Repeat Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumors: A NET Center of Excellence Experience.

INTRODUCTION: The available data for the safety and efficacy of repeat peptide receptor radionuclide therapy (PRRT) are almost exclusively from European centers. We present an updated experience with repeat PRRT in a cohort of US patients with neuroendocrine tumors (NETs) at our NET center of excellence. METHODS: We used our single-center longitudinal NET registry to identify patients who had been previously treated with at least one dose of PRRT (PRRT 1, either 177Lu DOTATATE or 90Y DOTATOC) and following radiographic disease progression were re-treated with a second course of PRRT (PRRT 2). We reviewed patient, tumor and treatment characteristics, objective response rates, and toxicities after PRRT 1 and PRRT 2. RESULTS: A total of 11 patients were included in the analysis. 45.5% (5/11) of patients received 177Lu DOTATATE PRRT only, both for PRRT1 and PRRT 2, while 54.5% (6/11) of patients received 90Y DOTATOC PRRT for PRRT1. At first restaging scan after PRRT2 (3-6 months), 18.2% (2/11), 36.4% (4/11), and 27.3% (3/11) of patients had PR, SD, and PD, respectively; 2/11 patients (18.2%) died before the first restaging scan. Therefore, 5/11 (45.5%) patients were noted to have disease progression. Median PFS for PRRT1 was 25.4 months and median PFS for PRRT2 was 13.1 months (p = 0.0001). We did not find a statistically significant difference between the occurrence of short and long-term hematological toxicities as well as renal toxicity after PRRT1 and PRRT2. CONCLUSION: We show that repeat PRRT may benefit select patients and have an acceptable safety profile. In our cohort, PFS was significantly lower after PRRT2 as compared to PRRT1.

Surgical Management of G3 Gastroenteropancreatic Neuroendocrine Neoplasms: A Systematic Review and Meta-analysis.

BACKGROUND: Grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are rare, aggressive tumors with poor prognosis. The World Health Organization 2017 and 2019 classifications further subdivided G3 NENs into G3 neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). Current guidelines favor medical management in most of these patients, and the role of surgical management is not well defined. We performed a systematic literature review and meta-analysis of surgical management versus nonsurgical management for G3 GEP NENs. MATERIALS AND METHODS: A PRISMA-compliant systematic review of the MEDLINE, Embase, Scopus, and Cochrane Library databases (end-of-search date: 16 July 2021) was conducted. Individual patient survival data were reconstructed, and random-effects meta-analyses were performed. RESULTS: Fourteen studies comprising 1810 surgical and 910 nonsurgical patients were systematically reviewed. Publication bias adjusted meta-analysis of 12 studies (1788 surgical and 857 nonsurgical patients) showed increased overall survival (OS) after surgical compared with nonsurgical management for G3 GEP NENs [hazard ratio (HR) 0.40, 95% confidence interval (CI) 0.31-0.53]. Subgroup meta-analyses showed increased OS after surgical management for both pancreatic and gastrointestinal primary sites separately. In another subgroup meta-analysis of G3 GEP NETs (not NECs), surgical management was associated with increased OS compared with nonsurgical management (HR 0.26, 95% CI 0.11-0.61). CONCLUSIONS: Surgical management of G3 GEP NENs may provide a potential survival benefit in well-selected cases. Further research is needed to define which patients will benefit most from surgical versus nonsurgical management. The current literature is limited by inconsistent reporting of survival outcomes in surgical versus nonsurgical groups, tumor grade, differentiation, primary tumor site, and selection criteria for surgical and nonsurgical management.

Biomarker response to high-specific-activity I-131 meta-iodobenzylguanidine in pheochromocytoma/paraganglioma.

The objective of this study is to present the complete biomarker response dataset from a pivotal trial evaluating the efficacy and safety of high-specific-activity I-131 meta-iodobenzylguanidine in patients with advanced pheochromocytoma or paraganglioma. Biomarker status was assessed and post-treatment responses were analyzed for catecholamines, metanephrines, and serum chromogranin A. Complete biomarker response (normalization) or partial response, defined as at least 50% reduction from baseline if above the normal range, was evaluated at specified time points over a 12-month period. These results were correlated with two other study objectives: blood pressure control and objective tumor response as per RECIST 1.0. In this open-label, single-arm study, 68 patients received at least one therapeutic dose (~18.5 GBq (~500 mCi)) of high-specific-activity I-131 meta-iodobenzylguanidine. Of the patients, 79% and 72% had tumors associated with elevated total plasma free metanephrines and serum chromogranin A levels, respectively. Best overall biomarker responses (complete or partial response) for total plasma free metanephrines and chromogranin A were observed in 69% (37/54) and 80% (39/49) of patients, respectively. The best response for individual biomarkers was observed 6-12 months following the first administration of high-specific-activity I-131 meta-iodobenzylguanidine. Biochemical tumor marker response was significantly associated with both reduction in antihypertensive medication use (correlation coefficient 0.35; P = 0.006) as well as objective tumor response (correlation coefficient 0.36; P = 0.007). Treatment with high-specific-activity I-131 meta-iodobenzylguanidine resulted in long-lasting biomarker responses in patients with advanced pheochromocytoma or paraganglioma that correlated with blood pressure control and objective response rate. ClinicalTrials.gov number: NCT00874614.

Is There a Role for Surgical Resection of Grade 3 Neuroendocrine Neoplasms?

BACKGROUND: Grade 3 (G3) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are aggressive tumors with poor survival outcomes for which medical management is generally recommended. This study sought to evaluate outcomes of surgically treated G3 GEP-NEN patients. METHODS: A single-institutional prospective NEN database was reviewed. Patients with G3 GEP-NENs based on World Health Organization (WHO) 2019 definitions included well-differentiated neuroendocrine tumors (G3NET) and poorly differentiated neuroendocrine carcinomas (G3NEC). Clinicopathologic factors were compared between groups. Overall survival from G3 diagnosis was assessed by the Kaplan-Meier method. RESULTS: Surgical resection was performed for 463 patients (211 G1, 208 G2, 44 G3). Most had metastatic disease at presentation (54% G1, 69% G2, 91% G3; p < 0.001). The G3 cohort included 39 G3NETs and 5 G3NECs, 22 of pancreatic and 22 of midgut origin. Median overall survival (mOS; in months) was 268.1 for G1NETs, 129.9 for G2NETs, 50.5 for G3NETs, and 28.5 for G3NECs (p < 0.001). Over the same period, 31 G3 patients (12 G3NETs, 19 G3NECs) were treated non-surgically, with mOS of 19.0 for G3NETs and 12.4 for G3NECs. CONCLUSIONS: Surgical resection of G3 GEP-NENs remains controversial due to poor prognosis, and surgical series are rare. This large, single-institutional study found significantly lower mOS in patients with resected G3NENs than those with G1/G2 tumors, reflecting more aggressive tumor biology and a higher proportion with metastatic disease. The mOS for resected G3NETs and G3NECs exceeded historical non-surgical G3NEN series (mOS 11-19 months), suggesting surgery should be considered in carefully selected patients with G3NENs, especially those with well-differentiated tumors.

Management of Duodenal Neuroendocrine Tumors: Surgical versus Endoscopic Mucosal Resection.

BACKGROUND: Management of duodenal neuroendocrine tumors (DNETs) is not standardized, with smaller lesions (< 1-2 cm) generally treated by endoscopic mucosal resection (EMR) and larger DNETs by surgical resection (SR). This study reviewed how patients were selected for treatment and compared outcomes. PATIENTS AND METHODS: Patients with DNETs undergoing resection were identified through institutional databases, and clinicopathologic data recorded. χ2 and Wilcoxon tests compared variables. Survival was determined by Kaplan-Meier, and Cox regression tested association with survival. RESULTS: Among 104 patients, 64 underwent EMR and 40 had SR. Patients selected for SR had larger tumor size, younger age, and higher T, N, and M stage. There was no difference in progression-free (PFS) or overall survival (OS) between SR and EMR. In 1-2 cm DNETs, there was no difference in PFS between SR and EMR [median not reached (NR), P = 0.1]; however, longer OS was seen in SR (median NR versus 112 months, P = 0.03). In 1-2 cm DNETs, SR patients were more likely to be node-positive and younger. After adjustment for age, resection method did not correlate with survival. Comparison of surgically resected DNETs versus jejunoileal NETs revealed longer PFS (median NR versus 73 months, P < 0.001) and OS (median NR versus 119 months, P = 0.004) DISCUSSION: In 1-2 cm DNETs, there was no difference in survival between EMR and SR after adjustment for age. Recurrences could be salvaged, suggesting that EMR is a reasonable strategy. Compared with jejunoileal NETs, DNETs treated by SR had improved PFS and OS.

High-Specific-Activity-131I-MIBG versus 177Lu-DOTATATE Targeted Radionuclide Therapy for Metastatic Pheochromocytoma and Paraganglioma.

Targeted radionuclide therapies (TRT) using 131I-metaiodobenzylguanidine (131I-MIBG) and peptide receptor radionuclide therapy (177Lu or 90Y) represent several of the therapeutic options in the management of metastatic/inoperable pheochromocytoma/paraganglioma. Recently, high-specific-activity-131I-MIBG therapy was approved by the FDA and both 177Lu-DOTATATE and 131I-MIBG therapy were recommended by the National Comprehensive Cancer Network guidelines for the treatment of metastatic pheochromocytoma/paraganglioma. However, a clinical dilemma often arises in the selection of TRT, especially when a patient can be treated with either type of therapy based on eligibility by MIBG and somatostatin receptor imaging. To address this problem, we assembled a group of international experts, including oncologists, endocrinologists, and nuclear medicine physicians, with substantial experience in treating neuroendocrine tumors with TRTs to develop consensus and provide expert recommendations and perspectives on how to select between these two therapeutic options for metastatic/inoperable pheochromocytoma/paraganglioma. This article aims to summarize the survival outcomes of the available TRTs; discuss personalized treatment strategies based on functional imaging scans; address practical issues, including regulatory approvals; and compare toxicities and risk factors across treatments. Furthermore, it discusses the emerging TRTs.

Presacral neuroendocrine tumors associated with the Currarino syndrome.

Currarino syndrome (CS) is an autosomal dominant syndrome caused by mutations in MNX1 and characterized by anorectal abnormalities, partial sacral agenesis, and presacral masses. The presacral masses are typically benign; however, malignant degeneration can occur, and presacral neuroendocrine tumors (NETs) have been reported in six cases. We report three individuals from two families affected by CS in which multiple individuals developed presacral NETs. The first family, 491, had six members with features of CS, including two siblings who presented with presacral, Grade 2 NETs, one of which had metastasized to bone and lymph nodes. A germline c.874C>T (p.Arg292Trp) mutation was found in a highly conserved region of MNX1 in three affected members who underwent sequencing. A second somatic variant/deletion in MNX1 was not detected in either patient's tumor. In the second family, 342, the proband presented with an incidentally discovered presacral NET. The proband's father had previously undergone resection of a presacral NET, and so genetic testing was performed, which did not reveal an MNX1 mutation or copy number variants. The lack of a second, somatic mutation in the tumors from family 491 argues against MNX1 acting as a tumor suppressor, and the absence of a germline MNX1 mutation in family 342 suggests that other genetic and anatomic factors contribute to the development of presacral NETs. These cases highlight the variable presentation of CS, and the potential for malignancy in these patients.

High-specific-activity 131iodine-metaiodobenzylguanidine for therapy of unresectable pheochromocytoma and paraganglioma.

Pheochromocytomas and paragangliomas (PPG) are rare cancers arising from the adrenal medulla (pheochromocytoma) or autonomic ganglia (paraganglioma). They have highly variable biological behavior. Most PPG express high-affinity norepinephrine transporters, allowing active uptake of the norepinephrine analog, 131iodine-metaiodobenzylguanidine (131I-MIBG). Low-specific-activity forms of 131I-MIBG have been used since 1983 for therapy of PPG. High-specific-activity 131I-MIBG therapy improves hypertension management, induces partial radiological response or stable disease, decreases biochemical markers of disease activity and is well tolerated by patients. This drug, approved in the USA in July 2018, is the first approved agent for patients with unresectable, locally advanced or metastatic PPG and imaging evidence of metaiodobenzylguanidine uptake, who require systemic anticancer therapy.

It Is Time to Rethink Biomarkers for Surveillance of Small Bowel Neuroendocrine Tumors.

BACKGROUND: Tumor biomarkers (TBMs) reflect disease burden and correlate with survival for small bowel neuroendocrine tumors (SBNETs). This study sought to determine the performance of chromogranin A (CgA), pancreastatin (PST), neurokinin A (NKA), and serotonin (5HT) during follow-up assessment of resected SBNETs. METHODS: An institutional database identified patients undergoing surgery for SBNETs. Tumor biomarker levels were assessed as categorical (normal vs elevated) and continuous variables for association with progression-free survival (PFS) and overall survival (OS) via the Kaplan-Meier method with Cox multivariable models adjusted for confounders. Sensitivity, specificity, and predictive values of TBM levels in identifying imaging-confirmed progression were calculated. RESULTS: In 218 patients (44% female, 92% node + , 73% metastatic, 97% G1 or G2), higher levels of CgA, PST, NKA, and 5HT correlated with higher-grade and metastatic disease at presentation (p < 0.05). Elevated pre- and postoperative CgA, PST, and NKA correlated with lower PFS and OS (p < 0.05; median follow-up period, 49.6 months). Normal CgA, PST, and NKA were present in respectively 20.3%, 16.9%, and 72.6% of the patients with progression, whereas elevated levels were present in respectively 69.5%, 24.8%, and 1.3% of the patients without progression. Using TBMs to determine progression showed superiority of PST (78.9% accuracy) over CgA (63.3% accuracy) or CgA and PST together (60.3% accuracy). CONCLUSION: Although specific for progression, NKA was rarely elevated, limiting its usefulness. Pre- and postoperative PST and CgA correlated with disease burden and survival, with PST providing better discrimination of outcomes. During the follow-up period, use of PST most accurately detected progression. These results suggest that PST should replace CgA for SBNET surveillance.

Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl: Analyses of Phase III Studies in Carcinoid Syndrome.

BACKGROUND: Telotristat ethyl is approved to treat carcinoid syndrome diarrhea in combination with somatostatin analogs. In TELESTAR and TELECAST phase III studies, patients with carcinoid syndrome received telotristat ethyl 250 or 500 mg 3 times per day (tid) or placebo tid in addition to somatostatin analogs. The aim of this prespecified analysis was to examine the time to reductions in bowel movements (BMs) in the TELESTAR and TELECAST studies using survival analysis methods. METHODS: First occurrence of sustained response was defined as the time to the first day of 2 consecutive weeks with a mean BM frequency improvement of ≥ 30% from baseline during the 12-week double-blind treatment periods. Time to first ≥ 30% worsening in BM frequency was also measured. Treatments were compared with the log-rank test; Cox regression models provided point and confidence interval estimates of the hazard ratios for each trial. RESULTS: In TELESTAR and TELECAST, majority of patients (69%) on telotristat ethyl experienced a sustained ≥ 30% improvement in BM frequency. The median time to sustained reduction of at least 30% in BM frequency was significantly faster (fewer days to onset) for telotristat ethyl compared with placebo in both TELESTAR (250 mg, HR = 2.3 [95% CI, 1.3-4.1, P = 0.004]; 500 mg, HR = 2.2 [95% CI, 1.2-3.9, P = 0.009]) and TELECAST (250 mg, HR = 3.9 [95% CI, 1.6-11.1, P = 0.003]; 500 mg, HR = 4.2 [95% CI, 1.7-11.7, P = 0.002]). In TELECAST, 42% of patients on placebo experienced sustained worsening in BM frequency compared with 20% on telotristat ethyl; no significant difference was observed in TELESTAR. CONCLUSION: The time of onset of sustained BM frequency improvement mean and range are important when considering use of telotristat ethyl in patients with carcinoid syndrome diarrhea. Telotristat ethyl may also reduce sustained worsening in BM frequency. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01677910, NCT02063659.

Workup of Gastroenteropancreatic Neuroendocrine Tumors.

Neuroendocrine tumors of the gastrointestinal tract or pancreas are rare. Their presentation overlaps with other intra-abdominal neoplasms, but can have unique features. The workup involves recognition of unusual clinical features associated with the tumors, imaging, analysis of blood or urine concentrations, and biopsy. Functional imaging takes advantage of the neuroendocrine tumor-specific expression of somatostatin receptors. There are characteristic features supporting the diagnosis on contrast-enhanced cross-sectional imaging. The use of tumor markers for biochemical diagnosis requires an understanding of the confounding variables affecting these assays. There are unique and specific immunohistochemical staining and grading requirements for appropriate diagnosis of these tumors.

Gene Expression Signatures Identify Novel Therapeutics for Metastatic Pancreatic Neuroendocrine Tumors.

PURPOSE: Pancreatic neuroendocrine tumors (pNETs) are uncommon malignancies noted for their propensity to metastasize and comparatively favorable prognosis. Although both the treatment options and clinical outcomes have improved in the past decades, most patients will die of metastatic disease. New systemic therapies are needed. EXPERIMENTAL DESIGN: Tissues were obtained from 43 patients with well-differentiated pNETs undergoing surgery. Gene expression was compared between primary tumors versus liver and lymph node metastases using RNA-Seq. Genes that were selectively elevated at only one metastatic site were filtered out to reduce tissue-specific effects. Ingenuity pathway analysis (IPA) and the Connectivity Map (CMap) identified drugs likely to antagonize metastasis-specific targets. The biological activity of top identified agents was tested in vitro using two pNET cell lines (BON-1 and QGP-1). RESULTS: A total of 902 genes were differentially expressed in pNET metastases compared with primary tumors, 626 of which remained in the common metastatic profile after filtering. Analysis with IPA and CMap revealed altered activity of factors involved in survival and proliferation, and identified drugs targeting those pathways, including inhibitors of mTOR, PI3K, MEK, TOP2A, protein kinase C, NF-kB, cyclin-dependent kinase, and histone deacetylase. Inhibitors of MEK and TOP2A were consistently the most active compounds. CONCLUSIONS: We employed a complementary bioinformatics approach to identify novel therapeutics for pNETs by analyzing gene expression in metastatic tumors. The potential utility of these drugs was confirmed by in vitro cytotoxicity assays, suggesting drugs targeting MEK and TOP2A may be highly efficacious against metastatic pNETs. This is a promising strategy for discovering more effective treatments for patients with pNETs.

The Pancreas as a Site of Metastasis or Second Primary in Patients with Small Bowel Neuroendocrine Tumors.

BACKGROUND: The small bowel and pancreas are the most common primary sites of neuroendocrine tumors (NETs) giving rise to metastatic disease. Some patients with small bowel NETs (SBNETs) present with synchronous or metachronous pancreatic NETs (PNETs), and it is unclear whether these are separate primaries or metastases from one site to the other. METHODS: A surgical NET database including patients undergoing operations for SBNETs or PNETs was reviewed. Patients with synchronous or metachronous tumors in both the small bowel and pancreas were identified, and available tissues from primary tumors and metastases were examined using a 4-gene quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC) panel developed for evaluating NETs of unknown primary. RESULTS: Of 338 patients undergoing exploration, 11 had NETs in both the small bowel and pancreas. Tissues from 11 small bowel tumors, 9 pancreatic tumors, and 10 metastases were analyzed. qPCR and IHC data revealed that three patients had separate SBNET and PNET primaries, and five patients had SBNETs that metastasized to the pancreas. Pancreatic tissue was unavailable in two patients, and qPCR and IHC gave discrepant results in one patient. CONCLUSIONS: NETs in both the small bowel and pancreas were found in 3% of our patients. In nearly two-thirds of evaluable patients, the pancreatic tumor was a metastasis from the SBNET primary, while in the remaining one-third of patients it represented a separate primary. Determining the origin of these tumors can help guide the choice of systemic therapy and surgical management.

Long-Term Safety Experience with Telotristat Ethyl Across Five Clinical Studies in Patients with Carcinoid Syndrome.

BACKGROUND: Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome. SUBJECTS, MATERIALS, AND METHODS: Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long-term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated. RESULTS: Mean (median; range) duration of exposure and follow-up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient-years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4. CONCLUSION: Based on long-term safety data, telotristat ethyl is well tolerated and has a favorable long-term safety profile in patients with carcinoid syndrome. IMPLICATIONS FOR PRACTICE: Carcinoid syndrome can cause persistent diarrhea, even in patients treated with somatostatin analogs. Across five clinical trials in patients with carcinoid syndrome, telotristat ethyl has been well tolerated and efficacious, providing clinicians with a new approach to help control carcinoid syndrome diarrhea, in addition to somatostatin analog therapy. By reducing the stool frequency in patients with carcinoid syndrome whose diarrhea is refractory to anticholinergics, such as loperamide and atropine/diphenoxylate, and somatostatin analog dose escalation, improvement in quality of life becomes an achievable goal.

Efficacy and Safety of High-Specific-Activity 131I-MIBG Therapy in Patients with Advanced Pheochromocytoma or Paraganglioma.

Patients with metastatic or unresectable (advanced) pheochromocytoma and paraganglioma (PPGL) have poor prognoses and few treatment options. This multicenter, phase 2 trial evaluated the efficacy and safety of high-specific-activity 131I-meta-iodobenzylguanidine (HSA 131I-MIBG) in patients with advanced PPGL. Methods: In this open-label, single-arm study, 81 PPGL patients were screened for enrollment, and 74 received a treatment-planning dose of HSA 131I-MIBG. Of these patients, 68 received at least 1 therapeutic dose (∼18.5 GBq) of HSA 131I-MIBG intravenously. The primary endpoint was the proportion of patients with at least a 50% reduction in baseline antihypertensive medication use lasting at least 6 mo. Secondary endpoints included objective tumor response as assessed by Response Evaluation Criteria in Solid Tumors version 1.0, biochemical tumor marker response, overall survival, and safety. Results: Of the 68 patients who received at least 1 therapeutic dose of HSA 131I-MIBG, 17 (25%; 95% confidence interval, 16%-37%) had a durable reduction in baseline antihypertensive medication use. Among 64 patients with evaluable disease, 59 (92%) had a partial response or stable disease as the best objective response within 12 mo. Decreases in elevated (≥1.5 times the upper limit of normal at baseline) serum chromogranin levels were observed, with confirmed complete and partial responses 12 mo after treatment in 19 of 28 patients (68%). The median overall survival was 36.7 mo (95% confidence interval, 29.9-49.1 mo). The most common treatment-emergent adverse events were nausea, myelosuppression, and fatigue. No patients had drug-related acute hypertensive events during or after the administration of HSA 131I-MIBG. Conclusion: HSA 131I-MIBG offers multiple benefits, including sustained blood pressure control and tumor response in PPGL patients.

Effective cytoreduction can be achieved in patients with numerous neuroendocrine tumor liver metastases (NETLMs).

BACKGROUND: Cytoreductive surgery for neuroendocrine tumor liver metastases improves survival and symptomatic control. However, the feasibility of adequate cytoreduction in patients with many liver metastases remains uncertain. We compared patient outcomes based on the number of lesions treated to better define the efficacy of cytoreductive surgery for numerous neuroendocrine tumor liver metastases. METHODS: Patients undergoing hepatic cytoreductive surgery for gastroenteropancreatic neuroendocrine tumors were identified in our institutional surgical neuroendocrine tumor database. Imaging studies were reviewed to determine the liver tumor burden and percent cytoreduced. Overall survival and progression-free survival were compared, using the number of lesions treated, percent tumor debulked, and additional clinicopathologic characteristics. RESULTS: A total of 188 hepatic cytoreductive procedures were identified and stratified into groups according to the number of metastases treated: 1-5, 6-10, and >10. Median overall survival and progression-free survival were 89.4 and 22.5 months, respectively, and did not differ significantly between groups. Greater than 70% cytoreduction was associated with significantly better overall survival than <70% cytoreduction (134 months versus 38 months). CONCLUSION: In patients with gastroenteropancreatic neuroendocrine tumors and liver metastases, >70% cytoreduction led to improved overall survival and progression-free survival and was achieved reliably in patients undergoing debulking of >10 lesions. These data support an aggressive approach to patients with numerous neuroendocrine tumor liver metastases to achieve >70% cytoreduction.