Dataset Information

Association of a Prophylactic Surgical Approach to Stage IV Small Intestinal Neuroendocrine Tumors With Survival.

ABSTRACT:

Importance

Primary tumor resection and mesenteric lymph node dissection in asymptomatic patients with stage IV small intestinal neuroendocrine tumors (SI-NETs) are controversial.

Objective

To determine the association of locoregional surgery (LRS) performed at diagnosis with outcomes in patients with asymptomatic SI-NETs and distant metastases.

Design, setting, and participants

This cohort study included asymptomatic patients with stage IV SI-NETs diagnosed from January 1, 1985, through December 31, 2015, and identified using the prospective database of SI-NETs from Uppsala University Hospital, Uppsala, Sweden. Patients included were treated at a tertiary referral center and followed up until May 31, 2016, with data from the Swedish National Patient Register. The 363 patients with stage IV SI-NETs without abdominal symptoms were divided between those who underwent prophylactic up-front surgery within 6 months from diagnosis combined with oncologic treatment (hereafter referred to as LRS group [n?=?161]) and those who underwent nonsurgical treatment or delayed surgery as needed combined with oncologic treatment (hereafer referred to as delayed LRS group [n?=?202]).

Exposures

Prophylactic up-front surgery within 6 months from diagnosis combined with oncologic treatment vs nonsurgical treatment or delayed surgery as needed combined with oncologic treatment.

Main outcomes and measures

Overall survival (OS), length of hospital stay (LOS), postoperative morbidity and mortality, and reoperation rates measured from baseline. Propensity score matching was performed between the 2 groups.

Results

The 363 patients included 173 women (47.7%) and 190 men (52.3%), with a mean (SD) age at diagnosis of 62.4 (11.1) years. Two isonumerical groups with 91 patients in each resulted after propensity score matching. The LRS and delayed LRS groups were comparable in median OS (7.9 years [range, 5.1-10.7 years] vs 7.6 years [range, 5.8-9.5 years]; hazard ratio [HR], 0.98; 95% CI, 0.70-1.37; log-rank P?=?.93) and cancer-specific survival (7.7 years [range, 4.5-10.8 years] vs 7.6 years [range, 5.6-9.7 years]; HR, 0.99; 95% CI, 0.71-1.40; log-rank P?=?.99). No difference was found in 30-day mortality (0 patients in both matched groups) or postoperative morbidity (2 [2.2%] vs 1 [1.1%]; P?>?.99), median LOS (73 days [range, 2-270 days] vs 76 days [range, 0-339 days]; P?=?.64) or LOS due to local tumor-related symptoms (7.0 days [range, 0-90 days] vs 11.5 days [range, 0-69 days]; P?=?.81), or incisional hernia repairs (4 patients [4.4%] in both groups; P?>?.99). Patients in the LRS group underwent more reoperative procedures (13 [14.3%]) compared with those in the delayed LRS group (3 [3.3%]) owing to intestinal obstruction (P?Conclusions and relevanceProphylactic up-front LRS conferred no survival advantage in asymptomatic patients with stage IV SI-NETs. Delayed surgery as needed was comparable in all examined outcomes and was associated with fewer reoperations for intestinal obstruction. The value of a priori LRS in the presence of distant metastases is challenged and needs to be elucidated in a randomized clinical study.

SUBMITTER: Daskalakis K

PROVIDER: S-EPMC5838704 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Publications

Association of a Prophylactic Surgical Approach to Stage IV Small Intestinal Neuroendocrine Tumors With Survival.

Daskalakis Kosmas K Karakatsanis Andreas A Hessman Ola O Stuart Heather C HC Welin Staffan S Tiensuu Janson Eva E Öberg Kjell K Hellman Per P Norlén Olov O Stålberg Peter P

JAMA oncology 20180201 2

<h4>Importance</h4>Primary tumor resection and mesenteric lymph node dissection in asymptomatic patients with stage IV small intestinal neuroendocrine tumors (SI-NETs) are controversial.<h4>Objective</h4>To determine the association of locoregional surgery (LRS) performed at diagnosis with outcomes in patients with asymptomatic SI-NETs and distant metastases.<h4>Design, setting, and participants</h4>This cohort study included asymptomatic patients with stage IV SI-NETs diagnosed from January 1, ...[more]

PMID: 29049611

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Project description:ImportanceThe number of patients with small nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs) is increasing. However, the role of surgery for small NF-PanNETs remains unclear.ObjectiveTo evaluate the association between surgical resection for NF-PanNETs measuring 2 cm or smaller and survival.Design, setting, and participantsThis cohort study used data from the National Cancer Database and included patients with NF-pancreatic neuroendocrine neoplasms who were diagnosed between January 1, 2004, and December 31, 2017. Patients with small NF-PanNETs were divided into 2 groups: group 1a (tumor size, ≤1 cm) and group 1b (tumor size, 1.1-2.0 cm). Patients without information on tumor size, overall survival, and surgical resection were excluded. Data analysis was performed in June 2022.ExposuresPatients with vs without surgical resection.Main outcomes and measuresThe primary outcome was overall survival of patients in group 1a or group 1b who underwent surgical resection compared with those who did not, which was evaluated using Kaplan-Meier estimates and multivariable Cox proportional hazards regression models. Interactions between preoperative factors and surgical resection were analyzed with a multivariable Cox proportional hazards regression model.ResultsOf the 10 504 patients with localized NF-PanNETs identified, 4641 were analyzed. These patients had a mean (SD) age of 60.5 (12.7) years and included 2338 males (50.4%). The median (IQR) follow-up time was 47.1 (28.2-71.6) months. In total, 1278 patients were in group 1a and 3363 patients were in group 1b. The surgical resection rates were 82.0% in group 1a and 87.0% in group 1b. After adjustment for preoperative factors, surgical resection was associated with longer survival for patients in group 1b (hazard ratio [HR], 0.58; 95% CI, 0.42-0.80; P < .001) but not for patients in group 1a (HR, 0.68; 95% CI, 0.41-1.11; P = .12). In group 1b, interaction analysis found that age of 64 years or younger, absence of comorbidities, treatment at academic institutions, and distal pancreatic tumors were factors associated with increased survival after surgical resection.Conclusions and relevanceFindings of this study support an association between surgical resection and increased survival in select patients with NF-PanNETs measuring 1.1 to 2.0 cm who were younger than 65 years, had no comorbidities, received treatment at academic institutions, and had tumors of the distal pancreas. Future investigations of surgical resection for small NF-PanNETs that include the Ki-67 index are warranted to validate these findings.

Project description:BackgroundPatients with small intestinal neuroendocrine tumors (SINETs) frequently present with lymph node and liver metastases at the time of diagnosis, but the molecular changes that lead to the progression of these tumors are largely unknown. Sequencing studies have only identified recurrent point mutations at low frequencies with CDKN1B being the most common harboring heterozygous mutations in less than 10% of all tumors. Although SINETs are genetically stable tumors with a low frequency of point mutations and indels, they often harbor recurrent hemizygous copy number alterations (CNAs) yet the functional implications of these CNA are unclear.MethodsUtilizing comparative genomic hybridization (CGH) arrays we analyzed the CNA profile of 131 SINETs from 117 patients. Two tumor suppressor genes and corresponding proteins i.e. SMAD4, and CDKN1B, were further characterized using a tissue microarray (TMA) with 846 SINETs. Immunohistochemistry (IHC) was used to quantify protein expression in TMA samples and this was correlated with chromosome number evaluated with fluorescent in-situ hybridization (FISH). Intestinal tissue from a Smad4+/- mouse model was used to detect entero-endocrine cell hyperplasia with IHC.ResultsAnalyzing the CGH arrays we found loss of chromosome 18q and SMAD4 in 71% of SINETs and that focal loss of chromosome 12 affecting the CDKN1B was present in 9.4% of SINETs. No homozygous loss of chromosome 18 was detected. Hemizygous loss of SMAD4, but not CDKN1B, significantly correlated with reduced protein levels but hemizygous loss of SMAD4 did not induce entero-endocrine cell hyperplasia in the Smad4+/- mouse model. In addition, patients with low SMAD4 protein expression in primary tumors more often presented with metastatic disease.ConclusionsHemizygous loss of chromosome 18q and the SMAD4 gene is the most common genetic event in SINETs and our results suggests that this could influence SMAD4 protein expression and spread of metastases. Although SMAD4 haploinsufficiency alone did not induce tumor initiation, loss of chromosome 18 could represent an evolutionary advantage in SINETs explaining the high prevalence of this aberration. Functional consequences of reduced SMAD4 protein levels could hypothetically be a potential mechanism as to why loss of chromosome 18 appears to be clonally selected in SINETs.

Dataset Information

Association of a Prophylactic Surgical Approach to Stage IV Small Intestinal Neuroendocrine Tumors With Survival.

Importance

Objective

Design, setting, and participants

Exposures

Main outcomes and measures

Results

Publications

Association of a Prophylactic Surgical Approach to Stage IV Small Intestinal Neuroendocrine Tumors With Survival.

Similar Datasets

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