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Purpose of ReviewTo comprehensively synthesise and appraise the available evidence regarding therapies for metastatic neuroendocrine neoplasms that exploit the hepatic vasculature to deliver therapy to liver metastases.Recent FindingsVarious techniques including transarterial embolisation/chemoembolisation (TAE/TACE) and selective internal radiotherapy (SIRT, also termed radioembolisation [RE]) have been examined in patents with neuroendocrine liver metastases. Variations in the radioactive agents for selective internal radiotherapy (SIRT) have been explored, such as the use of Holmium-166, in addition to more established agents such as Yttrium-90. Recent trials have examined the safety and efficacy of combining liver-targeted therapy with systemic treatments, such as peptide receptor radionuclide therapy.SummaryMore retrospective case series of liver-directed modalities will not provide additional knowledge. Randomised clinical trials have begun to compare the efficacy of different forms of liver-directed therapies, and also their combination with systemic treatment. Their results are expected to guide optimal treatment sequencing within multimodal concepts.

Neuroendocrine liver metastases often require multiple modes of treatment to attain disease control, which can utilize various forms of radiolabelled agents either delivered systemically or preferentially towards the liver. A recent trial suggested both safety and efficacy of a novel approach of combining the two to provide a radiation ‘boost’ to hepatic deposits.

IntroductionSurgery is the only cure for neuroendocrine tumors (NETs), with R0 resection being critical for successful tumor removal. Early detection of residual disease is key for optimal management, but both imaging and current biomarkers are ineffective post-surgery. NETest, a multigene blood biomarker, identifies NETs with >90% accuracy. We hypothesized that surgery would decrease NETest levels and that elevated scores post-surgery would predict recurrence.MethodsThis was a multicenter evaluation of surgically treated primary NETs (n = 153). Blood sampling was performed at day 0 and postoperative day (POD) 30. Follow-up included computed tomography/magnetic resonance imaging (CT/MRI), and messenger RNA (mRNA) quantification was performed by polymerase chain reaction (PCR; NETest score: 0–100; normal ≤20). Statistical analyses were performed using the Mann–Whitney U-test, Chi-square test, Kaplan–Meier survival, and area under the receiver operating characteristic curve (AUROC), as appropriate. Data are presented as mean ± standard deviation.ResultsThe NET cohort (n = 153) included 57 patients with pancreatic cancer, 62 patients with small bowel cancer, 27 patients with lung cancer, 4 patients with duodenal cancer, and 3 patients with gastric cancer, while the surgical cohort comprised patients with R0 (n = 102) and R1 and R2 (n = 51) resection. The mean follow-up time was 14 months (range 3–68). The NETest was positive in 153/153 (100%) samples preoperatively (mean levels of 68 ± 28). In the R0 cohort, POD30 levels decreased from 62 ± 28 to 22 ± 20 (p < 0.0001), but remained elevated in 30% (31/102) of patients: 28% lung, 29% pancreas, 27% small bowel, and 33% gastric. By 18 months, 25/31 (81%) patients with a POD30 NETest >20 had image-identifiable recurrence. An NETest score of >20 predicted recurrence with 100% sensitivity and correlated with residual disease (Chi-square 17.1, p < 0.0001). AUROC analysis identified an AUC of 0.97 (p < 0.0001) for recurrence-prediction. In the R1 (n = 29) and R2 (n = 22) cohorts, the score decreased (R1: 74 ± 28 to 45 ± 24, p = 0.0012; R2: 72 ± 24 to 60 ± 28, p = non-significant). At POD30, 100% of NETest scores were elevated despite surgery (p < 0.0001).ConclusionThe preoperative NETest accurately identified all NETs (100%). All resections decreased NETest levels and a POD30 NETest score >20 predicted radiologically recurrent disease with 94% accuracy and 100% sensitivity. R0 resection appears to be ineffective in approximately 30% of patients. NET mRNA blood levels provide early objective genomic identification of residual disease and may facilitate management.

Many management strategies exist for neuroendocrine liver metastases. These strategies range from surgery to ablation with various interventional radiology procedures, and include both regional and systemic therapy with diverse biological, cytotoxic, or targeted agents. A paucity of biological, molecular, and genomic information and an absence of data from rigorous trials limit the validity of many publications detailing management. This Review represents the views from an international conference, for which 15 expert working groups prepared evidence-based assessments addressing specific questions, and from which an independent jury derived final recommendations. The aim of the conference was to review the existing approaches to neuroendocrine liver metastases, assess the evidence on which management decisions were based, develop internationally acceptable recommendations for clinical practice (when evidence was available), and make recommendations for clinical and research endeavours. This report represents the final clinical statements and proposals for future research.

Management of neuroendocrine neoplasia represents a clinical challenge because of its late presentation, lack of treatment options, and limitations in present imaging modalities and biomarkers to guide management. Monoanalyte biomarkers have poor sensitivity, specificity, and predictive ability. A National Cancer Institute summit, held in 2007, on neuroendocrine tumours noted biomarker limitations to be a crucial unmet need in the management of neuroendocrine tumours. A multinational consensus meeting of multidisciplinary experts in neuroendocrine tumours assessed the use of current biomarkers and defined the perquisites for novel biomarkers via the Delphi method. Consensus (at >75%) was achieved for 88 (82%) of 107 assessment questions. The panel concluded that circulating multianalyte biomarkers provide the highest sensitivity and specificity necessary for minimum disease detection and that this type of biomarker had sufficient information to predict treatment effectiveness and prognosis. The panel also concluded that no monoanalyte biomarker of neuroendocrine tumours has yet fulfilled these criteria and there is insufficient information to support the clinical use of miRNA or circulating tumour cells as useful prognostic markers for this disease. The panel considered that trials measuring multianalytes (eg, neuroendocrine gene transcripts) should also identify how such information can optimise the management of patients with neuroendocrine tumours.

Neoadjuvant chemotherapy for unresectable colorectal liver metastases can downsize tumours for curative resection. We assessed the effectiveness of cetuximab combined with chemotherapy in this setting. Between Dec 2, 2004, and March 27, 2008, 114 patients were enrolled from 17 centres in Germany and Austria; three patients receiving FOLFOX6 alone were excluded from the analysis. Patients with non-resectable liver metastases (technically non-resectable or ≥5 metastases) were randomly assigned to receive cetuximab with either FOLFOX6 (oxaliplatin, fluorouracil, and folinic acid; group A) or FOLFIRI (irinotecan, fluorouracil, and folinic acid; group B). Randomisation was not blinded, and was stratified by technical resectability and number of metastases, use of PET staging, and EGFR expression status. They were assessed for response every 8 weeks by CT or MRI. A local multidisciplinary team reassessed resectability after 16 weeks, and then every 2 months up to 2 years. Patients with resectable disease were offered liver surgery within 4–6 weeks of the last treatment cycle. The primary endpoint was tumour response assessed by Response Evaluation Criteria In Solid Tumours (RECIST), analysed by modified intention to treat. A retrospective, blinded surgical review of patients with radiological images at both baseline and during treatment was done to assess objectively any changes in resectability. The study is registered with ClinicalTrials.gov, number NCT00153998. 56 patients were randomly assigned to group A and 55 to group B. One patient in each group were excluded from the analysis of the primary endpoint because they discontinued treatment before first full dose, one patient in group B was excluded because of early pulmonary embolism. A confirmed partial or complete response was noted in 36 (68%) of 53 patients in group A, and 30 (57%) of 53 patients in group B (difference 11%, 95% CI −8 to 30; odds ratio [OR] 1·62, 0·74–3·59; p=0·23). The most frequent grade 3 and 4 toxicities were skin toxicity (15 of 54 patients in group A, and 22 of 55 patients in group B), and neutropenia (13 of 54 patients in group A and 12 of 55 patients in group B). R0 resection was done in 20 (38%) of 53 patients in group A and 16 (30%) of 53 of patients in group B. In a retrospective analysis of response by KRAS status, a partial or complete response was noted in 47 (70%) of 67 patients with KRAS wild-type tumours versus 11 (41%) of 27 patients with KRAS-mutated tumours (OR 3·42, 1·35–8·66; p=0·0080). According to the retrospective review, resectability rates increased from 32% (22 of 68 patients) at baseline to 60% (41 of 68) after chemotherapy (p<0·0001). Chemotherapy with cetuximab yields high response rates compared with historical controls, and leads to significantly increased resectability. Merck-Serono, Sanofi-Aventis, and Pfizer.

Radiofrequency ablation is an accepted treatment for non-surgical patients with liver cancer. The purpose of this study was to identify the feasibility, safety, and effectiveness of percutaneous radiofrequency ablation of malignant lung tumours. Between July 1, 2001, and Dec 10, 2005, a series of 106 patients with 183 lung tumours that were 3·5 cm in diameter or smaller (mean 1·7 cm [SD 1·3]) were enrolled in a prospective, intention-to-treat, single-arm, multicentre clinical trial from seven centres in Europe, the USA, and Australia. Proof of malignancy was obtained by biopsy in all patients. Diagnoses included non-small-cell lung cancer (NSCLC) in 33 patients, metastasis from colorectal carcinoma in 53 patients, and metastasis from other primary malignancies in 20 patients. All patients were considered by the treating physician to be unsuitable for surgery and unfit for radiotherapy or chemotherapy. Patients underwent radiofrequency ablation in accordance with standard rules for CT-guided lung biopsy and were then followed for up to 2 years. Primary endpoints were technical success (defined as correct placement of the ablation device into all tumour targets with completion of the planned ablation protocol), safety (including identification of treatment-related complications and changes in pulmonary function), and confirmed complete response of tumours (according to modified Response Evaluation Criteria in Solid Tumors). Secondary endpoints were overall survival, cancer-specific survival, and quality of life. This trial is registered with ClinicalTrials.gov, number NCT00690703. Correct placement of the ablation device into the target tumour with completion of the planned treatment protocol was feasible in 105 (99%) of 106 patients. The technical failure in one patient was caused by the inability to place the device inside a small tumour. No procedure-related deaths occurred in any of the 137 ablation procedures. Major complications consisted of pneumothorax (n=27) or pleural effusion (n=4), which needed drainage. No significant worsening of pulmonary function was noted. A confirmed complete response of target tumours lasting at least 1 year was shown in 75 (88%) of 85 assessable patients. No differences in response were noted between patients with NSCLC or lung metastases. Overall survival was 70% (95% CI 51–83%) at 1 year and 48% (30–65%) at 2 years in patients with NSCLC, 89% (76–95%) at 1 year and 66% (53–79%) at 2 years in patients with colorectal metastases, and 92% (65–99%) at 1 year and 64% (43–82%) at 2 years in patients with other metastases. Cancer-specific survival was 92% (78–98%) at 1 year and 73% (54–86%) at 2 years in patients with NSCLC, 91% (78–96%) at 1 year and 68% (54–80%) at 2 years in patients with colorectal metastases, and 93% (67–99%) at 1 year and 67% (48–84%) at 2 years in patients with other metastases. Patients with stage I NSCLC (n=13) had a 2-year overall survival of 75% (45–92%) and a 2-year cancer-specific survival of 92% (66–99%). Percutaneous radiofrequency ablation yields high proportions of sustained complete responses in properly selected patients with pulmonary malignancies, and is associated with acceptable morbidity. Randomised controlled trials comparing radiofrequency ablation with standard non-surgical treatment options are warranted. Angiodynamics (Queensbury, NY, USA).

Re-resection for gallbladder carcinoma incidentally discovered after cholecystectomy is routinely advocated. However, the incidence of finding additional disease at the time of re-resection remains poorly defined. Between 1984 and 2006, 115 patients underwent re-resection at six major hepatobiliary centers for gallbladder carcinoma incidentally discovered during cholecystectomy. Data on clinicopathologic factors, operative details, TNM tumor stage, and outcome were collected and analyzed. Data on the incidence and location of residual/additional carcinoma discovered at the time of re-resection were also recorded. On pathologic analysis, T stage was T1 7.8%, T2 67.0%, and T3 25.2%. The median time from cholecystectomy to re-resection was 52 days. At the time of re-resection, hepatic surgery most often consisted of formal segmentectomy (64.9%). Patients underwent lymphadenectomy (LND) (50.5%) or LND + common bile duct resection (43.3%). The median number of lymph nodes harvested was 3 and did not differ between LND alone (n = 3) vs LND + common duct resection (n = 3) (P = 0.35). Pathology from the re-resection specimen noted residual/additional disease in 46.4% of patients. Of those patients staged as T1, T2, or T3, 0, 10.4, and 36.4%, respectively, had residual disease within the liver (P = 0.01). T stage was also associated with the risk of metastasis to locoregional lymph nodes (lymph node metastasis: T1 12.5%; T2 31.3%, T3 45.5%; P = 0.04). Cystic duct margin status predicted residual disease in the common bile duct (negative cystic duct, 4.3% vs positive cystic duct, 42.1%) (P = 0.01). Aggressive re-resection for incidental gallbladder carcinoma is warranted as the majority of patients have residual disease. Although common duct resection does not yield a greater lymph node count, it should be performed at the time of re-resection for patients with positive cystic duct margins because over one-third will have residual disease in the common bile duct.

Introduction: The optimal treatment for small, asymptomatic, nonfunctioning pancreatic neuroendocrine neoplasms (NF-PanNEN) is still controversial. European Neuroendocrine Tumor Society (ENETS) guidelines recommend a watchful strategy for asymptomatic NF-PanNEN <2 cm of diameter. Several retrospective series demonstrated that a non-operative management is safe and feasible, but no prospective studies are available. Aim of the ASPEN study is to evaluate the optimal management of asymptomatic NF-PanNEN ≤2 cm comparing active surveillance and surgery. Methods: ASPEN is a prospective international observational multicentric cohort study supported by ENETS. The study is registered in ClinicalTrials.gov with the identification code NCT03084770. Based on the incidence of NF-PanNEN the number of expected patients to be enrolled in the ASPEN study is 1,000 during the study period (2017–2022). Primary endpoint is disease/progression-free survival, defined as the time from study enrolment to the first evidence of progression (active surveillance group) or recurrence of disease (surgery group) or death from disease. Inclusion criteria are: age >18 years, the presence of asymptomatic sporadic NF-PanNEN ≤2 cm proven by a positive fine-needle aspiration (FNA) or by the presence of a measurable nodule on high-quality imaging techniques that is positive at 68 Gallium DOTATOC-PET scan. Conclusion: The ASPEN study is designed to investigate if an active surveillance of asymptomatic NF-PanNEN ≤2 cm is safe as compared to surgical approach.

Neuroendocrine tumors have a disposition toward metastasis to the liver. A range of treatment modalities for neuroendocrine liver metastases is available in the clinical arena, the indications for which depend on tumor characteristics such as patterns of metastasis, tumor grade, and anatomical origin. The complete surgical resection of liver deposits represents the only option with the intent to cure and is the gold standard approach, whereas cytoreductive resection (debulking) presents another surgical option aiming to ameliorate the symptoms and prolong survival. Liver transplantation is generally an accepted option for highly selected patients. For patients ineligible for radical surgery, liver-directed therapies-transarterial embolization/chemoembolization, selective internal radiotherapy, and local tumor ablation-present alternative strategies. Systemic therapies include peptide receptor radiotherapy, somatostatin analogues, cytotoxic chemotherapeutics, and novel molecularly targeted drugs. However, despite the variety of treatments available, there exists little evidence to guide optimal clinical practice with currently available data predominantly retrospective in nature. In this review, we discuss the diagnostic procedures that influence the trajectory of treatment of patients with neuroendocrine liver metastases before critically appraising the evidence pertaining to these therapeutic strategies.