The Prognostic Significance of Nativity, Enclave Residence, and Socioeconomic Status Among Hispanic Patients with Hepatocellular Carcinoma.

BACKGROUND: Residence in ethnic enclaves and nativity are both associated with survival in Hispanic patients with cancer, although their prognostic significance in patients with hepatocellular carcinoma (HCC) is unknown. We aimed to determine the association between nativity, neighborhood socioeconomic status (nSES), and ethnic enclave residency with overall survival in Hispanic patients with HCC. METHODS: Hispanic patients diagnosed with HCC from 2004 to 2017 were identified in the Texas Cancer Registry. Existing indices were applied to tract-level 2000 US Census data to measure enclave residence and nSES. Enclaves were defined by seven measures. Multivariable Cox proportional hazard models were used to evaluate the association between nativity, enclave residency, and nSES with survival. RESULTS: Among 9496 Hispanic patients with HCC, 2283 (24%) were foreign-born. Compared with US-born Hispanic patients, foreign-born Hispanic patients were less likely to present with localized HCC (45.3% vs. 48.8%, p = 0.03) and less likely to receive HCC treatment (53.9% vs. 47.6%, p < 0.001); however, foreign-born Hispanic patients had lower mortality in adjusted models (adjusted hazard ratio [aHR] 0.86, 95% confidence interval [CI] 0.79-0.93). Neighborhood SES, but not enclave residence, was also associated with overall survival. Compared with those in low nSES non-enclaves, Hispanic patients in high nSES neighborhoods, with either enclave (aHR 0.80, 95% CI 0.72-0.88) or non-enclave (aHR 0.89, 95% CI 0.80-0.98) residence status and low nSES enclaves (aHR 0.93, 95% CI 0.86-0.98) had improved survival. CONCLUSION: In Hispanic patients with HCC, foreign birthplace and higher nSES, but not enclave residence, are associated with improved survival. Additional research on intersectionality between ethnicity, nativity, and neighborhood context is warranted.

The phosphatidylserine targeting antibody bavituximab plus pembrolizumab in unresectable hepatocellular carcinoma: a phase 2 trial.

Immune checkpoint inhibitors targeting PD-1/L1 have modest efficacy in hepatocellular carcinoma as single agents. Targeting membranous phosphatidylserine may induce pro-inflammatory and -immune stimulating effects that enhance immunotherapy activity. This hypothesis was tested in a single-arm phase 2 trial evaluating frontline bavituximab, a phosphatidylserine targeting antibody, plus pembrolizumab (anti-PD-1) in patients with unresectable hepatocellular carcinoma (NCT03519997). The primary endpoint was investigator-assessed objective response rate among evaluable patients, and secondary end points included progression-free survival, incidence of adverse events, overall survival, and duration of response. Among 28 evaluable patients, the confirmed response rate was 32.1%, which met the pre-specified endpoint, and the median progression-free survival was 6.3 months (95% CI, 1.3-11.3 months). Treatment related-adverse events of any grade occurred in 45.7% of patients, with grade 3 or greater adverse events in 14.3% of patients. Adverse events of any cause were observed in 33 patients (94.3%), with grade 3 or greater adverse events in 11 patients (31.4%). Prespecified exploratory analyses of baseline tumor specimens showed that a depletion of B cells, and the presence of fibrotic tissue and expression of immune checkpoints in stroma was associated with tumor response. These results suggest that targeting phosphatidylserine may lead to synergistic effects with PD-1 blockade without increasing toxicity rates, and future studies on this therapeutic strategy may be guided by biomarkers characterizing the pre-treatment tumor microenvironment.

Presence of underlying cirrhosis is associated with increased in-hospital mortality and length of stay following pancreatoduodenectomy.

BACKGROUND: Patient- and hospital-level factors associated with outcomes following pancreatoduodenectomy (PD) are well established. However, despite theoretical disruption in hepatopetal flow, the impact of cirrhosis on in-hospital mortality following PD is not well-studied. The objective of this study was to evaluate in-hospital mortality, length of stay (LOS), and post-discharge disposition in patients with cirrhosis undergoing PD. METHODS: A retrospective analysis of the National Inpatient Sample (January 2002-August 2015) was conducted identifying patients undergoing PD. Using previously validated ICD-9-CM codes, patients were stratified into presence and absence of cirrhosis. Factors associated with in-hospital mortality following PD were analyzed adjusting for patient- and hospital-level factors. Following PD were analyzed after adjusting for patient- and hospital-level factors. RESULTS: In 16,344 patients that underwent PD, 203 (1.2 %) patients had underlying cirrhosis prior to resection. Overall in-hospital mortality following PD was significantly worse in the cirrhosis cohort (11.3 % vs. 3.6 %, p < 0.001). Patients with underlying cirrhosis were less likely to be discharged home (73.9 % vs. 83.2 %, p < 0.001) and had a longer median LOS (12.0 vs. 10.0 days, p = 0.001). CONCLUSION: The presence of underlying cirrhosis is associated with increased in-hospital mortality, longer LOS, and decreased likelihood of home discharge following PD. Given the prohibitive risks, PD should not be performed in patients with underlying cirrhosis.

Association of race, demographic and socioeconomic factors with failure to rescue after hepato-pancreato-biliary surgery in the United States.

BACKGROUND: We aimed to describe the association of patient-related factors such as race, socioeconomic status, and insurance on failure to rescue (FTR) after hepato-pancreato-biliary (HPB) surgeries. METHODS: Using the National Inpatient Sample, we analyzed 98,788 elective HPB surgeries between 2004 and 2017. Major and minor complications were identified using ICD9/10 codes. We evaluated mortality rates and FTR (inpatient mortality after major complications). We used multivariate logistic regression analysis to assess racial, socioeconomic, and demographic factors on FTR, adjusting for covariates. RESULTS: Overall, 43 % of patients (n = 42,256) had pancreatic operations, 36% (n = 35,526) had liver surgery, and 21% (n = 21,006) had biliary interventions. The overall major complication rate was 21% (n = 20,640), of which 8% (n = 1655) suffered FTR. Factors independently associated with increased risk for FTR were male sex, older age, higher Charlson Comorbidity Index, Hispanic ethnicity, Asian or other race, lower income quartile, Medicare insurance, and southern region hospitals. CONCLUSIONS: Medicare insurance, male gender, Hispanic ethnicity, and lower income quartile were associated with increased risk for FTR. Efforts should be made to improve the identification and subsequent treatment of complications for those at high risk of FTR.

Expanding Indications for Surgical Resection in Hepatocellular Carcinoma: What is the Evidence?

Hepatic resection is one of the mainstays of curative therapy for hepatocellular carcinoma (HCC). The appropriate selection of resectable candidates requires careful consideration of a multitude of factors including tumor burden (size and number of nodules, presence of vascular involvement, extrahepatic spread), patient factors (performance status, underlying liver function), and availability of other therapies (access to transplantation, interventional procedures, immunotherapies). Historically, hepatic resection for HCC has been reserved for patients with solitary tumors without vascular invasion. However, in well-selected patients HCC tumors multifocal in nature or with vascular invasion should be considered for hepatic resection.

Cost Analysis and Financial Implications of a Peritoneal Surface Malignancy Program in the USA.

BACKGROUND: We aimed to describe the financial implications of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in the USA. MATERIALS AND METHODS: We conducted a retrospective cost analysis of 100 CRS/HIPEC procedures to examine the impact of patient and procedural factors on hospital costs and reimbursement. A comparison of surgeons' work relative value units (wRVUs) between CRS/HIPEC and a representative sample of complex surgical oncology procedures was made to assess the physicians' compensation rate. Univariable and multivariable backward logistic regression was used to analyze the association between perioperative variables and high direct cost (HDCs). RESULTS: The median direct cost per CRS/HIPEC procedure was US $44,770. The median hospital reimbursement was US $43,066, while professional reimbursement was US $8608, resulting in a positive contribution margin of US $7493/procedure. However, the contribution margin significantly varied with the payer mix. Privately insured patients had a positive median contribution margin of US $23,033, whereas Medicare-insured patients had a negative contribution margin of US $13,034. Length of stay (LOS) had the most significant association with HDC, and major complications had the most significant association with LOS. Finally, CRS/HIPEC procedures generated a median of 13 wRVU/h, which is significantly lower than the wRVU/h generated by open pancreatoduodenectomies, open gastrectomies, and hepatectomies. However, higher operation complexity and multiple visceral resections help compensate for the relatively low wRVU/h. CONCLUSIONS: CRS/HIPEC is an expensive operation, and prolonged LOS has the most significant impact on the total cost of the procedure. High-quality care is essential to improve patient outcomes and maintain the economic sustainability of the procedure.

Impact of Neoadjuvant Treatment and Minimally Invasive Surgery on Perioperative Outcomes of Pancreatoduodenectomy: an ACS NSQIP Analysis.

BACKGROUND: There is an increasing use of neoadjuvant treatment (NAT) for pancreatic cancer (PC) followed by minimally invasive pancreatoduodenectomy (MIPD). We evaluate the impact of the surgical approach on 30-day outcomes in PC patients who underwent NAT. METHODS: Patients with PC who had NAT followed by MIPD or open pancreatoduodenectomy (OPD) were identified from a pancreatectomy-targeted dataset (2014-2020) of the National Surgical Quality Improvement Program. Comparisons were made between MIPD and OPD within NAT groups. RESULTS: A total of 5588 patients were analyzed. Of those, 4907 underwent OPD and 476 underwent MIPD. In addition, 3559 patients received neoadjuvant chemotherapy alone and 1830 received neoadjuvant chemoradiation. In the chemotherapy-alone group, the MIPD subgroup had lower rates of any complication (38.2% vs. 45.8%, P = 0.005), but there were no differences in mortality (2.1% for MIPD vs 1.9% for OPD, P=0.8) or serious complication (11.8% for MIPD vs 15% for OPD, P=0.1). On multivariable analysis, MIPD was independently predictive of lower rates of any complication (OR: 0.74, 95% CI 0.6-0.93, P = 0.0009), CR-POPF (OR: 0.58, 95% CI 0.35-0.96, P = 0.04), and shorter LOS (estimate: -1.03, 95% CI -1.73 to -0.32, P = 0.004). In the chemoradiation group, patients undergoing MIPD had higher rates of preoperative diabetes (P < 0.05), but there were no significant differences in any outcomes between the two approaches in this group. CONCLUSION: MIPD is safe and feasible after NAT. Patients having neoadjuvant chemotherapy alone followed by MIPD had lower rates of complications, shorter LOS, and fewer CR-POPFs compared to OPD.

Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave050): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: No adjuvant treatment has been established for patients who remain at high risk for hepatocellular carcinoma recurrence after curative-intent resection or ablation. We aimed to assess the efficacy of adjuvant atezolizumab plus bevacizumab versus active surveillance in patients with high-risk hepatocellular carcinoma. METHODS: In the global, open-label, phase 3 IMbrave050 study, adult patients with high-risk surgically resected or ablated hepatocellular carcinoma were recruited from 134 hospitals and medical centres in 26 countries in four WHO regions (European region, region of the Americas, South-East Asia region, and Western Pacific region). Patients were randomly assigned in a 1:1 ratio via an interactive voice-web response system using permuted blocks, using a block size of 4, to receive intravenous 1200 mg atezolizumab plus 15 mg/kg bevacizumab every 3 weeks for 17 cycles (12 months) or to active surveillance. The primary endpoint was recurrence-free survival by independent review facility assessment in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT04102098. FINDINGS: The intention-to-treat population included 668 patients randomly assigned between Dec 31, 2019, and Nov 25, 2021, to either atezolizumab plus bevacizumab (n=334) or to active surveillance (n=334). At the prespecified interim analysis (Oct 21, 2022), median duration of follow-up was 17·4 months (IQR 13·9-22·1). Adjuvant atezolizumab plus bevacizumab was associated with significantly improved recurrence-free survival (median, not evaluable [NE]; [95% CI 22·1-NE]) compared with active surveillance (median, NE [21·4-NE]; hazard ratio, 0·72 [adjusted 95% CI 0·53-0·98]; p=0·012). Grade 3 or 4 adverse events occurred in 136 (41%) of 332 patients who received atezolizumab plus bevacizumab and 44 (13%) of 330 patients in the active surveillance group. Grade 5 adverse events occurred in six patients (2%, two of which were treatment related) in the atezolizumab plus bevacizumab group, and one patient (<1%) in the active surveillance group. Both atezolizumab and bevacizumab were discontinued because of adverse events in 29 patients (9%) who received atezolizumab plus bevacizumab. INTERPRETATION: Among patients at high risk of hepatocellular carcinoma recurrence following curative-intent resection or ablation, recurrence-free survival was improved in those who received atezolizumab plus bevacizumab versus active surveillance. To our knowledge, IMbrave050 is the first phase 3 study of adjuvant treatment for hepatocellular carcinoma to report positive results. However, longer follow-up for both recurrence-free and overall survival is needed to assess the benefit-risk profile more fully. FUNDING: F Hoffmann-La Roche/Genentech.

Current Practices in Hepatic Artery Infusion (HAI) Chemotherapy: An International Survey of the HAI Consortium Research Network.

BACKGROUND: An increasing number of hepatic artery infusion (HAI) programs have been established worldwide. Practice patterns for this complex therapy across these programs have not been reported. This survey aimed to identify current practice patterns in HAI therapy with the long-term goal of defining best practices and performing prospective studies. METHODS: Using SurveyMonkeyTM, a 28-question survey assessing current practices in HAI was developed by 12 HAI Consortium Research Network (HCRN) surgical oncologists. Content analysis was used to code textual responses, and the frequency of categories was calculated. Scores for rank-order questions were generated by calculating average ranking for each answer choice. RESULTS: Thirty-six (72%) HCRN members responded to the survey. The most common intended initial indications for HAI at new programs were unresectable colorectal liver metastases (uCRLM; 100%) and unresectable intrahepatic cholangiocarcinoma (uIHC; 56%). Practice patterns evolved such that uCRLM (94%) and adjuvant therapy for CRLM (adjCRLM; 72%) have become the most common current indications for HAI at established centers. Referral patterns for pump placement differed between uCRLM and uIHC, with most patients referred while receiving second- and first-line therapy, respectively, with physicians preferring to evaluate patients for HAI while receiving first-line therapy for CRLM. Concern for extrahepatic disease was ranked as the most important factor when considering a patient for HAI. CONCLUSIONS: Indication and patient selection factors for HAI therapy are relatively uniform across most HCRN centers. The increasing use of adjuvant HAI therapy and overall consistency of practice patterns among HCRN centers provides a robust environment for prospective data collection and randomized clinical trials.

Association Between Biliary Pathogens, Surgical Site Infection, and Pancreatic Fistula: Results of a Randomized Trial of Perioperative Antibiotic Prophylaxis in Patients Undergoing Pancreatoduodenectomy.

OBJECTIVE: To establish the association between bactibilia and postoperative complications when stratified by perioperative antibiotic prophylaxis. BACKGROUND: Patients undergoing pancreatoduodenectomy experience high rates of surgical site infection (SSI) and clinically relevant postoperative pancreatic fistula (CR-POPF). Contaminated bile is known to be associated with SSI, but the role of antibiotic prophylaxis in mitigation of infectious risks is ill-defined. METHODS: Intraoperative bile cultures (IOBCs) were collected as an adjunct to a randomized phase 3 clinical trial comparing piperacillin-tazobactam with cefoxitin as perioperative prophylaxis in patients undergoing pancreatoduodenectomy. After compilation of IOBC data, associations between culture results, SSI, and CR-POPF were assessed using logistic regression stratified by the presence of a preoperative biliary stent. RESULTS: Of 778 participants in the clinical trial, IOBC were available for 247 participants. Overall, 68 (27.5%) grew no organisms, 37 (15.0%) grew 1 organism, and 142 (57.5%) were polymicrobial. Organisms resistant to cefoxitin but not piperacillin-tazobactam were present in 95 patients (45.2%). The presence of cefoxitin-resistant organisms, 92.6% of which contained either Enterobacter spp. or Enterococcus spp., was associated with the development of SSI in participants treated with cefoxitin [53.5% vs 25.0%; odds ratio (OR)=3.44, 95% CI: 1.50-7.91; P =0.004] but not those treated with piperacillin-tazobactam (13.5% vs 27.0%; OR=0.42, 95% CI: 0.14-1.29; P =0.128). Similarly, cefoxitin-resistant organisms were associated with CR-POPF in participants treated with cefoxitin (24.1% vs 5.8%; OR=3.45, 95% CI: 1.22-9.74; P =0.017) but not those treated with piperacillin-tazobactam (5.4% vs 4.8%; OR=0.92, 95% CI: 0.30-2.80; P =0.888). CONCLUSIONS: Previously observed reductions in SSI and CR-POPF in patients that received piperacillin-tazobactam antibiotic prophylaxis are potentially mediated by biliary pathogens that are cefoxitin resistant, specifically Enterobacter spp. and Enterococcus spp.

Implications of the interaction between travel burden and area deprivation for patients with pancreatic cancer.

INTRODUCTION: Fragmentation of care and distance traveled are classically surrogates for poor access to care, but little is known about how social determinants of health interact with travel burden to affect survival for patients with pancreatic cancer (PC). We sought to characterize the individual and composite impact of these factors. METHODS: 20769 patients treated for PC between 2005 and 2019 in the Texas Cancer Registry were included. The Area Deprivation Index and Poverty Index were used to quantify social determinants of health. Survival analyses were performed at 2 years as well as subgroup analysis on patients with the greatest travel burden. RESULTS: Improved survival was associated with FC (HR 0.74, CI 0.71-0.77) and distance from an accredited cancer center (Quartile 4 HR 0.90, CI 0.81-1.00). High ADI led to worse outcomes while low ADI led to improved outcomes with increasing travel burden. CONCLUSIONS: This data shows a complex relationship between travel burden and survival for patients with pancreatic cancer where stratifying by area deprivation reveals divergent outcomes and the potential to exacerbate disparities.

Factors associated with failure to operate and its impact on survival in early-stage pancreatic cancer.

INTRODUCTION: Curative intent for localized pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) requires surgery, but despite improved perioperative outcomes, surgery remains underutilized. This study analyzed the Texas Cancer Registry (TCR) to identify resectable PDAC patients who underwent curative-intent surgery in Texas between 2004 and 2018. We then evaluated demographic and clinical factors associated with failure to operate and survival (OS). METHODS: We identified patients with localized PDAC or regional lymph node spread between 2004 and 2018 in the TCR. Resection rates were determined and multivariable regression and cox proportional hazards were used to identify factors associated with failure to OS. RESULTS: Of 4274 patients, 22% underwent resection, 57% were not offered surgery, 6% had comorbidities precluding surgery, and 3% refused. Resection rates decreased from 31% in 2004 to 22% in 2018. Increasing age was associated with failure to operate (odds ratio [OR] 2.55; 95% confidence interval [CI] 1.80-3.61; p < 0.0001) while treatment at a Commission on Cancer (CoC) center correlated with reduced failure to operate (OR 0.63; 95% CI 0.50-0.78; p < 0.0001). Resection correlated with survival (HR 0.34; 95% CI 0.31-0.38; p < 0.0001) as did treatment at a National Cancer Institute (NCI)-designated center (hazard ratio 0.79; 95% CI 0.70-0.89; p < 0.0001). CONCLUSIONS: Surgery is underutilized for the treatment of resectable PDAC in Texas with decreasing utilization, annually. Evaluation at CoC was associated with improved resection rates and NCI was associated with increased survival. Expanding access to multidisciplinary care including trained hepato-pancreatico-biliary surgeons may improve outcomes for PDAC patients.

Multidisciplinary care for patients with HCC: a systematic review and meta-analysis.

BACKGROUND: Given the complexity of managing HCC, professional society guidelines advocate multidisciplinary care (MDC) for patients with HCC. However, implementation of MDC programs requires a significant investment of time and resources. We conducted a systematic review and meta-analysis to enumerate potential benefits of MDC for patients with HCC. METHODS: We conducted a search of the PubMed/MEDLINE and EMBASE databases and national conference abstracts to identify studies published after January 2005 that reported early-stage presentation, treatment receipt, or overall survival among patients with HCC, stratified by MDC status. We calculated pooled risk ratios and HRs for clinical outcomes according to MDC receipt using the DerSimonian and Laird method for random effects models. RESULTS: We identified 12 studies (n = 15,365 patients with HCC) with outcomes stratified by MDC status. MDC was associated with improved overall survival (HR = 0.63, 95% CI: 0.45-0.88); however, its association with curative treatment receipt was not statistically significant (risk ratio = 1.60, 95% CI: 0.89-2.89) and pooled estimates were limited by high heterogeneity (I2 > 90% for both). Studies (n = 3) were discordant regarding an association between MDC and time-to-treatment initiation. MDC was associated with early-stage HCC (risk ratio = 1.60, 95% CI: 1.12-2.29), suggesting possible referral bias contributing to improved outcomes. Limitations of studies also included risk of residual confounding, loss to follow-up, and data preceding the availability of immune checkpoint inhibitors. CONCLUSION: MDC for patients with HCC is associated with improved overall survival, underscoring the likely benefit of managing patients with HCC in a multidisciplinary care setting.