Defining Volume Targets for Regionalization of Pancreaticoduodenectomy, Esophagectomy, and Major Lung Resection Centers to Improve Oncologic and Surgical Outcomes.

BACKGROUND: Performance of complex cancer surgeries at high-volume (HV) centers has been shown to reduce operative mortality. However, the case volume threshold that should be used to define HV centers is unknown. In this study, we determined thresholds to define HV pancreaticoduodenectomy, esophagectomy, and major lung resection centers based on clinical parameters. Then, we assessed the association of hospital volume with oncologic outcomes and overall survival. METHODS: We identified adult NCDB patients undergoing pancreaticoduodenectomy, esophagectomy, and major lung resections between 2004 and 2015. Multivariable models with restricted cubic splines were built to predict 5-year overall survival for each surgery group according to average yearly case volume, adjusting for demographic and clinicopathologic factors. The change point procedure was then used to identify volume cut-points for each surgery type. RESULTS: We identified the following thresholds to define HV status: 25 cases/year for pancreaticoduodenectomy; 18 cases/year for esophagectomy; and 54 cases/year for major lung resections. For all surgery types, treatment at a HV center was associated with an increased likelihood of R0 resection and adequate lymph node evaluation. HV centers had significantly decreased 30- and 90-day, postoperative mortality after adjusting for age, sex, race, comorbidities, histology, and stage. An overall survival benefit also was observed for patients undergoing resections at HV centers. CONCLUSIONS: Using novel methodology, our study identified volume thresholds for HV pancreaticoduodenectomy, esophagectomy, and major lung resection centers that were associated with improved oncologic outcomes and overall survival. These definitions of HV centers should be considered when evaluating regionalization of complex cancer care.

Intensifying supportive care is associated with improved survival in gastric cancer patients with malignant ascites.

BACKGROUND: Gastric cancer patients with malignant ascites often have poor functional status and malnutrition that preclude receipt of systemic therapies. Thus, these patients have a very poor prognosis. Beginning in 2019, our multidisciplinary gastric cancer disease-oriented team implemented a more aggressive supportive care plan for gastric cancer patients with malignant ascites. The initiative included measures such as supplemental enteral nutrition, ascites drainage, and initiation of chemotherapy on an inpatient basis. We compared outcomes for gastric cancer patients who presented with synchronous malignant ascites treated before and after the implementation of the care plan. METHODS: We performed a retrospective review of our institutional database to identify patients diagnosed with gastric adenocarcinoma and synchronous malignant ascites between 2010 and 2022. We compared overall survival (OS) between patients diagnosed from 2010 to 2018, which will be referred to as the historical control era and patients diagnosed from 2019 to 2022, which will be called the aggressive supportive care era. RESULTS: Fifty-four patients were included in our analysis; 31 patients were treated in the historical control time frame, and 23 patients were treated during the aggressive supportive care era. Demographic, clinical, and pathologic characteristics were similar between groups. 3% of historical controls received supplemental tube feeds at diagnosis as compared to 30% of the aggressive supportive care cohort (p < 0.01). 3% of historical controls received their first cycle of chemotherapy in the inpatient setting versus 39% of patients treated during the aggressive supportive care era (p < 0.01). The median number of chemotherapy cycles received was 5 among historical controls and 9.5 among aggressive supportive care era patients (p = 0.02). There was no difference in the number of days spent as an inpatient between the two groups. The median OS for historical control patients was 5.4 months as compared with 10.4 months for patients treated during aggressive supportive care era (p = 0.04). CONCLUSIONS: Gastric cancer patients with synchronous malignant ascites treated during a timeframe when our multidisciplinary team implemented more aggressive supportive care measures had improved OS as compared with historic controls. Our results suggest that aggressive supportive measures for these patients with highly challenging clinical issues and poor prognosis can prolong survival. Specifically, initiation of chemotherapy in the inpatient setting and supplemental nutrition should be considered for patients at high risk for treatment intolerance.

Serum Interleukin 6 Level is Associated With Overall Survival and Treatment Response in Gastric and Gastroesophageal Junction Cancer.

OBJECTIVE: To identify novel prognostic and predictive biomarkers for gastric and gastroesophageal junction (G+GEJ) adenocarcinoma. BACKGROUND: There are few biomarkers to guide treatment for G+GEJ. The systemic inflammatory response of G+GEJ patients is associated with survival. In this study, we evaluated the relationship of circulating serum cytokine levels with overall survival (OS) and pathologic tumor regression grade (TRG) in G+GEJ patients. PATIENTS AND METHODS: We queried the UT Southwestern gastric cancer biobank to identify consecutive patients diagnosed with G+GEJ from 2016 to 2022; these patients had pretreatment serum collected at diagnosis. For patients who received neoadjuvant therapy, an additional serum sample was collected immediately before surgical resection. An unbiased screen of 17 cytokines was measured in a discovery cohort. A multivariable Cox proportional hazards model was used to assess the association of cytokine concentration with OS. Findings were validated in additional patients. In patients who received neoadjuvant therapy, we assessed whether the change in interleukin 6 (IL-6) after therapy was associated with TRG. RESULTS: Sixty-seven patients were included in the discovery cohort, and IL-6 was the only pretreatment cytokine associated with OS; this was validated in 134 other patients (hazard ratio: 1.012 per 1 pg/mL increase, 95% CI: 1.006-1.019, P = 0.0002). Patients in the top tercile of IL-6 level had worse median OS (10.6 months) compared with patients in the intermediate (17.4 months) and bottom tercile (35.8 months, P < 0.0001). Among patients who underwent neoadjuvant therapy (n = 50), an unchanged or decrease in IL-6 level from pretreatment to posttreatment, had a sensitivity and specificity of 80% for predicting complete or near-complete pathologic tumor regression (TRG 0-1). CONCLUSIONS: Pretreatment serum level of IL-6 is a promising prognostic biomarker for G+GEJ patients. Comparing pre and post-neoadjuvant IL-6 levels may predict pathologic response to neoadjuvant therapy.

Lenvatinib inhibits the growth of gastric cancer patient-derived xenografts generated from a heterogeneous population.

BACKGROUND: Lenvatinib is a multitargeted tyrosine kinase inhibitor that is being tested in combination with immune checkpoint inhibitors to treat advanced gastric cancer; however, little data exists regarding the efficacy of lenvatinib monotherapy. Patient-derived xenografts (PDX) are established by engrafting human tumors into immunodeficient mice. The generation of PDXs may be hampered by growth of lymphomas. In this study, we compared the use of mice with different degrees of immunodeficiency to establish PDXs from a diverse cohort of Western gastric cancer patients. We then tested the efficacy of lenvatinib in this system. METHODS: PDXs were established by implanting gastric cancer tissue into NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) or Foxn1nu (nude) mice. Tumors from multiple passages from each PDX line were compared histologically and transcriptomically. PDX-bearing mice were randomized to receive the drug delivery vehicle or lenvatinib. After 21 days, the percent tumor volume change (%Δvtumor) was calculated. RESULTS: 23 PDX models were established from Black, non-Hispanic White, Hispanic, and Asian gastric cancer patients. The engraftment rate was 17% (23/139). Tumors implanted into NSG (16%; 18/115) and nude (21%; 5/24) mice had a similar engraftment rate. The rate of lymphoma formation in nude mice (0%; 0/24) was lower than in NSG mice (20%; 23/115; p < 0.05). PDXs derived using both strains maintained histologic and gene expression profiles across passages. Lenvatinib treatment (mean %Δvtumor: -33%) significantly reduced tumor growth as compared to vehicle treatment (mean %Δvtumor: 190%; p < 0.0001). CONCLUSIONS: Nude mice are a superior platform than NSG mice for generating PDXs from gastric cancer patients. Lenvatinib showed promising antitumor activity in PDXs established from a diverse Western patient population and warrants further investigation in gastric cancer.

Trends and Disparities in Treatment Utilization for Early-Stage Hepatocellular Carcinoma in the Veteran Population.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) has substantially increased over the last two decades within the Veteran Affairs Health System (VAHS). This study aims to describe the temporal trend of early-stage HCC (ES-HCC) treatment in the VAHS and identify patient/hospital factors associated with treatment disparities. PATIENTS AND METHODS: VA Corporate Data Warehouse was used to identify patients diagnosed with ES-HCC (stages I/II) from 2001 to 2015. Initial course of therapy was categorized as curative treatment (CT), noncurative treatment (NCT), or no treatment (NT). Univariate logistic regression and stepwise multivariate logistic regression models were used to analyze factors associated with receipt of treatment (CT/NCT) versus NT and receipt of CT versus NCT. RESULTS: Our study included 9504 patients (15% CT, 51% NCT, and 34% NT). During the study period, the rate of overall treatment increased, while the rate of CT decreased (p < 0.001). Stage II, age > 65 years, presence of non-alcoholic fatty liver disease (NAFLD), Child-Pugh C, higher Model for End-Stage Liver Disease (MELD) score, platelets < 100,000/mm3, low hospital complexity score, and Southwest location were significantly associated with higher rates of NT (all p < 0.05). Factors significantly associated with decreased utilization of CT included Hispanic race, lower hospital complexity score, and treatment in the Midwest, West, or Southeast regions (all p < 0.05). CONCLUSIONS: There is a significant trend toward increased overall treatment utilization with decreased use of curative-intent approaches for ES-HCC in the national veteran population, and significant hospital and regional disparities exist. Further characterization and investigation of these factors may facilitate implementation of interventions to improve treatment utilization for the veteran population with HCC.

Nativity Status is an Important Social Determinant of Health for Hispanic Patients with Gastric Cancer in Texas.

BACKGROUND: The U.S. foreign-born population is rapidly increasing, and cancer incidence/mortality rates have been shown to differ by nativity status. Our study aimed to characterize differences in gastric cancer presentation and survival among Hispanic patients in Texas by nativity status. METHODS: We conducted a retrospective review of the Texas Cancer Registry to identify Hispanic patients diagnosed with gastric adenocarcinoma between 2004 and 2017. Existing indices applied to 2010 census tract-level data were utilized to measure neighborhood socioeconomic status (nSES) and Hispanic enclaves. Nativity status was imputed for patients with missing data. Multivariable Cox proportional hazard models were fit for overall survival adjusted for age, insurance status, diagnosis year, tumor location, stage, grade, reporting source, nativity status, nSES, and Hispanic enclave. RESULTS: Our study cohort consisted of 6186 patients and 39% were foreign-born. A greater proportion of foreign-born patients were diagnosed at < 45 years old (16% vs. 11%, p < 0.0001) and had metastatic disease at presentation (47% vs. 34%, p < 0.0001). Foreign-born patients were more often uninsured, in the lowest nSES quintile, and the highest (most ethnically distinct) quintile for Hispanic enclave. Stage-specific overall survival was significantly higher among foreign-born patients. In our multivariate model, foreign-born Hispanic patients had improved survival versus US-born (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.82-0.99). CONCLUSIONS: The clinical presentation of gastric cancer differs significantly between foreign-born and U.S.-born Hispanic patients. Foreign-born Hispanic patients have improved survival after adjusting for socioeconomic, neighborhood, and clinical factors. Further studies are needed to identify specific causal mechanisms driving the observed survival difference by nativity status.

Variation of Hepatocellular Carcinoma Treatment Patterns and Survival Across Geographic Regions in a Veteran Population.

BACKGROUND: Veteran populations have five times the incidence of hepatocellular carcinoma (HCC) compared with the general population. The incidence of HCC has increased in the Veteran's Affairs Health System (VAHS), primarily due to the increased prevalence of cirrhosis. This study aimed to characterize differences in treatment patterns and overall survival rates across the five VAHS geographic regions. METHODS: Using the VA Corporate Data Warehouse, the authors built a comprehensive national dataset of Veteran patients with HCC diagnosed between 2001 and 2015 to compare patients across VAHS regions. A multivariable Cox proportional hazards model was used to identify factors associated with 5-year all-cause mortality. Kaplan-Meier curves were used to visualize the patient survival function, and the log-rank test was applied to test statistical significance. RESULTS: This retrospective study analyzed 13,434 patients. The West region had the highest rate of overall treatment receipt (63.6%), and the Southwest had the lowest rate (52.9%). After adjustment for demographic, clinicopathologic, treatment, and hospital factors, treatment in a non-West region continued to be significantly associated with a 10% to 13% increased risk of 5-year mortality (Midwest: hazard ratio [HR], 1.11; 95% confidence interval [CI], 1.03-1.17; Northeast: HR, 1.10; 95% CI, 1.03-1.17; Southeast: HR, 1.13; 95% CI, 1.06-1.21; Southwest: HR, 1.11; 95% CI, 1.03-1.19) (p < 0.01). CONCLUSIONS: Treatment patterns and overall survival rates of HCC patients differ significantly across VAHS geographic regions. Targeted interventions to increase the rate of treatment in the non-West regions are needed to improve survival of HCC Veterans and provide uniformly high-quality care across VAHS facilities.

Redefining High-Volume Gastric Cancer Centers: The Impact of Operative Volume on Surgical Outcomes.

BACKGROUND: Performance of technically complex surgery at high-volume (HV) centers is associated with improved outcomes. OBJECTIVE: The aim of this study was to assess whether hospital gastrectomy volume is associated with surgical outcomes, and what threshold of case volume meaningfully impacts surgical outcomes. METHODS: We conducted a retrospective review of adult NCDB patients with gastric adenocarcinoma undergoing gastrectomy between 2004 and 2015. A multivariable Cox proportional hazards model with restricted cubic splines was used to examine the association of annual hospital gastrectomy volume and overall survival. Bootstrap simulation was used to estimate the cut-point corresponding to maximum change in log hazard ratio. Hospitals were divided into HV (≥ 17 cases/year) and low-volume (LV; < 17 cases/year) groups. We examined the relationship between volume groups and adequate nodal examination, R0 resection, unplanned readmission, and 30- and 90-day mortality. RESULTS: Our cohort consisted of 29,559 patients (7.8% treated at an HV center). Treatment at an HV center was associated with an increased likelihood of adequate nodal examination [odds ratio (OR) 2.12, 95% confidence interval (CI) 1.94-2.32] and R0 resection among patients with cardia tumors (OR 1.42, 95% CI 1.07-1.88). Patients treated at HV centers had decreased 30- and 90-day postoperative mortality, which was more pronounced in those undergoing total gastrectomy. CONCLUSIONS: Treatment at an HV gastrectomy center is associated with improved surgical outcomes. Our study identified 17 cases/year as a clinically meaningful distinction between HV and LV centers. This definition of an HV center should be considered when evaluating regionalization of gastric cancer care to improve patient outcomes.

Inaccurate Clinical Stage Is Common for Gastric Adenocarcinoma and Is Associated with Undertreatment and Worse Outcomes.

BACKGROUND: Accurate clinical staging (CS) of gastric cancer is critical for appropriate treatment selection and prognostication, but CS remains highly imprecise. Our study evaluates factors associated with inaccurate CS, the impact of inaccurate CS on outcomes, and utilization of adjuvant therapy in patients who are understaged. METHODS: We conducted a retrospective review of NCDB patients diagnosed with clinical early stage gastric adenocarcinoma (cT1-2N0M0) between 2004 and 2016. Patients not undergoing upfront gastrectomy or with missing pathologic staging were excluded. Patients were classified as accurately staged, inaccurately staged with receipt of adjuvant therapy (IS+), and inaccurately staged with no receipt of adjuvant therapy (IS-). Logistic regression was utilized to assess the impact of factors on CS accuracy and receipt of adjuvant therapies. Kaplan-Meier and Cox proportional hazard methods were used for survival analysis. RESULTS: Approximately 40% of patients were inaccurately staged (IS). cT2, moderately/poorly differentiated, and site-overlapping tumors were associated with increased likelihood of being IS. Treatment at an academic facility was associated with decreased likelihood of understaging. Only 54% of patients who were IS received adjuvant therapy. CONCLUSION: Accurate CS of gastric cancer remains inadequate. Understaging is associated with detrimental effects on receiving guideline-concordant care and, possibly, patient outcomes. Targeted interventions reducing the proportion of understaged patients and ensuring receipt of appropriate therapy is needed to optimize outcomes. Patients with high-risk disease that are frequently understaged may benefit from selective neoadjuvant therapy. Centralization of gastric cancer care may also be a key strategy in improving receipt of guideline-concordant therapies.

Socioeconomic and racial/ethnic disparities in receipt of palliative care among patients with metastatic hepatocellular carcinoma.

BACKGROUND: Patients with metastatic hepatocellular carcinoma (HCC) suffer symptoms of both end-stage liver disease and cancer. Palliative care (PC) enhances the quality of life via symptom control and even improves survival for some cancers. Our study characterized rates of PC utilization among metastatic HCC patients and determined factors associated with PC receipt. METHODS: We conducted a retrospective review of adult National Cancer Database patients diagnosed with metastatic HCC between 2004 and 2016. Chi-square tests were used to analyze two cohorts: those who received PC and those who did not. Logistic regression was performed to assess the impact of clinicodemographic factors on the likelihood of receiving PC. RESULTS: PC utilization was low at just 17%. Later year of diagnosis, insured status, and higher education level were associated with an increased likelihood of receiving PC. Treatment at academic centers or integrated network cancer programs increased the likelihood of receiving PC compared to treatment at a community center (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.03-1.33 and OR = 1.25, 95% CI = 1.07-1.45; respectively). Hispanics were significantly less likely to received PC than non-Hispanic Whites (OR = 0.73, 95% CI = 0.64-0.82). CONCLUSIONS: PC utilization among patients with metastatic HCC remains low. Targeted efforts should be enacted to increase the delivery of PC in this group.

The presentation of Hispanic gastric cancer patients varies by location of patient ancestry.

BACKGROUND AND OBJECTIVES: The clinical presentation of gastric cancer varies between racial and ethnic groups. While historically studied as a monolithic population, the Hispanic ethnicity is comprised of heterogenous groups with considerable biologic, socioeconomic, and cultural variability; therefore, intragroup differences among Hispanic gastric cancer patients may have been overlooked in past research. METHODS: We conducted a retrospective review of the National Cancer Database (NCDB) to compare Hispanic patients with gastric adenocarcinoma diagnosed between 2004 and 2015, by NCDB-reported location of patient ancestry. RESULTS: We identified a cohort of 3811 patients. There were higher proportions of females, patients with early disease onset, and stage 4 disease among patients of Mexican and South/Central American ancestry. Additionally, a significantly larger proportion of Mexican (15%) and South/Central American patients (11%) were diagnosed before age 40, in contrast to Cubans (2%), Dominicans (6%), and Puerto Ricans (3%; p < 0.0001). Mexican ancestry was independently associated with an increased rate of all-cause mortality at 5 years (hazard ratio: 1.34; 95% confidence interval: 1.09-1.64). CONCLUSIONS: Significant clinical and epidemiological differences exist among Hispanic gastric cancer patients based on location of ancestry. Future data collection endeavors should strive to capture this granularity inherent to the Hispanic ethnicity.

Is there a difference in utilization of a perioperative treatment approach for gastric cancer between safety net hospitals and tertiary referral centers?

BACKGROUND AND OBJECTIVES: Perioperative therapy is a favored treatment strategy for gastric cancer. We sought to assess utilization of this approach at safety net hospitals (SNH) and tertiary referral centers (TRC). MATERIALS AND METHODS: Patients in the US Safety Net Collaborative (2012-2014) with resectable gastric cancer across five SNH and their sister TRC were included. Primary outcomes were receipt of neoadjuvant chemotherapy (NAC) and perioperative therapy. RESULTS: Of 284 patients, 36% and 64% received care at SNH and TRC. The distribution of Stage II/III resectable disease was similar across facilities. Receipt of NAC at SNH and TRC was similar (56% vs. 46%, p = 0.27). Compared with overall clinical stage, 38% and 36% were pathologically downstaged at SNH and TRC, respectively. Among patients who received NAC, those who also received adjuvant chemotherapy at SNH and TRC were similar (66% vs. 60%, p = 0.50). Asian race and higher clinical stage were associated with receipt of perioperative therapy (both p < 0.05) while treatment facility type was not. CONCLUSIONS: There was no difference in utilization of a perioperative treatment strategy between facility types for patients with gastric cancer. Pathologic downstaging from NAC was similar across treatment facilities, suggesting similar quality and duration of therapy. Treatment at an SNH is not a barrier to receiving standard-of-care perioperative therapy for gastric cancer.

Minimally invasive gastrectomy for cancer and anastomotic options.

In this review article, we explore patient selection criteria for minimally invasive surgery (MIS) gastrectomy, present evidence on the risks and benefits of minimally invasive techniques, describe operative techniques focusing specifically on reconstruction options, and discuss the learning curve associated with these operations.