Stucky, Chee‐Chee

Objectives: We aimed to quantify the contributions of patient characteristics (PC), hospital structural characteristics (HC), and hospital operative volumes (HOV) to in-hospital mortality (IHM) after major surgery in the United States (US). Background: The volume-outcome relationship correlates higher HOV with decreased IHM. However, IHM after major surgery is multifactorial, and the relative contribution of PC, HC, and HOV to IHM after major surgery is unknown. Study Design: Patients undergoing major pancreatic, esophageal, lung, bladder, and rectal operations between 2006 and 2011 were identified from the Nationwide Inpatient Sample linked to the American Hospital Association survey. Multilevel logistic regression models were constructed using PC, HC, and HOV to calculate attributable variability in IHM for each. Results: Eighty thousand nine hundred sixty-nine patients across 1025 hospitals were included. Postoperative IHM ranged from 0.9% for rectal to 3.9% for esophageal surgery. Patient characteristics contributed most of the variability in IHM for esophageal (63%), pancreatic (62.9%), rectal (41.2%), and lung (44.4%) operations. HOV explained < 25% of variability for pancreatic, esophageal, lung, and rectal surgery. HC accounted for 16.9% and 17.4% of the variability in IHM for esophageal and rectal surgery. Unexplained variability in IHM was high in the lung (44.3%), bladder (39.3%), and rectal (33.7%) surgery subgroups. Conclusions: Despite recent policy focus on the volume-outcome relationship, HOV was not the most important contributor to IHM for the major organ surgeries studied. PC remains the largest identifiable contributor to hospital mortality. Quality improvement initiatives should emphasize patient optimization and structural improvements, in addition to investigating the yet unexplained sources contributing to IHM.

AbstractBackground and ObjectivesSerum tumor markers are widely used for diagnosis, prognosis, treatment response, and surveillance. Our study evaluated cancer embryonic antigen (CEA) in patients with appendiceal adenocarcinoma.MethodsThe National Cancer Database was reviewed (2004–2011) for patients with surgical treatment for appendiceal adenocarcinoma. Patients were stratified into two groups: normal and elevated CEA. Multivariable adjusted Cox proportional hazards regression analyses were used to determine the independent effect of CEA on survival.ResultsOur study consisted of 2867 patients, 54.0% having elevated CEA. Patients with elevated CEA were more likely to have Stage IV disease, be female, and African American; all p < 0.001. Three‐year overall survival (OS) was significantly higher with normal CEA (75.5% vs. 62.8%, p < 0.001). On multivariable analysis, elevated CEA was associated with worse survival (hazard ratio 1.49, 95% confidence interval 1.23–1.80). Patients with elevated CEA had improved 3‐year OS with neo‐adjuvant compared to adjuvant chemotherapy (p = 0.004), while those with normal CEA showed no difference.ConclusionsIn patients with surgically treated appendiceal adenocarcinoma, preoperative elevation in CEA independently predicts decreased 3‐year survival and correlates with improved OS with neo‐adjuvant therapy. CEA levels should be considered in clinical decision‐making regarding neo‐adjuvant therapy in patients with appendiceal adenocarcinoma.

Abstract Background Despite multiple randomized trials, the role of perioperative chemotherapy in colorectal cancer liver metastasis (CRLM) is still under debate. In this systematic review and network meta-analysis (NMA), we aim to evaluate the efficacy of perioperative systemic therapies for patients with CRLM. Methods We searched various databases for abstracts and full-text articles published from database inception through May 2021.We included randomized controlled trials (RCTs) comparing the addition of perioperative (post, pre, or both) systemic therapies to surgery alone in patients with CRLM. The outcomes were compared according to the chemotherapy regimen using a random effects model. Outcomes of interest included disease-free survival (DFS) and overall survival (OS). Results Seven RCTs with a total of 1504 patients with CRLM were included. Six studies included post-operative treatment and one evaluated perioperative (pre- and postoperative) therapy. Fluoropyrimidine-based chemotherapy was the most used systemic therapy. NMA showed benefit of adding perioperative therapy to surgery in terms of DFS (HR 0.73, 95% CI 0.63 to 0.84). However, these findings did not translate into a statistically significant OS benefit (HR 0.88, 95% CI 0.74 to 1.05). NMA did not show any advantage of one regimen over another including oxaliplatin or irinotecan. Conclusions This systematic review and NMA of 7 RCTs found that the addition of perioperative systemic treatment for resectable CRLM could improve disease-free survival but not overall survival. Based on the findings, addition of perioperative treatment in resectable CRLM should be individualized weighing the risks and benefits.

BACKGROUND: Current literature has identified textbook outcome (TO) as a quality metric after cancer surgery. We studied whether TO after pancreatic resection has a stronger association with long-term survival than individual hospital case volume. STUDY DESIGN: Patients undergoing surgery for pancreatic adenocarcinoma from 2010 to 2015 were identified from the National Cancer Database. Hospitals were stratified by volume (low less than 6, medium 6 to 19, and high 20 cases or more per year), and overall survival data were abstracted. We defined TO as adequate lymph node count, negative margins, length of stay less than the 75th percentile, appropriate systemic therapy, timely systemic therapy, and without a mortality event or readmission within 30 days. The association of TO and case volume was assessed using a multivariable Cox regression model for survival. RESULTS: Overall, 7270 patients underwent surgery, with 30.7%, 48.7%, and 20.6% performed at low-, medium-, and high-volume hospitals, respectively. Patients treated at low-volume hospitals were more likely to be Black, be uninsured or on Medicaid, have higher Charlson comorbidity scores, and be less likely to achieve TO (23.4% TO achievement vs 37.5% achievement at high-volume hospitals). However, high hospital volume was no longer associated with overall survival once TO was added to the multivariable model stratified by volume status. Achievement of TO corresponded to a 31% decrease in mortality (hazard ratio 0.69; p < 0.001), independent of hospital volume. CONCLUSIONS: Improved long-term survival after pancreatic resection was associated with TO rather than high hospital volume. Quality improvement efforts focused on TO criteria have the potential to improve outcomes irrespective of case volume.

4128 Background: Pancreatic cancer (PC) is a challenging target for immunotherapy due to suppressive immune-microenvironment. Neoadjuvant chemoradiation (CRT) can increase the presence of tumor-infiltrating lymphocytes (TILs). We hypothesized that the combination of CRT and pembrolizumab can lead to further increase in TILs and their activation. Methods: Patients with resectable or borderline resectable PC were randomized 2:1 to the investigational treatment (Arm A) of pembrolizumab 200mg IV every 3 weeks concurrently with CRT (capecitabine 825 mg/m2 orally twice daily and radiation 50.4 Gy in 28 fractions over 28 days) or CRT only (Arm B) prior to surgical resection. The primary endpoints were treatment safety and density of TILs with the objective to estimate differences in TILs density between the investigational and the control arms. Immune cell densities were assessed using multiplexed immunofluorescence on resected tumor specimens. Densities of CD8+TILs were measured in 2-10 representative regions containing residual cancer per case and then averaged to obtain overall densities. The study was amended after enrollment of 37 patients to allow FOLFIRINOX prior to CRT, given changes in standard of care. Results: 37 patients were enrolled (24 Arm A and 13 Arm B). Post-neoadjuvant therapy, 13 patients had unresectable disease (9 on A and 4 on B), and 24 patients underwent surgery and were evaluable for the TILs primary endpoint (17 arm A and 7 arm B). The mean difference (A-B) in CD8+ cell density was 36 cells/mm2 (95% CI -85 to 157, stdev 130) (p 0.48). Additional analysis did not show significant differences in CD8+Ki67+ (activated cytotoxic T-cells), CD4+, and CD4+FOXP3+ (regulatory T cells), M1- or M2-like polarized macrophages, or granulocytes. The median recurrence free survival (RFS) was 18.2 months on Arm A and 14.1 on Arm B (p 0.41) and Overall Survival was 27.8 months on Arm A and 24.3 on Arm B (p 0.68) with a median follow up of 2.2 years. The most common grade 3 treatment-related toxicities were lymphopenia reported in 29% on Arm A and 31% on Arm B followed by diarrhea in 8% on Arm A attributed to CRT. There was only 1 DLT of increased ALT attributed to the combination on Arm A that resolved after holding the treatment and receiving steroids. There were no major surgical complications reported within 30 days post-surgery. Conclusions: The combination of CRT and pembrolizumab is safe. Preliminary analysis shows that the addition of pembrolizumab to CRT has minimal effects on several immune cell populations including CD8+TILs in the PC microenvironment. The study is currently enrolling 25 more patients who receive FOLFIRINOX prior to randomization to CRT+/- Pembrolizumab, which will help to dissect the immune modulatory effect of chemotherapy followed by CRT. Clinical trial information: NCT02305186.

Abstract Background Appendiceal cancers represent a diverse group of malignancies with varying biological behavior. The significance of lymph node metastases in relation to long‐term survival and chemotherapy response is poorly defined. Methods The National Cancer Database was queried to find patients diagnosed with appendiceal cancer from 1998 to 2012. Kaplan–Meier curves and multivariable Cox regression analyses were used to study the association between lymph node status and overall survival. Stage IV patients were excluded. Results The rate of nodal positivity of the 9841 patients with known node status was: signet ring 47.4%, carcinoid 42.3%, nonmucinous adenocarcinoma 28.8%, goblet cell 21.9%, and mucinous adenocarcinoma 20.4%. Node‐positive patients had worse long‐term survival for all subtypes with the exception of carcinoid tumors ( p < 0.001). The strongest association was for signet cell and goblet cell. Adjuvant chemotherapy in node‐positive patients improved survival for mucinous, nonmucinous, and signet ring cell histology ( p < 0.01), but not for goblet cell. Conclusions Nodal involvement in patients with appendiceal cancer varies in incidence, association with adverse survival, and response to systemic therapy. Individualized treatment algorithms for the management of the subtypes of appendiceal cancer are needed.

355 Background: In this study, we sought to determine the prognostic factors impacting survival of patients with NELM who underwent LT at Mayo Clinic. Methods: We performed a three-site retrospective analysis of patients with unresectable NELM treated with LT from 1990 -2017. Cases were identified from clinical databases at Mayo Clinic. Data on demographics, timing of diagnosis and transplant, extent of liver involvement, and tumor grade, were extracted. Extent of liver involvement was calculated using previously validated standardized volumetry with high defined as > 25% increase in the weight of the extracted liver at the time of the transplant as compared to the standard liver volume. Survival was calculated using the Kaplan–Meier method. Results: We identified 37 patients. Median age at LT was 47 (range 17.0-64.0), male: female (73% vs. 27%, respectively). Primary tumor site was in the pancreas in 51.3% and in the small bowels in 43.2%; 78.4% had NELM at presentation. While primary tumor resection was done at the time of LT in 5 (13.9%) cases, most patients (80.6%) had ˃6-months interval between primary tumor resection and LT surgery. Prior to LT, 25 (74.3%) patients received somatostatin analogues and 18 (61.3%) had liver-directed therapy. Median time from diagnosis to transplant was 33.6 months (0-246). High extent of liver involvement was identified in 12 patients (33.3%). Disease-Free Survival (DFS) at 3, 5, and 10 years was 56.8%, 43.1%, and 22.4% respectively. Overall-survival (OS) at 3, 5, and 10 years was 86.9%, 79.6%, and 52.6% respectively. High extent of liver involvement at the time of transplantation was associated with inferior DFS and OS and patients˃45 years-old at the time of transplantation had worse DFS. Patients whose disease met the OPTN (Organ Procurement and Transplantation Network) criteria for NELM transplantation had significantly better DFS and OS with median 10-year OS of 80.7 % vs. 17%. Conclusions: LT is a reasonable therapeutic option for selected patients with unresectable NELM with 10-year OS of 52.6%. High extent of liver involvement was associated with worse long-term outcomes while meeting OPTN criteria resulted in best outcomes.