Patterns of Recurrence after Resection for Pancreatic Neuroendocrine Tumors: Who, When, and Where?

Background/Aims: Pancreatic neuroendocrine tumors (pan-NENs) represent an increasingly common indication for pancreatic resection, but there are few data regarding possible recurrence after surgery. The aim of the study was to describe the frequency, timing, and patterns of recurrence after resection for pan-NENs with consequent implications for postoperative follow-up. Methods: We performed a retrospective analysis of pan-NENs resected between 1990 and 2015 at The Pancreas Institute, University of Verona Hospital Trust. Predictors of recurrence were assessed. Survival analysis was conducted using the Kaplan-Meier and conditional survival (CS) methods. Results: The cohort consisted of 487 patients with a median follow-up of 71 months. Recurrence developed in 12.3%: 54 (11.1%) liver metastases, 11 (2.3%) local recurrence, 10 (2.1%) nodal recurrence, and 8 (1.6%) metastases in other organs. Thirty-one (6.4%) died due to disease recurrence. Size > 21 mm, G3 grade, nodal metastasis, and vascular infiltration were independent predictors of overall recurrence. Recurrence occurred either during the first year of follow-up (n = 9), or after 10 years (n = 4). CS analysis revealed that nonfunctioning G1 pan-NEN ≤20 mm without nodal metastasis or vascular invasion had a negligible risk of developing recurrence. In the present series, after 5 years of follow-up without developing recurrence, tumor recurrence occurred only in the form of liver metastases. Conclusions: Recurrence of pan-NENs is rare and is predicted by tumor size, nodal metastasis, grading, and vascular invasion. Patients with G1 pan-NEN without nodal metastasis and vascular invasion may be considered cured by surgery. After 5 years without recurrence, follow-up should focus on excluding the development of liver metastases.

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A retrospective cohort study of pancreatic neuroendocrine tumors at single institution over 15 years: New proposal for low- and high-grade groups, validation of a nomogram for prognosis, and novel follow-up strategy for liver metastases

International Journal of Surgery ◽

10.1016/j.ijsu.2016.03.036 ◽

2016 ◽

Vol 29 ◽

pp. 108-117 ◽

Cited By ~ 7

Author(s):

Liangtao Ye ◽

Huilin Ye ◽

Quanbo Zhou ◽

Zhihua Li ◽

Qing Lin ◽

...

Keyword(s):

Cohort Study ◽

Liver Metastases ◽

Neuroendocrine Tumors ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

High Grade ◽

Pancreatic Neuroendocrine Tumors ◽

Single Institution ◽

Grade Groups

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Predictors of recurrence in patients with surgically resected pancreatic neuroendocrine tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.408 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 408-408

Author(s):

Cynthia Harris ◽

Michelle Kang Kim ◽

Kiwoon Joshua Baeg ◽

Mi Ri Lee ◽

Julie Starr ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Cox Regression ◽

Disease Free Survival ◽

Tumor Grade ◽

Disease Recurrence ◽

Stage Ii ◽

Pancreatic Neuroendocrine Tumors ◽

Cox Regression Analysis ◽

Grade 3

408 Background: Current surveillance guidelines regarding follow up of patients with resected pancreatic neuroendocrine tumors (PNETs) are based on limited data, and there have been few studies evaluating recurrence risk in such patients. We assessed disease-free survival (DFS) in a large, multi-institutional cohort of patients with resected PNETs. Methods: Patients with surgically resected, non-metastatic PNETs between 1990-2017 were identified using institutional databases at three institutions: Mount Sinai Hospital, Dana-Farber Cancer Institute, and University of Pennsylvania. Recurrence date was defined as the imaging date documenting first recurrence (n = 56); if an imaging date was not available, then July 1 of that year was used in calculations (n = 9). Kaplan-Meier analysis was used to estimate DFS; multivariate Cox regression analysis was used to assess DFS adjusted for patient and disease-related characteristics, including tumor stage and grade. Results: We identified a total of 418 patients with surgically resected, non-metastatic PNETs between 1990-2017. Of these patients, 299 patients had complete stage and tumor grade information and were used for subsequent analysis. Patients were 48.6% male with a median age of 57.5 years at time of surgery. The distribution of AJCC stage and grade was as follows: 170 (56.9%) patients were stage I, 129 (43.1%) were stage II; 167 (55.9%) had grade 1, 121 (40.5%) had grade 2, and 11 (3.7%) had grade 3 tumors. Median follow-up was 2.6 years (interquartile range = 4.2); during this time, 65 (21.7%) patients developed disease recurrence. After adjusting for potential confounders, patients with more advanced stage and higher tumor grade were significantly more likely to develop disease recurrence (Hazard Ratio (HR): 6.9, 95% CI: 2.5-19.1 for stage II; HR 4.0 (1.7-9.5) for grade 2; HR 2.6 (0.4-17.8) for grade 3). Both higher stage and tumor grade were associated with decreased DFS (p < 0.0001 for both). Conclusions: In surgically resected PNETs, with a median follow-up time of 2.6 years, both higher stage and higher grade are associated with decreased DFS. Further follow up of this cohort is planned.

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Measurement of circulating transcript levels (NETest) to detect disease recurrence and improve follow-up after curative surgical resection of well-differentiated pancreatic neuroendocrine tumors

Journal of Surgical Oncology ◽

10.1002/jso.25129 ◽

2018 ◽

Vol 118 (1) ◽

pp. 37-48 ◽

Cited By ~ 11

Author(s):

Cansu G. Genç ◽

Anneke P.J. Jilesen ◽

Els J.M. Nieveen van Dijkum ◽

Heinz-Josef Klümpen ◽

Casper H.J. van Eijck ◽

...

Keyword(s):

Surgical Resection ◽

Neuroendocrine Tumors ◽

Disease Recurrence ◽

Pancreatic Neuroendocrine Tumors ◽

Transcript Levels ◽

Well Differentiated

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Analysis of recurrence after resection of pancreatic neuroendocrine tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.304 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 304-304

Author(s):

Naeem A Newman ◽

Gary N. Mann ◽

Mrinal Shukla ◽

Katrina R Swett ◽

Edward A. Levine ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Hepatic Metastases ◽

Disease Free Survival ◽

Retrospective Chart Review ◽

Disease Recurrence ◽

Pancreatic Neuroendocrine Tumors ◽

Free Survival ◽

Ajcc Stage ◽

Disease Free

304 Background: Outcomes after recurrence of resected pancreatic neuroendocrine tumors (PNETs) are not well described. Our aim is to assess the rate and sites of recurrence and its effect on clinical outcomes. Methods: Retrospective chart review of patients (n= 80) who underwent surgical resection of PNETs at two institutions. Patients were treated from September 2002 to July 2010. Charts were reviewed for disease recurrence, date, site, and treatment of recurrence. Results: There were a total of 14 (17.5%) recurrences. The most common site of recurrence was the liver (10 patients, 71.4%). The most common treatment of recurrences was chemotherapy (5 patients, 35.7%). The 1, 3, and 5 year disease-free survival (DFS) was 90.9%, 82.7%, and 72.5% respectively. Median recurrence free survival (RFS) was 127 months. The median follow-up for all PNET patients was 25.8 months (range 1 to 140 months). Three-year survival was 97%. Local, distant, and combined recurrences occurred in 7.5%, 12.5%, and 5% of all patients, respectively. Multivariate analysis found AJCC stage (p=0.03) to be an independent predictor for DFS. Median follow-up of patients after they were found to have a recurrence was 13.8 months. Three-year survival for those with and without recurrence was 96.3% and 100%, respectively (p=0.36). Conclusions: AJCC stage is a significant predictor of recurrence after resection of PNETs with hepatic metastases being most common. Survival of patients with recurrence is not significantly different from patients without recurrence and is likely due to the indolent nature of the disease.

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Colorectal Liver Metastases - Does the Number of Lesions Determine the Sensibility of Resection?

Swiss Surgery ◽

10.1024/1023-9332.6.1.6 ◽

2000 ◽

Vol 6 (1) ◽

pp. 6-10

Author(s):

Knoefel ◽

Brunken ◽

Neumann ◽

Gundlach ◽

Rogiers ◽

...

Keyword(s):

Liver Metastases ◽

Colorectal Liver Metastases ◽

Rank Test ◽

Log Rank Test ◽

Kaplan Meier ◽

Chirurgische Entfernung

Die komplette chirurgische Entfernung von Lebermetastasen bietet Patienten nach kolorektalem Karzinom die einzige kurative Chance. Es gibt jedoch eine, anscheinend unbegrenzte, Anzahl an Parametern, die die Prognose dieser Patienten bestimmen und damit den Sinn dieser Therapie vorhersagen können. Zu den am häufigsten diskutierten und am einfachsten zu bestimmenden Parametern gehört die Anzahl der Metastasen. Ziel dieser Studie war es daher die Wertigkeit dieses Parameters in der Literatur zu reflektieren und unsere eigenen Patientendaten zu evaluieren. Insgesamt konnte von 302 Patienten ein komplettes Follow-up erhoben werden. Die gebildeten Patientengruppen wurden mit Hilfe einer Kaplan Meier Analyse und konsekutivem log rank Test untersucht. Die Literatur wurde bis Dezember 1998 revidiert. Die Anzahl der Metastasen bestätigte sich als ein prognostisches Kriterium. Lagen drei oder mehr Metastasen vor, so war nicht nur die Wahrscheinlichkeit einer R0 Resektion deutlich geringer (17.8% versus 67.2%) sondern auch das Überleben der Patienten nach einer R0 Resektion tendenziell unwahrscheinlicher. Das 5-Jahres Überleben betrug bei > 2 Metastasen 9% bei > 2 Metastasen 36%. Das 10-Jahres Überleben beträgt bislang bei > 2 Metastasen 0% bei > 2 Metastasen 18% (p < 0.07). Die Anzahl der Metastasen spielt in der Prognose der Patienten mit kolorektalen Lebermetastasen eine Rolle. Selbst bei mehr als vier Metastasen ist jedoch gelegentlich eine R0 Resektion möglich. In diesen Fällen kann der Patient auch langfristig von einer Operation profitieren. Das wichtigere Kriterium einer onkologisch sinnvollen Resektabilität ist die Frage ob technisch und funktionell eine R0 Resektion durchführbar ist. Ist das der Fall, so sollte auch einem Patienten mit mehreren Metastasen die einzige kurative Chance einer Resektion nicht vorenthalten bleiben.

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NATURAL HISTORY AFTER LONG-TERM FOLLOW UP OF PANCREATIC NEUROENDOCRINE TUMORS (PNET), BASED ON THE DETECTION OF THE PROLIFERATION CELL INDEX (KI-67) OBTAINED BY EUS-GUIDED FINE NEEDLE ASPIRATION (EUS-FNA)

10.26226/morressier.57c5383dd462b80296c9bdf4 ◽

2016 ◽

Author(s):

Carolin Nava

Keyword(s):

Natural History ◽

Neuroendocrine Tumors ◽

Fine Needle Aspiration ◽

Needle Aspiration ◽

Pancreatic Neuroendocrine Tumors ◽

Ki 67 ◽

Fine Needle ◽

Long Term Follow Up

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FAS and Subsequent Therapies in Pancreatic Neuroendocrine Tumors

Neuroendocrinology ◽

10.1159/000514339 ◽

2021 ◽

Author(s):

Jane E. Rogers ◽

Michael Lam ◽

Daniel M. Halperin ◽

Cecile G. Dagohoy ◽

James C. Yao ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Cox Regression ◽

Progression Free Survival ◽

Pancreatic Neuroendocrine Tumors ◽

Free Survival ◽

Prior Therapy ◽

Well Differentiated ◽

Grade 3 ◽

Line Of Therapy

We evaluated outcomes of treatment with 5-fluorouracil (5-FU), doxorubicin, and streptozocin (FAS) in well-differentiated pancreatic neuroendocrine tumors (PanNETs) and its impact on subsequent therapy (everolimus or temozolomide). Advanced PanNET patients treated at our center from 1992 to 2013 were retrospectively reviewed. Patients received bolus 5-FU (400 mg/m2), streptozocin (400 mg/m2) (both IV, days 1-5) and doxorubicin (40 mg/m2 IV, day 1) every 28 days. Overall response rate (ORR) was assessed using RECIST version 1.1. Of 243 eligible patients, 220 were evaluable for ORR, progression-free survival (PFS), and toxicity. Most (90%) had metastatic, nonfunctional PanNETs; 14% had prior therapy. ORR to FAS was 41% (95% confidence interval [CI]: 36-48%). Median follow-up was 61 months. Median PFS was 20 (95% CI: 15-23) months; median overall survival (OS) was 63 (95% CI: 60-71) months. Cox regression analyses suggested improvement with first-line vs subsequent lines of FAS therapy. Main adverse events ≥ grade 3 were neutropenia (10%) and nausea/vomiting (5.5%). Dose reductions were required in 32% of patients. Post-FAS everolimus (n=108; 68% second line) had a median PFS of 10 (95% CI: 8-14) months. Post-FAS temozolomide (n=60; 53% > fourth line) had an ORR of 13% and median PFS of 5.2 (95% CI: 4-12) months. In this largest reported cohort of PanNETs treated with chemotherapy, FAS demonstrated activity without significant safety concerns. FAS did not appear to affect subsequent PFS with everolimus; this sequence is being evaluated prospectively. Responses were noted with subsequent temozolomide-based regimens although PFS was possibly limited by line of therapy.

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Expression of the phosphorylated variant of the AKT1-kinase (p-AKT1) in well-differentiated pancreatic neuroendocrine tumors: immunohistochemical evaluation

Almanac of Clinical Medicine ◽

10.18786/2072-0505-2018-46-4-314-322 ◽

2018 ◽

Vol 46 (4) ◽

pp. 314-322

Author(s):

V. V. Delektorskaya ◽

O. N. Solov'eva ◽

G. Yu. Chemeris ◽

Yu. I. Patyutko

Keyword(s):

Liver Metastases ◽

Neuroendocrine Tumors ◽

Treatment Effectiveness ◽

Disease Free Survival ◽

Immunohistochemical Analysis ◽

Pancreatic Neuroendocrine Tumors ◽

Ki 67 ◽

New Treatment ◽

Well Differentiated ◽

High Level

Background:Well-differentiated pancreatic neuroendocrine tumors (pNETs) represent a group of rare epithelial neoplasms with a highly variable clinical course. AKT1 is one of the most frequently activated protein kinases in pNETs, which promotes the tumor growth and is of interest as a prognostic factor and a target for new treatment approaches.Aim:To study the expression of the phosphorylated variant of AKT1-kinase (p-AKT1) in primary pNETs and their liver metastases and to correlate the results with various clinical and pathological parameters and the disease prognosis.Materials and methods:P-AKT1 expression was studied by the immunohistochemical analysis of the primary lesions and liver metastases in 52 pNETs patients.Results:A high level of cytoplasmic and/or nuclear immunoreactivity was detected in 24/52 of the primary pNETs (46.2%) and in 16/27 of their liver metastases (59.3%). p-AKT1 expression was observed in 3 (21.4%) of NET grade (G) 1, in 14 (46.7%) of NET G2, and in 7 (87.5%) of NET G3. p-AKT1 expression was more frequently identified in pNET G3 category and increased during the tumor progression in metachronous liver metastases, as compared to the corresponding primary tumor. In addition, p-AKT1 positivity was significantly associated with an increase of grade from G1 to G3 (p = 0.004), the Ki-67 index (p = 0.029), the pTNM stage (p = 0.0008), perineural invasion (p = 0.031) and a decrease in disease-free survival (p = 0.05).Conclusion:The results suggest that p-АКТ1 plays an important role in the pathogenesis of pNETs and may be an additional criterion for assessment of the prognosis and treatment effectiveness in this type of tumors.

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Prognostic Factors Associated with Outcomes in Small Bowel Neuroendocrine Tumors

The American Surgeon ◽

10.1177/000313481708301033 ◽

2017 ◽

Vol 83 (10) ◽

pp. 1174-1178 ◽

Cited By ~ 1

Author(s):

Nicholas Manguso ◽

Jeffrey Johnson ◽

Attiya Harit ◽

Nicholas Nissen ◽

James Mirocha ◽

...

Keyword(s):

Small Bowel ◽

Neuroendocrine Tumors ◽

Cox Regression ◽

Univariate Analysis ◽

Disease Free Survival ◽

Nodal Metastasis ◽

Cox Regression Analysis ◽

Kaplan Meier ◽

Open Operation ◽

Recurrence Group

Small bowel neuroendocrine tumors (SBNET) account for most gastrointestinal neuroendocrine tumors. Patients often present with late-stage disease; however, there is little information regarding factors that contribute to recurrence. Database review identified 301 patients diagnosed with SBNET between 1990 and 2013. Univariate analysis included patients who underwent complete resection. Survival was estimated by the Kaplan–Meier method. A total of 147 patients met study criteria. Average age was 60 years (range 21–91); 49 per cent were male. Thirty-seven (25.3%) patients had laparoscopic resection, and 29 (19.9%) patients had only small bowel disease, whereas 108 (72.6%) had nodal metastasis. Five-year overall and disease-free survival were 97.5 and 73.5 per cent. Forty-seven (32%) patients had recurrence. The recurrence group was more likely to have an open operation (59.6 vs 32%, P < 0.01), mesenteric invasion, or lymphatic metastasis (87.2 vs 67%, P < 0.01) compared with the no-recurrence group. Cox regression analysis showed that variables associated with recurrence included nodal disease (HR 9.06, P = 0.03), lymphovascular invasion (LVI) (3.95, P < 0.01), perineural invasion (PNI) (3.48, P < 0.01), and mesenteric involvement (3.77, P = 0.03). Patients with SBNET presenting with nodal metastasis, mesenteric involvement, LVI, or PNI have a higher risk of recurrence. Closer surveillance should be considered after operative resection.

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