Biomarkers to Inform Prognosis and Treatment for Unresectable or Metastatic GEP-NENs.

Importance: Evidence-based treatment decisions for advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) require individualized patient-centered decision-making that accounts for patient and cancer characteristics. Objective: To create an accessible guidance document to educate clinicians and patients on biomarkers informing prognosis and treatment in unresectable or metastatic GEP-NENs. Methods: A multidisciplinary panel in-person workshop was convened to define methods. English language articles published from January 2016 to January 2023 in PubMed (MEDLINE) and relevant conference abstracts were reviewed to investigate prognostic and treatment-informing features in unresectable or metastatic GEP-NENs. Data from included studies were used to form evidence-based recommendations. Quality of evidence and strength of recommendations were determined using the Grading of Recommendations, Assessment, Development and Evaluations framework. Consensus was reached via electronic survey following a modified Delphi method. Findings: A total of 131 publications were identified, including 8 systematic reviews and meta-analyses, 6 randomized clinical trials, 29 prospective studies, and 88 retrospective cohort studies. After 2 rounds of surveys, 24 recommendations and 5 good clinical practice statements were developed, with full consensus among panelists. Recommendations focused on tumor and functional imaging characteristics, blood-based biomarkers, and carcinoid heart disease. A single strong recommendation was made for symptomatic carcinoid syndrome informing treatment in midgut neuroendocrine tumors. Conditional recommendations were made to use grade, morphology, primary site, and urinary 5-hydroxyindoleacetic levels to inform treatment. The guidance document was endorsed by the Commonwealth Neuroendocrine Tumour Collaboration and the North American Neuroendocrine Tumor Society. Conclusions and Relevance: The study results suggest that select factors have sufficient evidence to inform care in GEP-NENs, but the evidence for most biomarkers is weak. This article may help guide management and identify gaps for future research to advance personalized medicine and improve outcomes for patients with GEP-NENs.

Consideration of quality of life in the treatment decision-making for patients with advanced gastroenteropancreatic neuroendocrine tumors.

INTRODUCTION: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a complex and heterogenous family of solid malignancies that originate from neuroendocrine tissue in the gastrointestinal tract or pancreas. Most patients diagnosed with GEP-NETs present with advanced or metastatic disease, and quality of life (QoL) is often an important priority when selecting treatments for these patients. Patients with advanced GEP-NETs often experience a substantial and persistent symptom burden that undermines their QoL. Addressing a patient's individual symptoms through judicious selection of treatment may improve QoL. AREAS COVERED: The objectives of this narrative review are to summarize the impact of advanced GEP-NETs on patient QoL, assess the potential value of current treatments for maintaining or improving patient QoL, and offer a clinical framework for how these QoL data can be translated to inform clinical decision-making for patients with advanced GEP-NETs. EXPERT OPINION: Patients with advanced GEP-NETs experience a significant and persistent symptom burden that impacts their daily lifestyle, activities, work life, and financial health, leading to erosion of their QoL. Ongoing and future studies incorporating longitudinal QoL assessments and head-to-head treatment evaluations will further inform the incorporation of QoL into clinical decision-making.

Shifting Paradigms in the Pathophysiology and Treatment of Carcinoid Crisis.

Carcinoid crisis is a potentially fatal condition characterized by various symptoms, including hemodynamic instability, flushing, and diarrhea. The incidence of carcinoid crisis is unknown, in part due to inconsistency in definitions across studies. Triggers of carcinoid crisis include general anesthesia and surgical procedures, but drug-induced and spontaneous cases have also been reported. Patients with neuroendocrine tumors (NETs) and carcinoid syndrome are at risk for carcinoid crisis. The pathophysiology of carcinoid crisis has been attributed to secretion of bioactive substances, such as serotonin, histamine, bradykinin, and kallikrein by NETs. The somatostatin analog octreotide has been considered the standard of care for carcinoid crisis due to its inhibitory effect on hormone release and relatively fast resolution of carcinoid crisis symptoms in several case studies. However, octreotide's efficacy in the treatment of carcinoid crisis has been questioned. This is due to a lack of a common definition for carcinoid crisis, the heterogeneity in clinical presentation, the paucity of prospective studies assessing octreotide efficacy in carcinoid crisis, and the lack of understanding of the pathophysiology of carcinoid crisis. These issues challenge the classical physiologic model of carcinoid crisis and its common etiology with carcinoid syndrome and raise questions regarding the utility of somatostatin analogs in its treatment. As surgical procedures and invasive liver-directed therapies remain important treatment modalities in patients with NETs, the pathophysiology of carcinoid crisis, potential benefits of octreotide, and efficacy of alternative treatment modalities must be studied prospectively to develop an effective evidence-based treatment strategy for carcinoid crisis.

Skeletal metastases in advanced pancreatic ductal adenocarcinoma: a retrospective analysis.

BACKGROUND: Skeletal metastases (SM) in advanced pancreatic ductal adenocarcinoma (PDAC) is an infrequent occurrence that has been previously reported in literature to occur in less than 2.5% of the cases. Complications such as pathological fractures can result in intractable pain, immobilization and a significant deterioration in quality of life. The purpose of this study is to improve the understanding of the increasing incidence of SM and the importance of surveillance and adequate management of SM in these patients. METHODS: A retrospective analysis was conducted using a clinical database at a single tertiary care institution for cancer patients; this included 207 patients with advanced PDAC diagnosed between December 2004 and March 2017 receiving palliative chemotherapy. SM were identified by computerized tomography (CT)/fluorodeoxyglucose positron emission tomography (FDG-PET)/magnetic resonance imaging (MRI). Information regarding demographics, clinical course and date of last follow-up/death were collected. After a median follow-up of 11 months, an analysis was conducted, including a Kaplan-Meier survival analysis. RESULTS: The study included 207 patients; 19 out of 207 patients (9.2%) developed SM; the primary tumor was located in the pancreatic body/tail in 12 out of 19 patients (63.2%). The thoracic and lumbar vertebrae were the most common sites of SM. Other common synchronous sites of metastases included the liver and lung. A majority of the lesions were osteolytic (63.2%). The median time of diagnosis from the initial diagnosis was 2 months (range, 0-60 months). Bone pain was observed as the initial symptom in 7 out of 19 patients (36.8%), 2 out of 19 patients (10.5%) had a pathological fracture and 1 out of 19 patients (5.3%) developed a para-spinal mass causing inferior vena cava compression. The median survival period for patients with SM was 11 months (range, 0-62 months) and for those without SM was 12 months (range, 0-147 months) [hazard ratio (HR) 1.24, 95% confidence interval (CI): 0.66-2.30, P=0.51]. CONCLUSIONS: There has been a challenge with regards to management of the increasing number of patients with SM. Thoracic and lumbar vertebrae are the most common sites and pathological fractures in these sites can be catastrophic. Careful evaluation of skeletal signs and symptoms, early detection and intervention are essential to prevent morbidity and mortality from complications in patients with PDAC and SM.

Differential Diagnosis of Diarrhea in Patients With Neuroendocrine Tumors.

Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience diarrhea that can have a debilitating effect on quality of life. Diarrhea also may develop in response to other hormonal syndromes associated with NETs, surgical complications, medical comorbidities, medications, or food sensitivities. Limited guidance on the practical approach to the differential diagnosis of diarrhea in these patients can lead to delays in appropriate treatment. This clinical review and commentary underscore the complexity in identifying the etiology of diarrhea in patients with NETs. Based on our collective experience and expertise, we offer a practical algorithm to guide medical oncologists and other care providers to expedite effective management of diarrhea and related symptoms in patients with NETs.

The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Pancreatic Neuroendocrine Tumors.

This article is the result of the North American Neuroendocrine Tumor Society consensus conference on the medical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The guidelines panel consisted of medical oncologists, pathologists, gastroenterologists, endocrinologists, and radiologists. The panel reviewed a series of questions regarding the medical management of patients with pancreatic neuroendocrine tumors as well as questions regarding surveillance after resection. The available literature was reviewed for each of the question and panel members voted on controversial topics, and the recommendations were included in a document circulated to all panel members for a final approval.

Management of Diarrhea in Patients With Carcinoid Syndrome.

Neuroendocrine tumors (NETs) arise from enterochromaffin cells found in neuroendocrine tissues, with most occurring in the gastrointestinal tract. The global incidence of NETs has increased in the past 15 years, likely due to better diagnostic methods. Small-bowel NETs are frequently associated with carcinoid syndrome (CS). Carcinoid syndrome diarrhea occurs in 80% of CS patients and poses a substantial symptomatic and economic burden. Patients with CS diarrhea frequently suffer from diarrhea and flushing and report corresponding impairment in quality of life, requiring substantial changes in daily activities and lifestyle. Treatment paradigms range from surgical debulking to liver-directed therapies to treatment with somatostatin analogs, nonspecific anti-diarrheal agents, and a tryptophan hydroxylase inhibitor. Other causes of diarrhea, including steatorrhea, short bowel syndrome, and bile acid malabsorption, should be considered in NET patients with refractory diarrhea. More therapeutic options are needed for symptomatic management of patients with NETs, and better understanding of the pathophysiology can empower clinicians with improved patient care.

Peptide Receptor Radionuclide Therapy for Patients With Advanced Lung Carcinoids.

Neuroendocrine neoplasms (NEN) are a family of malignancies of diverse origin, including the lung, gastrointestinal tract, and pancreas. Lung NEN include well differentiated neuroendocrine tumors (NET) classified as typical carcinoids or atypical carcinoids, and poorly differentiated neuroendocrine carcinomas classified as small-cell lung carcinoma or large-cell neuroendocrine carcinoma. According to a recent analysis of a large, population-based registry, approximately one-third of all patients with lung typical/atypical carcinoids have distant metastases at diagnosis, and median survival for these patients is 24 months. At present, only 1 therapy is approved by the US Food and Drug Administration (FDA) for patients with advanced lung typical/atypical carcinoids, everolimus, indicating a clear need for more treatment options in this patient population. Although not yet supported by results from randomized prospective trials, somatostatin analogues are considered an acceptable treatment option for patients with lung typical/atypical carcinoids expressing somatostatin receptors. Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE was recently approved by the FDA for the treatment of gastroenteropancreatic NET; however, the role of PRRT in patients with lung typical/atypical carcinoids remains unclear, because they were not included in the pivotal NETTER-1 (Neuroendocrine Tumors Therapy) trial. Herein we provide a comprehensive review of the available clinical evidence for efficacy and safety of PRRT in patients with lung typical/atypical carcinoids. On the basis of the preliminary evidence of efficacy and the consistent safety profile in this patient group, we propose that experienced multidisciplinary NET teams may consider PRRT alongside everolimus as an option for patients with advanced somatostatin receptor-positive lung typical/atypical carcinoids whose disease is progressing during first-line treatment with somatostatin analogues.

Peptide receptor radionuclide therapy for patients with advanced pancreatic neuroendocrine tumors.

177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) is now approved for patients with advanced gastroenteropancreatic neuroendocrine tumors (NET), and it is therefore important to understand the efficacy and safety of PRRT in this patient population. PRRT efficacy and safety outcomes have frequently been summarized for patient populations with gastroenteropancreatic NET, but not specifically in patients with pancreatic NET (panNET). The pivotal phase 3 trial of 177Lu-DOTATATE PRRT in NET was restricted to patients with a midgut primary site. No phase 3 trial data on PRRT treatment outcomes are currently available for the panNET patient population. This review presents the available evidence for panNET treatment outcomes with PRRT and demonstrates that the available data favor PRRT as a modality for this NET primary site. However, several other therapies for advanced panNET are currently available, and the sequencing and combination of PRRT with these other therapies is set to become the big challenge for the future of panNET management. Patient, tumor, and logistical factors (tumor burden, expression of somatostatin receptors, availability of PRRT, patient preferences, and concerns over long-term toxicity) need to be taken into consideration when selecting therapy.

Mechanisms of resistance to BRAF and MEK inhibitors and clinical update of US Food and Drug Administration-approved targeted therapy in advanced melanoma.

Approximately 50% of melanomas harbor an activating BRAF mutation. Combined BRAF and MEK inhibitors such as dabrafenib and trametinib, vemurafenib and cobimetinib, and encorafenib and binimetinib are US Food and Drug Administration (FDA)-approved to treat patients with BRAF V600-mutated advanced melanoma. Both genetic and epigenetic alterations play a major role in resistance to BRAF inhibitors by reactivation of the MAPK and/or the PI3K-Akt pathways. The role of BRAF inhibitors in modulating the immunomicroenvironment and perhaps enhancing the efficacy of checkpoint inhibitors is gaining interest. This article provides a comprehensive review of mechanisms of resistance to BRAF and MEK inhibitors in melanoma and summarizes landmark trials that led to the FDA approval of BRAF and MEK inhibitors in metastatic melanoma.

Peptide Receptor Radionuclide Therapy Outcomes in a North American Cohort With Metastatic Well-Differentiated Neuroendocrine Tumors.

OBJECTIVES: The objective of this study was to describe the outcomes of patients in the University of Iowa Neuroendocrine Tumor (NET) Database treated with peptide receptor radionuclide therapy (PRRT). METHODS: One hundred thirty-five patients from the University of Iowa NET Database who received PRRT were analyzed, their characteristics were described, and survival was calculated. RESULTS: The median age at diagnosis was 51 years, and 64% were men. The primary tumor was located in the small bowel (SBNET) in 37.8%, in the pancreas (PNET) in 26.0%, in the lung in 13.3%, in unknown primary in 9.6%, and in other sites in 13.3%. A radiographic response of any magnitude was observed in 65.8%, 11.1% had a mixed response, and 15.4% showed progression. The overall survival (OS) from the first PRRT was 40 months, and the median time to progression was 23.9 months. Higher pretreatment chromogranin A and pancreastatin levels predicted inferior OS. CONCLUSIONS: Peptide receptor radionuclide therapy resulted in a relatively long OS and time to progression in heavily pretreated North American patients with advanced NETs. Elevated pretreatment chromogranin A and pancreastatin predicted shorter OS after therapy. Peptide receptor radionuclide therapy is a valuable treatment option in patients with advanced NETs, especially SBNETS.

Comparison of transarterial liver-directed therapies for low-grade metastatic neuroendocrine tumors in a single institution.

OBJECTIVE: We compared the clinical outcomes of patients with metastatic neuroendocrine tumors treated with hepatic artery embolization (HAE), chemoembolization (HACE), and selective internal radiation therapy (SIRT) at our institution over the last 10 years. METHODS: The medical records of 42 patients with metastatic neuroendocrine tumors with hepatic metastases treated with HAE, HACE, or SIRT at the University of Iowa from 2001 to 2011 were analyzed. RESULTS: A total of 13 patients had HAE, 17 patients had HACE, and 12 patients had SIRT as their initial procedure. Time to progression (TTP) was similar between SIRT (15.1 months) and HACE/HAE groups (19.6 months; P = 0.968). There was a trend toward increased TTP in patients receiving HACE (33.4 months) compared with HAE (12.1 months) or SIRT (15.1 months), although not statistically significant (P = 0.512). The overall survival for all patients from the first intervention was 41.9 months. There was no difference between HACE/HAE and SIRT in posttherapy change of chromogranin A (P = 0.233) and pancreastatin (P = 0.158) levels. Time to progression did not correlate with the change in the posttherapy chromogranin A (P = 0.299) or pancreastatin (P = 0.208) levels. CONCLUSIONS: There was no significant difference in TTP in patients treated with SIRT compared with patients treated with HAE or HACE. Baseline and posttherapy marker changes were not predictive of TTP.

Current status and perspectives of targeted therapy in well-differentiated neuroendocrine tumors.

Although neuroendocrine tumors (NET) are a relatively rare malignancy, the reported incidence is increasing, and some of the current treatment options are limited in their efficacy. Standard first-line therapy for metastatic small bowel NET includes somatostatin analogs. Although these agents can provide symptom relief and can delay disease progression in many patients, ultimately, new treatments are required for patients with progressive disease. In recent years, there has been considerable interest in developing agents specifically targeted against some of the pathways known to be involved in cancer cell growth, survival and invasion. In 2011, the mammalian target of rapamycin (mTOR) inhibitor everolimus and the tyrosine kinase inhibitor sunitinib were approved for the treatment of pancreatic NET. Clinical trials evaluating novel targeted agents are ongoing, both as single agents and in combination regimens. We review the current clinical status of these potential new treatments and highlight those with particular promise for the management of well-differentiated NET.

Traumatic neuroma of the tympanic (Jacobson's) nerve as a possible cause of otalgia.

OBJECTIVE: To show that traumatic neuroma of the tympanic (Jacobson's) nerve may be a cause of recurrent intractable otalgia in patients following radical mastoidectomies. STUDY DESIGN: Histologic evaluation of four temporal bones from three patients with a history of recurrent otalgia following radical mastoidectomy. SUBJECTS AND METHODS: The medical records of three patients with multiple middle ear surgeries in four ears because of recurrent otalgia were reviewed. Histopathologic studies of the four temporal bones were performed. RESULTS: All four of the temporal bones that underwent multiple surgeries were found to have traumatic neuromas of the tympanic (Jacobson's) nerve. CONCLUSION: Recurrent otalgia in patients after radical middle ear surgery may be caused by a traumatic neuroma of the tympanic (Jacobson's) nerve.