Ashley K. Clift

Therapeutic strategies for neuroendocrine liver metastases.

Patients who have neuroendocrine tumors frequently present with liver metastases. A wide panel of treatment options exists for these patients. Liver resection with curative intent achieves the best long‐term results. Highly selected patients may be considered for liver transplantation. Substantial recurrence rates reported after surgical approaches call for neoadjuvant and adjuvant concepts. Liver‐directed, locally ablative procedures are recommended for patients with limited, nonresectable tumor burden. Angiographic liver‐directed techniques, such as transarterial embolization, transarterial chemoembolization, and selective internal radiotherapy, offer excellent palliation for patients with liver‐predominant disease. Peptide receptor radionuclide therapy is a promising palliative procedure for patients with hepatic and/or extrahepatic metastases. The efficacy of these treatment options needs to be evaluated in randomized trials. Somatostatin analogues have demonstrated effectiveness not only for symptomatic relief in patients with secreting tumors but also for the control of proliferation in small intestinal neuroendocrine tumors and most recently also in those originating from the pancreas. Chemotherapy is an option mainly for those with pancreatic neuroendocrine tumors and high‐grade tumors irrespective of the origin. Novel drugs targeting specific pathways within the tumor cell have produced improved progression‐free survival compared with placebo in patients with pancreatic neuroendocrine tumors. Despite such a diverse armamentarium, there is uncertainty with regard to the optimal treatment regimens. Newly introduced molecular‐based markers, along with the conduction of clinical trials comparing the efficacy of treatment modalities, offer a chance to move the treatment of neuroendocrine tumor disease toward personalized patient care. In this report, the authors review the approaches for treatment of neuroendocrine liver metastases, identify shortcomings, and anticipate future perspectives. Furthermore, clinical practice recommendations are provided for currently available treatment options. Although multiple modalities are available for the treatment of neuroendocrine liver metastases, optimal management is unclear. The current knowledge pertaining to these treatment options is analyzed. Cancer 2015;121:1172–1186.

Capsule endoscopy to detect primary tumour site in metastatic neuroendocrine tumours.

BACKGROUND In patients with metastatic neuroendocrine tumours, primary tumour localisation is often difficult with morphological and/or functional imaging. Although utilised in investigating various small bowel pathologies, evidence for using video capsule endoscopy to identify suspected small bowel primaries in patients exhibiting metastatic neuroendocrine tumours is limited. AIMS To assess the role of video capsule endoscopy in locating primary small bowel neuroendocrine tumours when conventional imaging fails to identify the origin of metastatic disease. METHODS We retrospectively compared our institutional database of patients presenting with metastatic neuroendocrine tumours between January 2010 and December 2013 with an analogous database of patients undergoing video capsule endoscopy for various indications. Patients whose primary tumours were not located radiologically and also underwent capsule endoscopy were identified. RESULTS 390 patients with metastasised neuroendocrine tumours presented within the study period. In 11 (2.8%) the primary tumour was not located radiologically. Video capsule endoscopy identified lesions suggestive of small bowel primary in 8/10 patients in whom it was successful. Small bowel primary was confirmed by histological analysis of surgical specimens. CONCLUSIONS Our study supports the use of video capsule endoscopy as part of the diagnostic work-up in selected patients presenting with metastatic neuroendocrine tumours of unknown primary. The clinical utility of this technology requires clearer definition.

Functional imaging in liver tumours

Functional imaging encompasses techniques capable of assessing physiological parameters of tissues, and offers useful clinical information in addition to that obtained from morphological imaging. Such techniques may include magnetic resonance imaging with diffusion-weighted sequences or hepatobiliary contrast agents, perfusion imaging, or molecular imaging with radiolabelled tracers. The liver is of major importance in oncological practice; not only is hepatocellular carcinoma one of the malignancies with steadily rising incidence worldwide, but hepatic metastases are regularly observed with a range of solid neoplasms. Within the realm of hepatic oncology, different functional imaging modalities may occupy pivotal roles in lesion characterisation, treatment selection and follow-up, depending on tumour size and type. In this review, we characterise the major forms of functional imaging, discuss their current application to the management of patients with common primary and secondary liver tumours, and anticipate future developments within this field.

Predicting the survival of patients with small bowel neuroendocrine tumours: comparison of 3 systems

Neuroendocrine tumours (NET) are clinically challenging due to their unpredictable behaviour. Nomograms, grading and staging systems are predictive tools with multiple roles in clinical practice, including patient prognostication. The NET nomogram allocates scores for various clinicopathological parameters, calculating percentage estimates for 5- and 10-year disease-specific survival of patients with small bowel (SB) NET. We evaluated the clinical utility of three prognostic systems in 70 SB NET patients: the NET nomogram, the World Health Organisation (WHO)/European Neuroendocrine Tumour Society (ENETS) grading system and the American Joint Commission on Cancer (AJCC)/Union Internationale Contre le Cancer (UICC) TNM staging method. Using Kaplan–Meier methodology, neither the WHO/ENETS grade (P = 0.6) nor the AJCC/UICC stage (P = 0.276) systems demonstrated significant differences in patient survival in the cohort. The NET nomogram was well calibrated to our data set, displaying favourable prediction accuracy. Harrel’s C-index for the nomogram (a measure of predictive power) was 0.65, suggesting good prediction ability. On Kaplan–Meier analyses, there were significant differences in patient survival when stratified into nomogram score-based risk groups: low-, medium- and high-risk tumours were associated with median estimated survivals of 156, 129 and 112 months, respectively (P = 0.031). Our data suggest that a multivariable analysis-based NET nomogram may be clinically useful for patient survival prediction. This study identifies the limitations of the NET nomogram and the imperfections of other currently used single or binary parameter methodologies for assessing neuroendocrine disease prognosis. The future addition of other variables to the NET nomogram will likely amplify the accuracy of this personalised tool.

Modified liver-free multivisceral transplantation for a metastatic small bowel neuroendocrine tumor: a case report.

Neuroendocrine tumors originating from the small bowel frequently metastasize to the lymph nodes and/or liver. Although surgical extirpation of the primary tumor and locoregional metastases epitomizes the management of patients with such tumors, this is not always possible with conventional surgical techniques. Nonresectable, slow-growing tumors involving the mesenteric root represent a generally accepted indication for deceased donor intestinal and multivisceral transplantation. Furthermore, vascularized sentinel forearm flaps offer opportunities for monitoring graft rejection and tailoring immunosuppression regimens. Here, we report the first documented case of modified liver-free multivisceral transplantation preceded by neoadjuvant 177-lutetium peptide receptor radionuclide therapy in a patient with a small bowel neuroendocrine tumor and extensive lymph node metastases in the mesenterium. At a follow-up of 21 months the patient is biochemically and radiologically disease-free.

Incidence of Second Primary Malignancies in Patients with Neuroendocrine Tumours

Background: An association between neuroendocrine tumours (NET) and increased risk of developing second primary malignancies (SPM) has been recognised. Methods: This was a retrospective review of our institutional prospectively maintained database of NET patients. We identified patients who had been diagnosed with both neuroendocrine and any additional malignancies via examination of patient notes. Results: Clinical data for 169 patients were analysed. After exclusion of patients known to have hereditary tumour predisposition syndromes, 29 SPM were identified in 26 patients (15.38%), the commonest being colorectal (n = 6), breast and renal carcinomas (both n = 5). SPM were classified as previous, synchronous or subsequent relative to NET diagnosis. Rates of SPM in pancreatic and small-bowel NET patients were comparable (15.7 vs. 19.6%, p = 0.78). A person-year methodology was used to compare observed numbers of SPM against expected values generated from age- and sex-specific incidence tables, with standardised incidence ratios (SIR) and 95% confidence intervals (CI) calculated. SPM incidence was significantly elevated in the synchronous subset (SIR 2.732, CI 1.177-5.382) whilst significantly fewer NET patients had a cancer history compared to the general population (SIR 0.4, CI 0.241-0.624). No overall differences were evident between observed and expected incidences of subsequent SPM (SIR 0.36, CI 0.044-1.051). The incidence of synchronous colorectal cancers was markedly elevated (SIR 13.079, CI 4.238-30.474). Conclusions: Our data support the use of colonoscopy in the diagnostic work-up of NET patients in anticipation of a colorectal SPM. The mechanistic underpinnings of this clinical phenomenon require further genetic investigation, and consideration of this knowledge in patient management pathways is warranted.

Management of patients with hepatic metastases from neuroendocrine tumors.

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.

Morphological and Functional Imaging for Detecting and Assessing the Resectability of Neuroendocrine Liver Metastases

This review evaluates the diagnostic efficacy of different morphological and functional imaging modalities (ultrasound [US], computed tomography [CT], magnetic resonance [MR] imaging, scintigraphy, and positron emission tomography [PET]) in detecting neuroendocrine liver metastases (NELM), assessing vascular and biliary involvement, and the presence of extrahepatic disease. MR imaging is superior for depicting NELM compared to US, CT, and somatostatin receptor scintigraphy. Diffusion-weighted MR imaging is more sensitive for detecting NELM than both T2-weighted and dynamic gadolinium-enhanced MR sequences, and should be systematically performed. Similarly, gadoxetic acid-enhanced MR imaging is more sensitive for detecting liver metastases than conventional extracellular gadolinium chelate-enhanced MR sequences. Its role in detecting NELM remains investigational but appears promising. Somatostatin receptor-targeted PET/CT is a highly effective approach in assessing the resectability of well-differentiated NELM due to very high specificity (and high sensitivity) and its ability to detect small volume extrahepatic disease; this molecular imaging modality is becoming increasingly available in and outside Europe after the recent approval of 6868-DOTATATE in the US. In addition, the information from multiphase, contrast-enhanced CT with 3D reconstruction - obtained concurrently with the information on somatostatin receptor expression of the metastases - is very helpful in planning the extent and type of resection of NELM.

Goblet cell carcinomas of the appendix: rare but aggressive neoplasms with challenging management

Goblet cell carcinomas (GCC) are a rare, aggressive sub-type of appendiceal tumours with neuroendocrine features, and controversy exists with regards to therapeutic strategy. We undertook a retrospective review of GCC patients surgically treated at two tertiary referral centres. Clinical and histopathological data were extracted from a prospectively maintained database. Survival analyses utilised Kaplan–Meier methodology. Twenty-one patients were identified (9 females). Median age at diagnosis was 55 years (range 32–77). There were 3, 6 and 9 grade 1, 2 and 3 tumours, respectively. One, 10, 5 and 5 patients had stage I, II, III and IV disease at diagnosis, respectively. There were 8, 10 and 3 Tang class A, B and C tumours, respectively. Index operation was appendectomy (n = 12), right hemicolectomy (n = 6) or resections including appendix/right colon, omentum and the gynaecological system (n = 3). Eight patients underwent completion right hemicolectomy. Surgery for recurrence included small bowel resection (n = 2), debulking with peritonectomy and heated intraperitoneal chemotherapy, and hysterectomy and bilateral salpingo-oophorectomy (all n = 1). Median follow-up was 30 months (range 2.5–123). One-, 3- and 5-year OS was 79.4, 60 and 60%, respectively. Mean OS (1-, 3-, and 5-year OS) for Tang class A, B and C tumours were 73.1 months (85.7, 85.7, 51.4%), 83.7 months (all 66.7%) and 28.5 months (66.7, 66.7%, not reached), respectively. Chromogranin A/B and 68Ga-DOTATATE PET/CT were not useful in follow-up, but CEA, CA 19-9, CA 125 and 18F-FDG PET/CT identified tumour recurrence. GCC must be clearly discriminated from relatively indolent appendiceal neuroendocrine neoplasms. 18F-FDG PET/CT and CEA/CA19-9/CA 125 are useful in detecting recurrence of GCC.

Surgical Management of Patients with Neuroendocrine Neoplasms of the Appendix: Appendectomy or More?

Background: Appendiceal neuroendocrine neoplasms (ANEN) are mostly indolent tumours treated effectively with simple appendectomy. However, controversy exists regarding the necessity of oncologic right hemicolectomy (RH) in patients with histologic features suggestive of more aggressive disease. We assess the effects of current guidelines in selecting the surgical strategy (appendectomy or RH) for the management of ANEN. Methods/Aims: This is a retrospective review of all ANEN cases treated over a 14-year period at 3 referral centres and their management according to consensus guidelines of the European and the North American Neuroendocrine Tumor Societies (ENETS and NANETS, respectively). The operation performed, the tumour stage and grade, the extent of residual disease, and the follow-up outcomes were evaluated. Results: Of 14,850 patients who had appendectomies, 215 (1.45%) had histologically confirmed ANEN. Four patients had synchronous non-ANEN malignancies. One hundred and ninety-three patients had index appendectomy. Seventeen patients (7.9%) had lymph node metastases within the mesoappendix. Forty-nine patients underwent RH after appendectomy. The percentages of 30-day morbidity and mortality after RH were 2 and 0%, respectively. Twelve patients (24.5%) receiving completion RH were found to have lymph node metastases. Two patients had liver metastases, both of them synchronous. The median follow-up was 38.5 months (range 1-143). No patient developed disease recurrence. Five- and 10-year overall survival for all patients with ANEN as the only malignancy was both 99.05%. Conclusions: The current guidelines appear effective in identifying ANEN patients at risk of harbouring nodal disease, but they question the oncological relevance of ANEN lymph node metastases. RH might present an overtreatment for a number of patients with ANEN.