grade 2, bilobar hepatic metastases, synchronous metastases, and high chromogranin A, alkaline-phosphatase and lactic-dehydrogenase were associated with a significant reduction of OS. Palliative/curative surgery and loco-regional hepatic interventions were significant factors improving OS. On multivariate analysis, ECOG status ≥2, synchronous metastases, Ki-67 ≥10%, and high alkaline-phosphatase correlated significantly with an increased risk of death. Both palliative/curative surgery and loco-regional hepatic interventions had a positive impact on OS. Although most parameters did not prove to be independent OS predictors at multivariate analysis, they showed a tendency towards that. Future prospective studies including larger patient populations may give greater clarity. We believe the integration of these parameters has the potential to provide a reliable prognostic score for the stratification of patients with sporadic well-differentiated metastatic non-functioning pNETs.

Bone Metastases in Neuroendocrine Tumors: Molecular Pathogenesis and Implications in Clinical Practice

“…Similar findings have been reported by other studies performed in ENETS Centers of Excellence across Europe, confirming the negative prognostic impact of bone metastases on patients’ survival [7, 10, 45]. Nevertheless, in a study enrolling 312 consecutive patients with sporadic, grade 1/2, stage IV, nonfunctioning panNETs, the presence of bone lesions predicted a shorter PFS, in the absence of any impact on overall survival [52]. Overall, median survival time from bone metastases identification ranges from 20 to 60 months [7, 9, 10, 45, 49], a figure that highlights the negative impact of this specific metastatic pattern compared with patients with stage IV disease without skeletal colonization, where median survival rates are usually comprised between 80 and 100 months [7, 9, 53].…”

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study

“…In the phase 3 PROMID study (which randomised patients with midgut NET to octreotide long-acting release [LAR] versus placebo), liver tumour burden > 10% was associated with a hazard ratio (HR) for progression of 2.63 on multivariate analysis [2]. Another prognostic factor is serum alkaline phosphatase (ALP) [9][10][11][12][13], which may be elevated with extensive liver involvement and bone metastases [10,14]. In one series of metastatic gastrointestinal NET, ALP ≥ upper limit of normal (ULN) was associated with a median progression-free survival (PFS) of 10 months versus 33 months with normal ALP (multivariate HR, 2.49, P = 0.017) [10].…”

Effect of metastatic site on survival in patients with neuroendocrine neoplasms (NENs). An analysis of SEER data from 2010 to 2014

“…Some exhibit an indolent, slow growth pattern, while others parallel the more aggressive, rapidly spreading tumors such as small cell lung cancer (SCLC); in between there are neoplasms of intermediate malignant potential. Research so far has identified stage, site of origin [4] and differentiation [5 6], as well as proliferative indices (Ki-67, mitotic count) as important prognostic factors and multiple scores have been published, trying to predict survival in metastatic disease or recurrence after curative surgery [5][6][7][8][9][10][11]. In general, well-differentiated tumors progress slowly and surveillance may be the best approach in some cases, whereas poorly differentiated neoplasms require urgent aggressive chemotherapy and are associated with markedly shorter survivals [12].…”