Impact of Regional Metastasis on Survival for Patients with Nonfunctional Pancreatic Neuroendocrine Tumors: A Systematic Review.

BACKGROUND: Controversy exists regarding the benefit of lymphadenectomy for nonfunctional pancreatic neuroendocrine tumors (NF-PNET). PATIENTS AND METHODS: MEDLINE/PubMed, EMBASE, and the Cochrane Library were searched for studies of pancreatic neuroendocrine tumors (PNET) published between 1990 and 2021. Studies of functional PNET were excluded. Reported incidence of lymph node metastasis (LNM) and survival analysis of either disease-free survival (DFS) or overall survival (OS) were required for inclusion. RESULTS: Overall, 52 studies analyzing 24,608 PNET met the inclusion criteria. The reported LNM rate for NF-PNET ranged from 7 to 64 % (median 24.5%). Reported LNM rates ranged from 7 to 51% (median 11%) for NF-PNET< 2 cm in 14 studies and 29-47% (median 38%) in NF-PNET > 2 cm. In total, 19 studies (66%) reported LNM to have a negative impact on DFS. Additionally, 21 studies (60%) reported LNM to have a negative impact on OS. Two studies investigating the impact of lymphadenectomy (LND) found LND had the greatest impact for large, high-grade tumors. The overall quality of available evidence was low as assessed by the Grading of Recommendations, Assessment, Development, and Evaluation System. CONCLUSIONS: Published literature evaluating the impact of regional LNM and LND in PNET is confounded by heterogeneity in practice patterns and the retrospective nature of these cohort studies. Most studies suggest high rates of LNM in NF-PNET that negatively impact DFS and OS. Given the high rate of LNM in NF-PNET and its potential detrimental effect on DFS and OS, we recommend lymphadenectomy be completed for NF-PNET > 2 cm and strongly considered for NF-PNET < 2 cm.

Neuroendocrine Tumors: a Relevant Clinical Update.

PURPOSE OF REVIEW: The field of neuroendocrine oncology has changed much since the time of Oberndorfer first described and coined the term carcinoid. The purpose of this review is to summarize recent findings and highlight clinically relevant updates in the management of NENs, particularly those that are practice changing. RECENT FINDINGS: Neuroendocrine tumors (NETs) have replaced carcinoid tumor, for the most part. The classification of neuroendocrine neoplasms (NENs) improved, and the epidemiological understanding of this disease group also expanded with global collaborations and maturation of large tumor registries. Clarity in the utility of some NET biomarkers continues to be evolving. Knowledge of molecular drivers of tumorigenesis increases, and scientific/technological advancements lead the way to multiple drug approvals for the treatment of advanced NETs. The incidence and prevalence of NENs continue to increase, and patients are living longer. Better understanding of molecular drivers and further understanding of the role of immunotherapy in NENs will further elevate the level of care and transform care for all patients with NENs.

A qualitative study to understand the experience of somatostatin analog treatments from the perspective of patients with neuroendocrine tumors.

PURPOSE: Neuroendocrine tumors (NETs) negatively impact patients' quality of life. Octreotide long-acting release (LAR) and lanreotide depot are somatostatin analogs (SSAs) approved to treat NETs. The study objective was to explore SSA treatment experiences and preferences of patients with NETs. METHODS: Qualitative interviews were conducted in US adults (≥ 21 years) with NETs who had ≥ 6 months' treatment with each SSA and transitioned from octreotide LAR to lanreotide depot within the previous year. Participants were asked open-ended questions about their experiences with octreotide LAR and lanreotide depot, treatment preferences, and SSA treatment attributes. RESULTS: Twenty participants (mean age: 58 years; 90% female; 85% white) completed interviews. The most common reasons for treatment transition were doctor recommendation (70%), treatment not working as expected (55%), and injection type preference (45%). Participants reported 34 unique favorable attributes of SSA treatment and 82 unique unfavorable attributes. Symptom control was the most frequently reported favorable attribute (associated with octreotide LAR by 60% of participants and lanreotide depot by 65%). Painful injection (65%) was most frequently cited unfavorable attribute for octreotide LAR and injection experience dependent on administrator (35%) for lanreotide depot. The three SSA treatment attributes rated as most important were side effects, symptom control, and ability to stabilize tumor. CONCLUSION: Our qualitative data provide valuable insight into the treatment attributes that patients with NETs consider important when making SSA treatment decisions. Factors related to injection administration, side effects, and symptom control are important to patients and should be included in patient-provider communications in clinical contexts.

Exploration of machine learning techniques to examine the journey to neuroendocrine tumor diagnosis with real-world data.

Aim: Machine learning reveals pathways to neuroendocrine tumor (NET) diagnosis. Patients & methods: Patients with NET and age-/gender-matched non-NET controls were retrospectively selected from MarketScan claims. Predictors (e.g., procedures, symptoms, conditions for which NET is misdiagnosed) were examined during a 5-year pre-period to understand presence of and time to NET diagnosis using conditional inference trees. Results: Among 3460 patients with NET, 70% had a prior misdiagnosis. 10,370 controls were included. Decision trees revealed combinations of factors associated with a high probability of being a patient with NET (e.g., abdominal pain, an endoscopic/biopsy procedure, vomiting) or longer times to diagnosis (e.g., asthma diagnosis with visits to >6 providers). Conclusion: Decision trees provided a unique examination of the journey to NET diagnosis.

Lay abstract We present the novel analytic approach of machine learning using real-world data to describe patient pathways to neuroendocrine tumor (NET) diagnosis. Due to the rarity and presentation of the disease, NET diagnosis is commonly inaccurate and delayed. We aimed to demonstrate the potential of analytics using conditional inference trees. Decision trees revealed specific combinations of characteristics associated with a high probability of being a patient with NET (e.g., abdominal pain, an endoscopic/biopsy procedure, vomiting) or longer times to diagnosis (e.g., asthma diagnosis with visits to >6 providers). Results from this study support prior literature and add advanced analyses that take initial steps toward developing tools aimed to help clinicians with early and accurate NET diagnosis. The methodology can be improved upon and translated to other diseases.

Epidemiological risk factors for adrenocortical carcinoma: A hospital-based case-control study.

Adrenocortical carcinoma (ACC) is a rare malignancy whose risk factors are unclear. We explored the association of ACC risk with exposure to selected environmental factors, with a focus on cigarette smoking. We conducted a hospital-based case-control study at The University of Texas MD Anderson Cancer Center. Cases (n = 432) patients with ACC treated at MD Anderson, and controls (n = 1,204) were healthy and genetically unrelated spouses of patients at MD Anderson who had cancers not associated with smoking. Information on the subjects' demographic features and selected risk factors was collected using a structured, validated questionnaire and medical records review. Unconditional logistic regression was used to calculate adjusted odds ratios (AORs) via the maximum-likelihood method. Cases had a younger mean (± standard deviation) age than did controls (47.0 ± 0.7 and 60.0 ± 0.3 years, respectively), and the majority of cases were female (60.6%) and non-Hispanic white (82.4%). We found a markedly increased risk of ACC among male cigarette smokers, with an AOR = 1.8 (95% confidence interval [CI] =1.2-2.9), but not among female smokers (AOR = 1.1, 95% CI = 0.7-1.6). Family history of cancer was associated with increased risk of ACC (AOR = 2.8, 95% CI 1.9-4.3) and in both men and women, whereas alcohol consumption was associated with reduced risk in men (AOR = 0.2, 95% CI = 0.1-0.3) but not women (AOR = 0.7, 95% CI = 0.5-1.1). Understanding these risk factors and their underlying mechanisms may help prevent ACC in susceptible individuals and eventually identify new therapeutic options for ACC.

Prognostic value of the neutrophil/lymphocyte ratio in enteropancreatic neuroendocrine tumors.

Accessible prognostic tools are needed to individualize treatment of neuroendocrine tumors (NETs). Data suggest neutrophil/lymphocyte ratios (NLRs) have prognostic value in some solid tumors, including NETs. In the randomized double-blind CLARINET study (NCT00353496; EudraCT 2005-004904-35), the somatostatin analog lanreotide autogel/depot increased progression-free survival (PFS) compared with placebo in patients with inoperable or metastatic intestinal and pancreatic NETs (grades 1-2, Ki-67 < 10%). The exploratory post-hoc analyses presented here evaluated the prognostic value of NLR in the CLARINET study cohort, in the context of and independently from treatment. Kaplan-Meier PFS plots were generated for patients with available NLR data, in subgroups based on NLR values, and 24-month survival rates were calculated. P values and hazard ratios for prognostic effects were generated using Cox models. 31216222 Baseline characteristics were balanced between lanreotide autogel/depot 120 mg (n = 100) and placebo (n = 101) arms. Irrespective of treatment, raw 24-month PFS rates were comparable across subgroups based on NLR tertiles [37.3% (low), 38.8% (middle), 38.8% (high); n = 67 per group] and NLR cutoff of 4 [38.1% (NLR ≤ 4; n = 176), 40.0% (NLR > 4; n = 25)]. Furthermore, NLRs were not prognostic in Cox models, irrespective of subgroups used. The therapeutic effect of lanreotide autogel/depot 120 mg was independent of NLRs (P > 0.1). These exploratory post-hoc analyses in patients with advanced intestinal and pancreatic NETs contrast with previous data suggesting NLR has prognostic potential in NETs. This may reflect the inclusion of patients with lower-grade tumors or use of higher NLR cutoff values in the current analysis.

Patterns of Care Among Real-World Patients with Metastatic Neuroendocrine Tumors.

BACKGROUND: Although recent pivotal trials (PROMID, CLARINET) have established somatostatin analogs (SSAs) as first-line agents for neuroendocrine tumors (NETs), their use in clinical practice is largely unknown. We aimed to understand real-world management and treatment of gastroenteropancreatic (GEP) NETs. MATERIALS AND METHODS: Patients with metastatic GEP-NETs treated with SSAs, lanreotide depot or octreotide long-acting release (LAR), between January 1, 2015, and December 31, 2015, were identified from a U.S. claims database supplemented with chart review for a subset of patients. Descriptive statistics summarized patients' demographics, clinical characteristics, treatment patterns, and healthcare resource use. Univariate and multivariate comparisons were made across SSA groups. RESULTS: Among 548 patients treated with an SSA for metastatic GEP-NET (lanreotide = 108; octreotide = 440), demographic and clinical characteristics were similar across groups, except more patients with pancreatic NETs were treated with lanreotide (38.7% vs. 6.3%, p < .01). More octreotide patients had a diagnosis of carcinoid syndrome compared with lanreotide patients (19.8% vs. 11.1%, p = .02). Approximately 1.1% of patients received lanreotide (>120 mg every 4 weeks [Q4W]) at a dose above label compared with 12.7% of octreotide patients (>30 mg Q4W; p < .01). At 1.5 years after SSA initiation, 85.7% (95% confidence interval, 74.3%-92.3%) were still on index SSA as reported by the physician. Variances between chart review and claims data were significant. CONCLUSION: SSAs were common in first-line systemic intervention, but dose escalations and dosing deviations outside of label were noted. Variances between claims and chart review warrant additional research to compare methodologies. With an increasing focus on value-based care in oncology, it is critical to understand the use of, and outcomes with, these agents in community practices. IMPLICATIONS FOR PRACTICE: The aim of this study was to enhance understanding of real-world management and treatment of metastatic neuroendocrine tumors (NETs), with particular focus on systemic therapy with a somatostatin analog (SSA). As per published guidelines, SSAs are common in first-line systemic intervention, but dose escalations and dosing deviations outside of the label are noted for symptom control. Nevertheless, oncologists must weigh the implications of the use of above-label dosing of SSAs to manage and treat patients with metastatic NET within a value-based care framework.

Effect of Lanreotide Depot/Autogel on Urinary 5-Hydroxyindoleacetic Acid and Plasma Chromogranin A Biomarkers in Nonfunctional Metastatic Enteropancreatic Neuroendocrine Tumors.

BACKGROUND: Urinary 5-hydroxyindoleacetic acid (5-HIAA) is an established biomarker in neuroendocrine tumors and carcinoid syndrome; however, its role in nonfunctional neuroendocrine tumors is not defined. We present post hoc data on urinary 5-HIAA and plasma chromogranin A (CgA) from the CLARINET study. METHODS: Patients with well- or moderately differentiated, nonfunctioning, locally advanced or metastatic enteropancreatic neuroendocrine tumors were randomized to deep subcutaneous lanreotide depot/autogel 120 mg or placebo once every 28 days for 96 weeks. Tumor response, evaluated centrally (RECIST 1.0), and progression-free survival (PFS) were assessed by treatment and biochemical response, defined as (a) baseline >upper limit of normal (ULN, 41.6 µmol per day 5-HIAA; 98.1 µg/L CgA) and (b) ≥50% decrease from baseline and to ≤ULN value on study. RESULTS: Forty-eight percent (82 of 171; lanreotide, n = 45; placebo, n = 37) and 66% (129 of 195; lanreotide, n = 65; placebo, n = 64) of randomized patients had 5-HIAA and CgA > ULN at baseline. Among patients with >ULN baseline values who did not progress after 96 weeks of treatment, significantly greater reductions in 5-HIAA and CgA were observed in lanreotide-treated versus placebo-treated patients throughout the study (all p < .05). PFS was significantly prolonged among 5-HIAA responders versus nonresponders (median not reached vs. 16.2 months, p < .0001; hazard ratio [HR] = 0.21, 95% confidence interval [CI], 0.09-0.48) and CgA responders versus nonresponders (median not reached vs. 16.2 months, p = .0070; HR = 0.30, 95% CI, 0.12-0.76), regardless of treatment arm. PFS was also significantly prolonged among lanreotide-treated 5-HIAA responders versus nonresponders (p = .0071) but was not significantly different among placebo-treated 5-HIAA responders versus nonresponders. There were no significant differences in PFS between lanreotide-treated CgA responders versus nonresponders or between placebo-treated CgA responders versus nonresponders. CONCLUSIONS: The 5-HIAA findings are noteworthy because they occurred in patients with nonfunctioning enteropancreatic neuroendocrine tumors. Monitoring 5-HIAA and CgA may be useful when treating patients with nonfunctional neuroendocrine tumors. IMPLICATIONS FOR PRACTICE: Current guidelines focus only on the monitoring of 5-hydroxyindoleacetic acid (5-HIAA) in the diagnosis and management of functional neuroendocrine tumors with carcinoid syndrome. The current post hoc analysis of patients with nonfunctional enteropancreatic neuroendocrine tumors in the CLARINET study demonstrated that measuring and following both 5-HIAA and chromogranin A as biomarkers of disease progression may be useful in the management of patients with nonfunctional neuroendocrine tumors.

Stereotactic body radiation therapy and immunotherapy.

Immunotherapy has revolutionized the treatment of various types of cancers in recent years. Since the US Food and Drug Administration approval of the anti-cytotoxic T-lymphocyte-associated antigen 4 agent ipilimumab for late-stage melanoma in 2011, results from multiple clinical trials have proven the benefit of immunotherapy in the treatment of other cancers. However, therapeutic resistance to immunotherapy often develops. This has led investigators to combine immunotherapy with stereotactic body radiation therapy (SBRT) in an attempt to improve outcomes. The benefit of the combination is believed to stem from stimulating and suppressing various immune pathways and is further aided by the abscopal effect, in which tumors respond to radiation therapy even in nonradiated metastatic sites. When combined with immunotherapy, radiation causes the tumor to act much like a vaccine by exposing the tumor antigens to activate the immune response. This article reviews the association between the immune system and cancer, as well as the additional systemic benefit that SBRT can have in patients with advanced-stage malignancies being treated with immunotherapy.

Molecular pathways and targeted therapy in cholangiocarcinoma.

Cholangiocarcinoma (CCA) encompasses a rare group of malignancies arising from epithelial cells lining the biliary tree that connects the liver and gallbladder to the small intestine. Most patients present with advanced incurable disease that has a poor prognosis, and standard treatment options remain limited. Effective nontoxic treatment options for advanced CCA are needed. Fibroblast growth factors (FGFs) and their fibroblast growth factor receptor (FGFR) pathways are crucial to cellular proliferation, cellular survival, and differentiation of many malignancies, but are especially relevant in CCA. The targeting of FGF/FGFR has become the most promising approach to treating patients with advanced/metastatic CCA. Here we review CCA, and discuss the promise of FGFR-directed therapy in advanced CCA.

BIOCHEMICAL RESPONSES IN SYMPTOMATIC AND ASYMPTOMATIC PATIENTS WITH NEUROENDOCRINE TUMORS: POOLED ANALYSIS OF 2 PHASE 3 TRIALS.

OBJECTIVE: Neuroendocrine tumors (NETs) are associated with elevated 5-hydroxyindoleacetic acid (5-HIAA) and chromogranin A (CgA) levels. This study aimed to analyze relationships between urinary 5-HIAA and plasma CgA levels and clinical outcomes. METHODS: Centrally assessed biomarker levels and correlations with progression-free survival (PFS) and carcinoid syndrome (CS) symptom control were evaluated in a pooled analysis of CLARINET (96-week randomized, double-blind, placebo-controlled) and ELECT (16-week randomized, double-blind, placebo-controlled, 32-week initial open label and ≥2 year long-term extension open label) studies of adults with NETs, with (ELECT) or without (CLARINET) CS at 97 institutions. Patients were treated with subcutaneous lanreotide depot 120 mg monthly. RESULTS: Of 319 pooled patients, 86% and 95% had baseline 5-HIAA and CgA data, respectively, with 47% and 74% having levels greater than the upper limit of normal (ULN). PFS was longer among patients who experienced a decrease in biomarker levels at week 12, with statistical significance reached in the CgA cohort (not reached vs. 14.4 months; P<.0001). A large proportion (87%) of patients without symptoms of CS in the CLARINET study had detectable levels of 5-HIAA (48% >ULN). In ELECT, patients with CS who received lanreotide and experienced a biochemical response (≥50% decrease from baseline) achieved greater symptom control. CONCLUSION: This pooled analysis of two randomized, placebo-controlled trials demonstrated that 5-HIAA and CgA are secreted as biochemical biomarkers in many patients with NETs, regardless of clinical syndromes. Significant biochemical response was associated with improved clinical outcomes, as measured by improved PFS or improved CS symptom control. ABBREVIATIONS: 5-HIAA = 5-hydroxyindoleacetic acid; CgA = chromogranin A; CI = confidence interval; CLARINET = Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors; CS = carcinoid syndrome; ELECT = Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment; HR = hazard ratio; ITT = intention-to-treat; NET = neuroendocrine tumor; PanNET = pancreatic NET; PFS = progression-free survival; PPI = proton pump inhibitor; SSA = somatostatin analogue; ULN = upper limit of normal.

Lanreotide in metastatic enteropancreatic neuroendocrine tumors.

BACKGROUND: Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited. METHODS: We conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety. RESULTS: Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval [CI], 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group). CONCLUSIONS: Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).

Estrogen Replacement Reduces Risk and Increases Survival Times of Women With Hepatocellular Carcinoma.

BACKGROUND & AIMS: Environmental factors have been identified that affect risk of hepatocellular carcinoma (HCC), but little is known about the effects of sex hormones on liver cancer development or outcome. The authors investigated whether menopause hormone therapy (MHT) affects risk, age at onset, or outcome of HCC. METHODS: We performed a case-control study of 234 female patients treated for HCC at a tertiary medical center and with 282 healthy women (controls) from January 1, 2004 through May 31, 2015. We collected detailed information on environmental exposures, ages of menarche and menopause, hysterectomies, and uses of birth control and MHT. We performed multivariable logistic and Cox regression analyses to determine the independent effects of factors associated with women on risk and clinical outcome in HCC. The primary outcomes were effect of MHT on HCC risk, the relationship between MHT with hepatitis virus infection on HCC development, and effect of MHT on age at HCC onset or survival after diagnosis of HCC. RESULTS: The estimated adjusted odds ratio (AOR) for HCC in women who ever used estrogen was 0.53 (95% confidence interval [CI], 0.32-0.88). This association was supported by the older age of HCC onset among estrogen users (mean, 64.5 ± 0.9 years) vs nonusers (mean 59.2 ± 1.1 years; P = .001) and the reduced risk of HCC among long-term users (more than 5 years) (AOR, 0.36; 95% CI, 0.20-0.63). Users of estrogen also had a reduced risk for hepatitis-associated HCC: AOR for users, 4.37 (95% CI, 1.67-11.44) vs AOR for nonusers, 17.60 (95% CI, 3.88-79.83). Estrogen use reduced risk of death from HCC (hazard ratio, 0.55; 95% CI, 0.40-0.77; P = .01). Median overall survival times were 33.5 months for estrogen users (95% CI, 25.7-41.3 months) and 24.1 months for nonusers (95% CI, 19.02-29.30 months; P = .008). CONCLUSION: In a case-control study of women with HCC vs female control subjects at a single center, we associated use of estrogen MHT with reduced risk of HCC and increased overall survival times of patients with HCC. Further studies are needed to determine the benefits of estrogen therapy for women and patients with HCC, and effects of tumor expression of estrogen receptor.

Recent advances in the management of gastroenteropancreatic neuroendocrine tumors: insights from the 2017 ASCO Gastrointestinal Cancers Symposium.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare malignancies that originate in the gastrointestinal system. GEP-NETs are typically indolent, but tumors known as "functional" secrete hormones that can lead to a complex of symptoms, including flushing, diarrhea, bronchospasm, and valvular heart disease. Management of patients with GEP-NETs requires a multidisciplinary approach, as treatment modalities include surgery, radiology, and pharmacotherapy. The available pharmacologic agents have increased in recently, and now include cytotoxic chemotherapies, somatostatin analogues, multitargeted tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and radioisotopic radiotherapies. The optimal sequencing of treatments is unknown. Advances in the management of GEP-NETs have been based on the results of recently completed clinical trials that have shown improvement in disease outcome and symptom management. The amount of positive data that has emerged from these studies is unprecedented in the GEP-NETs field. At the 2017 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, several abstracts provided subanalyses of previous trials and new data for emerging treatments. Management will likely evolve as these therapies are incorporated into clinical care.

Obesity Early in Adulthood Increases Risk but Does Not Affect Outcomes of Hepatocellular Carcinoma.

BACKGROUND & AIMS: Despite the significant association between obesity and several cancers, it has been difficult to establish an association between obesity and hepatocellular carcinoma (HCC). Patients with HCC often have ascites, making it a challenge to determine body mass index (BMI) accurately, and many factors contribute to the development of HCC. We performed a case-control study to investigate whether obesity early in adulthood affects risk, age of onset, or outcomes of patients with HCC. METHODS: We interviewed 622 patients newly diagnosed with HCC from January 2004 through December 2013, along with 660 healthy controls (frequency-matched by age and sex) to determine weights, heights, and body sizes (self-reported) at various ages before HCC development or enrollment as controls. Multivariable logistic and Cox regression analyses were performed to determine the independent effects of early obesity on risk for HCC and patient outcomes, respectively. BMI was calculated, and patients with a BMI of 30 kg/m(2) or greater were considered obese. RESULTS: Obesity in early adulthood (age, mid-20s to mid-40s) is a significant risk factor for HCC. The estimated odds ratios were 2.6 (95% confidence interval [CI], 1.4-4.4), 2.3 (95% CI, 1.2-4.4), and 3.6 (95% CI, 1.5-8.9) for the entire population, for men, and for women, respectively. Each unit increase in BMI at early adulthood was associated with a 3.89-month decrease in age at HCC diagnosis (P < .001). Moreover, there was a synergistic interaction between obesity and hepatitis virus infection. However, we found no effect of obesity on the overall survival of patients with HCC. CONCLUSIONS: Early adulthood obesity is associated with an increased risk of developing HCC at a young age in the absence of major HCC risk factors, with no effect on outcomes of patients with HCC.

Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study.

BACKGROUND: Treatment options for advanced, well-differentiated neuroendocrine tumours (NETs) remain scarce. Pazopanib is an orally bioavailable, small molecule, multitargeted kinase inhibitor that inhibits VEGF receptors 1, 2, and 3. We did a study of the efficacy of pazopanib with depot octreotide in patients with advanced NETs. METHODS: We did a parallel cohort study of patients with metastatic or locally advanced grade 1-2 carcinoid tumours or pancreatic NETs, by use of a single-group, two-stage design. Patients received pazopanib 800 mg orally once per day and octreotide at their preprotocol dosage. The primary endpoint was the proportion of patients achieving an objective response, as assessed by investigators, by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00454363, and was completed in March, 2014. FINDINGS: Between April 12, 2007, and July 2, 2009, we enrolled 52 patients, including 32 individuals with pancreatic NETs and 20 individuals with carcinoid tumours. Seven (21·9%, 95% CI 11·0-38·8) of 32 patients with pancreatic NETs achieved an objective response. We detected no responses in the first stage of the cohort with carcinoid tumours, and we terminated accrual at 20 patients. Toxic effects included one patient with grade 4 hypertriglyceridaemia and one with grade 4 thrombosis, with the most common grade three events being aminotransferase increases and neutropenia, each of which happened in 3 patients. In all 52 patients, the most frequently observed toxic effects were fatigue (39 [75%]), nausea (33 [63%]), diarrhoea (33 [63%]), and hypertension (28 [54%]). INTERPRETATION: Treatment with pazopanib is associated with tumour response for patients with pancreatic NETs, but not for carcinoid tumours; a randomised controlled phase 3 study to assess pazopanib in advanced pancreatic NETs is warranted. FUNDING: US National Cancer Institute of the National Institutes of Health.

A Comparison Between Appendiceal and Nonappendiceal Neuroendocrine Tumors in Children and Young Adults: A Single-institution Experience.

BACKGROUND: Pediatric neuroendocrine tumors (NETs) are rare tumors. The purpose of this study is to report the clinical characteristics and outcomes of pediatric patients treated for NET at a single institution. PROCEDURE: A retrospective record review. RESULTS: There were 33 evaluable patients with median age of 17.9 years (range, 9.9 to 21.9 y) and predominantly females (58%). There were 17 patients with well-differentiated appendiceal NET, whereas 16 were nonappendiceal. Most common nonappendiceal sites were unknown primary (N=6) and pancreas (N=4). Majority of tumors were low grade (N=24, 73%) and small (T1, N=22, 67%). Nonappendiceal tumors were more likely to be larger or high-grade tumors (5/16, 31%), or with metastasis. All appendiceal NET patients underwent curative surgery. All patients who experienced treatment failure had nonappendiceal NET, despite prior chemotherapy in 8 of 9 patients. The 5-year overall survival rates for patients with appendiceal and nonappendiceal NET were 100% and 66% (95% CI, 45%-95%; P=0.006); and 5-year relapse-free survival rate for patients with appendiceal and nonappendiceal NET were 100% and 41% (95% CI, 22%-75%; P=0.002). CONCLUSIONS: Well-differentiated appendiceal tumors were the most common pediatric NET and have an excellent prognosis. Better therapies are needed for patients with nonappendiceal NET.

New and Emerging Treatment Options for Gastroenteropancreatic Neuroendocrine Tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare, generally indolent neoplasms that can arise throughout the gastrointestinal system. Some GEP-NETs, known as functional, secrete hormones that can lead to a complex of symptoms. Classical carcinoid syndrome is associated with flushing, diarrhea, bronchospasm, and symptoms of valvular heart disease. GEP-NETs are classified according to the primary tumor site, functionality of the disease, and histology. Treatment is guided by the resectability of the tumor, the location and extent of metastases, and the presence of clinical symptoms. Typically, first-line treatment of patients with unresectable disease includes the use of somatostatin analogs, such as octreotide LAR depot or lanreotide depot/autogel, which was recently approved by the US Food and Drug Administration for treatment of GEP-NETs. Somatostatin analogs can improve the severe diarrhea/flushing episodes that may be associated with metastatic carcinoid tumors. For patients with pancreatic NETs, additional approved treatment options include the targeted agents everolimus and sunitinib, which have demonstrated antitumor activity. Chemotherapy may also have a selective role, particularly in pancreatic NETs. Localized approaches, including cytoreductive surgery, hepatic arterial embolization, and ablative therapies, may be used for palliative treatment in patients with liver metastases.

Impact of ¹8F-FDG PET/CT on the management of adrenocortical carcinoma: analysis of 106 patients.

PURPOSE: Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy. Limited data are available about on value of (18)F-FDG PET/CT in ACC. We evaluated the impact of PET/CT on the management of ACC. METHODS: We performed a retrospective review in patients with ACC who had undergone PET/CT. The impact of PET/CT on the management plan was evaluated by comparing the findings on PET/CT to the findings on contrast-enhanced CT. The sensitivity, specificity, and accuracy of each form of imaging were calculated. The correlations between PET/CT parameters, including maximum standardized uptake value (SUVmax), total lesion glycolysis, and decline in SUVmax after chemotherapy, and clinical outcome were evaluated. RESULTS: Included in the analysis were 106 patients with 180 PET/CT scans. Of the 106 patients, 7 underwent PET/CT only for initial staging, 84 underwent PET/CT only for restaging, and 15 underwent PET/CT for both initial staging and restaging. PET/CT changed the management plan in 1 of 22 patients (5%) at initial staging and 9 of 99 patients (9%) at restaging. In 5 of the patients in whom PET/CT changed the management plan, PET/CT showed response to chemotherapy but contrast-enhanced CT showed stable disease. Sensitivity, specificity, and accuracy were 100%, 100%, and 100% for PET/CT at initial staging; 92.6%, 100%, and 96.4% for CT at initial staging; 98.4%, 100%, and 99.5% for PET/CT at restaging; and 96.8%, 98.6%, and 98.0% for CT at restaging, respectively. No PET/CT parameters were associated with survival at either initial diagnosis or recurrence. CONCLUSION: PET/CT findings could substantially change the management plan in a small proportion of patients with ACC. Although lesion detection was similar between PET/CT and CT, PET/CT may be preferred for chemotherapeutic response assessment because it may predict response before anatomic changes are detected on CT.

A phase I study of imatinib, dacarbazine, and capecitabine in advanced endocrine cancers.

BACKGROUND: Patients with advanced endocrine cancers, such as adrenocortical carcinoma and medullary thyroid carcinoma, have few well-validated therapeutic options. Pre-clinical studies have suggested potential activity of imatinib in these tumors. We therefore sought to establish a safe, novel treatment regimen combining imatinib with cytotoxic chemotherapy for future study in endocrine cancers. METHODS: A standard 3 + 3 dose-escalation design was used with a 21-day cycle, including imatinib on days 1-21, dacarbazine on days 1-3, and capecitabine on days 1-14. RESULTS: Twenty patients were treated. The most frequent toxicities were edema and fatigue, with dose-limiting fatigue and dyspnea. The recommended phase II regimen is dacarbazine 250 mg/m2 daily on day 1-3, capecitabine 500 mg/m2 twice daily on days 1-14, and imatinib 300 mg daily on days 1-21 of a 21-day cycle. Interestingly, responses were seen in patients with adrenocortical carcinoma, with 1 of 6 patients experiencing a partial response and a second experiencing a minor response, with progression-free survival of 8.8 and 6.4 months, respectively. CONCLUSIONS: The regimen of imatinib, dacarbazine, and capecitabine is well-tolerated. It may have some activity in adrenocortical carcinoma, and further study of this combination or its components may be beneficial for this disease with limited treatment options. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00354523, registered July 18, 2006.