Halfdanarson, Thorvardur R

630 Background: Neuroendocrine tumors (NET) are heterogeneous in terms of prognosis based on location, grade, and stage. In this study we report causes of deaths (COD) in patients with NET. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) Program to query data of NET patients diagnosed between 2000 and 2016 and report COD following NET diagnosis. Results: We reviewed 94,399 NET cases of which 38,692 died during the follow-up period. The highest number of deaths (5,721) occurred within less than a year following grade 3 (G3) NET diagnosis while most deaths in grade 1/2 (G1/G2) cases occurred within 1-5 years of diagnosis (1,889 and 987, respectively). During the first year of diagnosis, most deaths were from NETs (73%), followed by other cancers (11.2%) and cardiac diseases (CD) (4.6%). As time passed, NET deaths decreased to be responsible for 24.3% of deaths after > 10 years of diagnosis, while other cancers (14%) and CD (19.7%) became more common. When dividing NET cases by grade, NETs were responsible for 42.8%, 63.4%, and 81.2% of deaths in G1, G2, and G3, respectively, while other cancers were responsible for 16.2%, 11.8%, and 7.2% of deaths, respectively and CDs were responsible for 12.3%, 7.2%, and 3.2% of deaths, respectively. For G1 localized NET: non-NET cancers (22.2%) was the most common COD followed by NET (19.7 %) and CD (16.8%). For G2 localized NET, NET was COD in 31.1% of cases followed by non-NET cancers (22.4%) and CD (13.8%). In metastatic disease, NET was the most common COD regardless of grade. Conclusions: In G1 and G2 localized NET, deaths were mostly secondary to non-NET causes. Therefore, counseling patients regarding survivorship with cancer-screening and focusing on prevention from non-cancer deaths is important. On the other hand, NET is responsible for most deaths in metastatic NET regardless of grade. Further advances in systemic therapies are needed to improve the outcomes of advanced disease.

Abstract This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the surgical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The group reviewed a series of questions of specific interest to surgeons taking care of patients with pancreatic neuroendocrine tumors, and for each, the available literature was reviewed. What follows are these reviews for each question followed by recommendations of the panel.

Background: Adherence to surveillance guidelines in resected colon cancer has significant implications for patient morbidity, cost of care, and healthcare utilization. This study measured the underuse and overuse of imaging for staging and surveillance in stage I–II colon cancer. Methods: The OptumLabs database was queried for administrative claims data on adult patients with stage I–II colon cancer who underwent surgery alone in 2008 through 2016. Use of PET and CT imaging was evaluated during both initial staging (n=6,921) and surveillance for patients with at least 1 year of follow-up (n=5,466). “High use” was defined as >2 CT abdominal/pelvic (CT A/P) or PET scans per year during surveillance. Results: Overall, 27% of patients with stage I–II colon cancer did not have a staging CT A/P or PET scan and 95% did not have a CT chest scan. However, rates of staging CT A/P and CT chest scans increased from 62.0% (2008) to 74.8% (2016) and from 2.3% (2008) to 7.1% (2016), respectively. Staging PET use was overall very low (5.2%). During surveillance, approximately 30% of patients received a CT A/P or PET and 5% received a CT chest scan within the first year after surgery. Of patients who had surveillance CT A/P or PET scans, the proportion receiving >2 scans within the first year (high use) declined from 32.4% (2008) to 9.6% (2016) (P = .01). Conclusions: Although PET use remains appropriately low, many patients with stage I–II colon cancer do not receive appropriate staging and surveillance CT chest scans. Among those who do receive these scans during surveillance, high use has declined significantly over time.

Abstract Introduction: The role of surveillance imaging in diffuse large B-cell lymphoma (DLBCL) after treatment with curative intent is debated. In 2013, the American Society of Hematology (ASH) Choosing Wisely® campaign (Hicks LK, et al. Blood 2013) released a recommendation to "limit surveillance CT scans in asymptomatic patients following curative-intent treatment for aggressive lymphoma." This was based on previous studies demonstrating a lack of survival benefit as well as a significant impact on the patient in terms of cost, anxiety, incidental findings and radiation exposure. Similar findings have been described regarding the use of PET imaging, especially in low risk patients. We aimed to study the changes in practice patterns of surveillance imaging for DLBCL survivors treated with curative intent before and after the publication of the ASH Choosing Wisely® campaign. Methods: Administrative claims data from a large U.S commercial insurance database (OptumLabs Data Warehouse) were used to retrospectively identify adult patients with an incident diagnosis of DLBCL between 2008 and 2016 and at least one year of follow-up. We excluded those who did not receive treatment with curative intent: RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) x 6 cycles or RCHOP x 3-5 cycles plus radiation. Patients were also excluded if they had a co-existing or second cancer, or if they received any chemotherapy/radiation during their surveillance period, as to exclude anyone with a recurrence of their lymphoma. The surveillance period started 90 days after the last chemotherapy or radiation and continued for the duration of follow-up. Surveillance imaging was defined as any PET, PET-CT, CT chest, CT abdomen, and/or CT pelvis. To examine trends over time, three time periods were defined: 2008-2010, 2011-2013 and 2014-2016. The Cochran Armitage test was used to test the trend hypothesis. Results: A total of 1,472 patients were included. Cohort characteristics by time period are described in Table 1. Surveillance imaging frequency decreased from 84% in Year 1 of surveillance to 43% in Year 5 (Figure 1). Overall, surveillance imaging during the first 3 surveillance years significantly decreased over the three time periods (Figure 2) (P<0.01 for Years 1 and 2, P=0.04 for Year 3). Imaging surveillance for the first two years of surveillance did not significantly decrease from 2008-2010 to 2011-2013 (P>0.05), but significantly decreased from 2011-2013 to 2014-2016 (P<0.01). Of the groups that received imaging surveillance during year 1, the median number of scans during the first year was 2 (inter-quartile range, 1-2) and did not significantly change over time. In addition, PET/PET-CT surveillance decreased from 49% in Year 1 to <10% in Year 5. PET/PET-CT also decreased over the three time periods, from 62% (2008-2010) to 48% (2011-2013) to 43% (2014-2016) during the first year of surveillance and 40% to 31% to 25% during the second year. Younger age (<65 years versus ≥65 years) was associated with higher imaging utilization (86% versus 81%, respectively), and specifically PET/PET-CT utilization (55% versus 43%, respectively), during the first year of surveillance. However, race (white versus non-white) did not significantly affect imaging (85% versus 83%) or PET utilization (50% versus 47%) during the first year of surveillance. Conclusions: Our study demonstrates that the rate of surveillance CT and PET imaging in DLBCL patients treated with curative intent decreased significantly in the years after the publication of the ASH Choosing Wisely® campaign. However, over half of the DLBCL patients diagnosed in 2014-2016 continued to undergo surveillance imaging, indicating either incomplete guideline dissemination or ongoing debate regarding optimal surveillance practice. Future studies are necessary to determine whether such a decline in surveillance imaging is sustained and to examine factors (patient, provider, and payer) associated with surveillance imaging in DLBCL. Disclosures No relevant conflicts of interest to declare.

Neuroendocrine neoplasms (NENs) are malignancies with rare reports of central nervous system development. A 34-year-old woman was found to have a primary NEN of the brain, and she had recurrence with identical histology 10 years later. Extracranial NENs were excluded. She had routine surveillance for the first 5 years with MRIs and positron emission tomography/CTs after the initial presentation which was treated with radiation followed by cisplatin and etoposide. This case highlights the difference in primary NENs versus NEN metastases to the brain, and that longer periods of surveillance are likely required for primary NENs. This is important because the prognosis between primary NENs and metastatic NENs to the brain are vastly different and should not be treated as equal diseases. The patient eventually died of her recurrence secondary to complications of a ventriculoperitoneal shunt placed for treatment of hydrocephalus from the disease.

Abstract 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.

6592 Background: Sex, age and ECOG performance status (PS) may affect immune response and the efficacy of cancer immunotherapy with immune checkpoint inhibitors (ICI). We did a meta-analysis to assess the potential sex, age and ECOG PS differences of immunotherapy efficacy in advanced cancer. Methods: PubMed was searched up to January 15, 2019 for randomized controlled trials (RCT) comparing overall survival (OS) in patients with advanced cancer treated with ICI immunotherapy vs control therapy (without ICI). For sex difference analysis, pooled hazard ratio (HR) of death for men and women was calculated separately, and the heterogeneity between the two estimates was assessed using an interaction test by pooling study-specific interaction HR. Age ( < 65 vs ≥65) and ECOG PS (0 vs ≥1) difference was analyzed similarly. Subgroup analysis by cancer type and line of therapy (frontline vs subsequent) was explored. All analyses were done in Comprehensive Meta Analysis (v2) with random effects models. Results: Thirty phase 2/3 RCTs involving 17,728 patients were included. An OS benefit of immunotherapy was found for both men (HR 0.75, 95% confidence interval [CI] 0.69-0.81, P < 0.01) and women (HR 0.79, 95% CI 0.69-0.90, P < 0.01); for both younger ( < 65; HR 0.75, 95% CI 0.68-0.83, P < 0.01) and older (≥65; HR 0.76, 95% CI 0.69-0.83, P < 0.01) patients; and for both ECOG PS 0 (HR 0.78, 95% CI 0.69-0.89, P < 0.01) and PS ≥1 (HR 0.77, 95% CI 0.71-0.84, P < 0.01) patients. No significant difference of relative benefit from immunotherapy over control therapy was found in patients with different sex ( P = 0.283), age ( P = 0.906) or ECOG PS ( P = 0.783). In melanoma RCTs, compared with women (HR 0.77, 95% CI 0.64-0.94, P < 0.01), men (HR 0.56, 95% CI 0.42-0.76, P < 0.01) had more OS benefit from immunotherapy ( P = 0.037). No significant difference was found in other subgroup analyses by cancer types or line of therapy. Conclusions: Overall we found no evidence of association of sex, age, or ECOG PS with cancer immunotherapy efficacy. However, in melanoma, men might benefit more from immunotherapy than women.

e15799 Background: Lymphocyte to monocyte ratio (LMR) has been described as a prognostic factor in many solid tumors including colorectal adenocarcinoma. LMR has not been investigated as a prognostic factor in small bowel cancers. In this study, we aimed to evaluate prognostic factors in resected small bowel adenocarcinoma including LMR. Methods: Two hundred forty-one patients who underwent resection for stage I-III small bowel adenocarcinoma were retrospectively identified utilizing the pathology database at a single tertiary referral institution from 1994 to 2015. All patients had complete follow up data and were included in the survival analysis. One hundred sixty-nine patients had preoperative peripheral blood counts available for analysis. Plot of martingale residuals against LMR were used to establish best cutoff points for LMR. A training set for LMR included consecutively identified patients from 2006 to 2015, and a validation cohort including patients identified from 1994 to 2005 was used. Overall survival was performed utilizing Kaplan-Meier method, and Wilcoxon tests were used for statistical comparisons. Cox proportional hazards were performed and all tests were two sided. P value of < 0.05 was considered significant. Results: Median overall survival for the entire group was 54.5 months (95% CI: 37.2-81.2 months) with 5- and 10-year overall survival of 48% and 35%. The training set for LMR included 81 patients, and the validation set included 88 patients. The cutoff of 1.56 was chosen based on most significant p value (p = 0.002). When combined, the overall area under the curve (AUC) for LMR was 0.63, p < 0.01, (specificity 37.3%, sensitivity 90.1%, positive predictive value 33.1%, and negative predictive value 92.2%). There were 126 patients with LMR > 1.56 and 43 patients with LMR < 1.56 in the entire cohort. In multivariate analysis, LMR under 1.56 was a negative prognostic factor, HR = 2.20 (95% CI: 1.27-3.84, p < 0.01). In addition to LMR, age > 60 years and advanced T stage were independently negative predictors of overall survival in all patients. Conclusions: Lymphocyte-to-monocyte ratio < 1.56 is a validated negative prognostic factor in resected small bowel adenocarcinoma.

e15688 Background: PNETs are marked by histological heterogeneity and variable clinical outcomes. Other than Ki67 index, reliable circulating or tissue biomarkers for prognosis do not exist. Methods: PubMed was searched through 01/31/2017. Inclusion criteria were: 1) prospective/retrospective cohort with defined source population, boundary dates, and justifications for exclusions; 2) assay of primary tumors; 3) clear descriptions of methods including techniques and controls; 4) use of multivariate proportional hazards modeling adjusted for prognostic factors including but not limited to stage or grade; and 5) reporting adjusted hazard ratios (HR) with 95 % confidence intervals and P values. Studies with < 50 % PNETs were excluded. PNET-specific data was summarized in the table. Results: A total of 2958 manuscripts were identified and 462 manuscripts were reviewed. Only 23 multivariate studies met all inclusion criteria. These altogether analyzed 24 unique targets and 14 were associated with survival. Conclusions: This meta-analysis identified 14 markers associated with survival of PNET patients. Future studies should adhere to the REMARK criteria and incorporate the 2017 WHO grading system for multivariate analysis. 1. I-immunohistochemistry, F-fluorescence in situ hybridization, E-enzyme linked immunosorbent assay, M- methylation specific PCR, P-polymerase chain reaction; 2. O-overall survival, F-disease free survival, S-disease specific survival, P- progression free survival.[Table: see text]