Although surgical resection is associated with the best long-term outcomes for neuroendocrine liver metastases (NELM), the current indications for and outcomes of surgery for NELM from a population perspective are not well understood.

To determine the current indications for and outcomes of liver resection (LR) for NELM using a population-based cohort.

A retrospective review of the 2014-2017 American College of Surgeons National Surgical Quality Improvement Program and targeted hepatectomy databases was performed to identify patients who underwent LR for NELM. Perioperative characteristics and 30-d morbidity and mortality were analyzed.

Among 669 patients who underwent LR for NELM, the median age was 60 (interquartile range: 51-67) and 51% were male. While the number of metastases resected ranged from 1 to 9, the most common (45%) number of tumors resected was one. The majority (68%) of patients had a largest tumor size of < 5 cm. Most patients underwent partial hepatectomy (71%) while fewer underwent a right or left hepatectomy or trisectionectomy. The majority of operations were open (82%) versus laparoscopic (17%) or robotic (1%). In addition, 30% of patients underwent intraoperative ablation while 45% had another concomitant operation including cholecystectomy (28.8%), bowel resection (20.2%), or partial pancreatectomy (3.4%). Overall 30-d morbidity and mortality was 29% and 1.3%, respectively. On multivariate analysis, American Society of Anesthesiologists class ≥ 3 [odds ratios (OR), OR = 2.089, 95% confidence intervals (CI): 1.197-3.645], open approach (OR = 1.867, 95%CI: 1.148-3.036), right hepatectomy (OR = 1.618, 95%CI: 1.014-2.582), and prolonged operative time of > 230 min (OR = 1.731, 95%CI: 1.168-2.565) were associated with higher 30-d morbidity while intraoperative ablation and concomitant procedures were not.

LR for NELM was performed with relatively low postoperative morbidity and mortality. Concomitant procedures performed at the time of LR did not increase morbidity.

Neuroendocrine tumors (NET) are a heterogeneous group of neoplasms that can occur anywhere in the body but commonly arise from the gastrointestinal tract. While relatively rare, the incidence and prevalence of NETs are steadily increasing, at least in part due to improved imaging and diagnostic techniques[1,2]. Despite their low grade nature, a substantial proportion (60%-80%) of well-differentiated NETs are diagnosed with or will develop neuroendocrine liver metastases (NELM), which is one of the strongest prognostic factors among patients with NETs[3]. For example, the 5-year overall survival of patients with untreated NELM range from 13% to 54%, compared with 61% to 79% among individuals who undergo treatment[4-8].

Multiple treatments exist for patients with NELM including surgical resection, ablative techniques, transarterial therapies, somatostatin analogs, cytotoxic chemotherapy, targeted therapies, and peptide receptor radionuclide therapy[4]. Other novel systemic and targeted therapies are rapidly emerging[9,10]. Despite the absence of level I evidence, surgical resection is associated with the best long-term outcomes based on retrospective cohort studies and meta-analyses[6,11,12]. Indeed, even cytoreductive surgery (i.e., surgical debulking) of NELM has been associated with improved overall survival if residual disease less than 10%-30% can be achieved[5,13-15]. Based on these data, surgical resection of NELM has been recommended as the preferred initial approach, when feasible, by the European Neuroendocrine Tumors Society and North American Neuroendocrine Tumors Society[16,17].

Previous studies evaluating the short-term outcomes of surgery for NELM have frequently been limited by their retrospective, single-institution nature[18-22]. Other more recent multi-institutional studies have been limited to high-volume institutions and conducted over long study periods[6,14,23]. Thus, there is a need for an evaluation of contemporary practice patterns and outcomes from a population-based perspective. Such information would inform patient selection and facilitate patient education and the informed consent process. Therefore, we utilized the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) targeted hepatectomy database to analyze contemporary characteristics of patients with NELM who underwent liver resection (LR) in the United States and evaluate factors associated with postoperative morbidity and mortality.

The incidence of NETs is increasing worldwide and a majority of patients will present with metastatic disease in their liver[1]. NELM is a strong negative prognostic factor for survival and is associated with significant reductions in patient quality of life[24]. While several systemic and liver-directed therapies are available, surgical resection is typically recommended when feasible[25]. In this paper, we used a contemporary, population-based, prospective database to define the characteristics and outcomes of patients undergoing surgery for NELM in the United States. These results highlight several important findings. First, the majority of operations are being performed for small tumors in the setting of multifocal disease and typically are minor resections. Second, a significant proportion of cases are being performed concomitant with another operation, either liver IA, cholecystectomy, or (presumably) primary tumor resection. Finally, modern surgery for NELM can be performed with relatively minimal postoperative morbidity (29%) and mortality (1.3%). These results are critical for informed preoperative discussions with patients as well as future comparative effectiveness research with other liver-directed treatments.

Recent advances in the perioperative management of patients undergoing LR have improved the safety of hepatectomy and expanded criteria for selecting patients for surgery. Indeed, a recent study by Cloyd et al[26] evaluated nearly 4000 patients who underwent LR over two decades and noted steady improvements in postoperative morbidity despite increases in case complexity. Improvements in the outcomes of LR are likely multifactorial but improved patient selection, evaluation and optimization, are paramount. Accurate liver volumetry and future liver remnant augmentation have been important strategies for minimizing post hepatectomy and postoperative liver failure[27,28]. Improved perioperative and anesthetic care, including reduced intravenous fluid administration and less blood loss, have similarly been critical advances in contemporary hepatic surgery. The introduction of enhanced recovery after surgery processes have further contributed to reduced morbidity following surgery and are now commonly routinized at major medical centers[29]. Finally, implementation of laparoscopic and robotic approaches for surgery have led to reduced postoperative pain, blood loss, and length of hospital stay with similar outcomes compared with open approaches[30-33].

Prior studies evaluating the role of IA for NELM have demonstrated that this therapeutic approach is generally well tolerated and is indicated for patients whose tumors are not amenable to resection[6,34] though the safety of IA during surgery for NELM has not been thoroughly evaluated[34-36]. In this study, we noted that IA was associated with decreased 30-d morbidity in univariate analysis though this association did not persist on multivariate analysis. These findings are consistent with a recent study evaluating IA during resection of colorectal liver metastasis which found lower overall morbidity, hospital length of stay, and readmission rates in patients who underwent LR and IA compared to patients who underwent LR alone[37]. Based on these results and others, IA appears to be a safe and effective strategy to expand the surgical options for patients with multifocal NELM.

While the role of primary tumor resection in the setting of unresectable NELM remains controversial, resection of the primary NET is indicated when liver metastases are resectable[19,38-41]. The current study suggests that resection of the primary (e.g., pancreatectomy, intestinal resection) can be performed safely and is not associated with increased postoperative morbidity. These findings are consistent with the large body of literature which suggests that most LRs for colorectal liver metastasis can be performed safely in a combined fashion with standard colorectal resections[42,43].

While the ACS-NSQIP targeted hepatectomy database has the advantage of containing hepatectomy-specific perioperative variables, a limitation of the current database was the lack of cancer- and patient-specific information. For example, the database lacked relevant information such as the symptomatic status of patients, functional status of tumors, tumor grade, or presence of extra-hepatic disease. In addition, it lacked Furthermore, as the study was limited to the 30-d postoperative period, we were unable to describe the long-term efficacy of LR for NELM. However, the purpose of the current study was to evaluate the indications for and short-term outcomes of surgery for NELM. Multiple prior studies have found that LR for NELM is associated with good long-term survival[4,6,44]. Similarly, the ACS-NSQIP database did not have information on carcinoid crisis, however, previous studies have shown this to be a relatively rare event[45,46]. This study had several other limitations, primarily related to its retrospective nature and the fact that data were limited to the 30-d postoperative period which may be insufficient to capture all complications.

In conclusion, in this contemporary population-based analysis, we demonstrated that LR can be performed for NELM with relatively low postoperative morbidity and mortality. Concomitant operations such as cholecystectomy, bowel resection, pancreatectomy, and IA can safely be performed and do not contribute to increased morbidity. Careful patient selection, minimizing operative time, and utilizing minimally invasive surgical approaches may help reduce postoperative morbidity. While multiple therapeutic options exist for NELM, given the excellent long-term outcomes observed in the literature and the satisfactory short-term outcomes demonstrated herein, surgical resection should remain the standard of care when feasible.