Outcomes of Hepatic Artery-Based Therapies and Systemic Multiagent Chemotherapy in Unresectable Colorectal Liver Metastases: A Systematic Review and Meta-analysis.

BACKGROUND: Treatment of unresectable colorectal liver metastases (UCRLM) includes locoregional and systemic therapy. A comprehensive analysis capturing long-term outcomes of these treatment options has not been performed. OBJECTIVE: A systematic review and meta-analysis was performed to calculate pooled outcomes of hepatic artery infusion with systemic chemotherapy (HAI-S), transarterial chemoembolization with systemic chemotherapy (TACE-S), transarterial radioembolization with systemic chemotherapy (TARE-S), doublet (FOLFOX, FOLFIRI), and triplet chemotherapy (FOLFOXIRI). METHODS: Outcomes included overall survival (OS), progression-free survival (PFS), rate of conversion to resection (CTR), and response rate (RR). RESULTS: A total of 32, 7, 9, and 14 publications were included in the HAI-S, TACE-S, and TARE-S chemotherapy arms. The 6/12/24/36-month OS estimates for HAI-S, TACE-S, TARE-S, FOLFOX, FOLFIRI, and FOLFOXIRI were 97%/80%/54%/35%, 100%/83%/40%/14%, 82%/61%/34%/21%, 96%/83%/53%/36%, and 96%/93%/72%/55%. Similarly, the 6/12/24/36-month PFS estimates were 74%/44%/19%/14%, 66%/20%/9%/3%, 57%/23%/10%/3%, 69%/30%/12%/7%, and 88%/55%/18%/11%. The corresponding CTR and RR rates were 31, 20%, unmeasurable (TARE-S), 35, 53; and 49, 45, 45, 50, 80%, respectively. The majority of chemotherapy studies included first-line therapy and liver-only metastases, whereas most HAI-S studies were pretreated. On subgroup analysis in first-line setting with liver-only metastases, the HAI-S arm had comparable outcomes to FOLFOXIRI and outperformed doublet chemotherapy regimens. Although triplet chemotherapy appeared to outperform other arms, high toxicity and inclusion of potentially resectable patients must be considered while interpreting results. CONCLUSIONS: HAI-S and multiagent chemotherapy are effective therapies for UCRLM. To make definitive conclusions, a randomized trial with comparable patient characteristics and line of therapy will be required. The upcoming EA2222 PUMP trial may help to address this question.

Surgical Resection Alone is Associated With Higher Long-Term Survival Than Multiagent Chemotherapy Alone for Patients With Localized Biliary Tract Cancers.

INTRODUCTION: We compared long-term survival of patients with localized biliary tract cancers (BTCs) treated with either surgical resection or multiagent chemotherapy. METHODS: Patients with localized BTC [gallbladder adenocarcinoma, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma] were identified within the National Cancer Database (2010-2017). Piecewise-constant hazard modeling was used to estimate hazard ratios (HRs) at prespecified intervals: 0-30 d, 31-60 d, 61-90 d, and >90 d post-treatment. RESULTS: A total of 5988 patients with localized BTC were identified: 2697 (45.0%) received multiagent chemotherapy and 3291 (55.0%) underwent surgical resection. Patients with gallbladder adenocarcinoma or extrahepatic cholangiocarcinoma who were treated with surgical resection had an associated decline in overall survival (OS) as compared to those treated with multiagent chemotherapy within 0-30 d of treatment initiation (gallbladder adenocarcinoma [adjusted HR = 3.94, 95% confidence interval [CI]: 1.77-8.80]; extrahepatic cholangiocarcinoma [adjusted HR = 4.88, 95% CI: 2.76-8.61]). However, there was an associated improvement in OS for patients treated with surgical resection after 90 d from treatment initiation (gallbladder adenocarcinoma [adjusted HR = 0.36, 95% CI: 0.28-0.46]; extrahepatic cholangiocarcinoma [adjusted HR = 0.27, 95% CI: 0.24-0.32]). Among patients with intrahepatic cholangiocarcinoma, those who underwent surgical resection had an associated improvement in OS at 31-60 d (adjusted HR = 0.63, 95% CI: 0.40-0.99) and a further associated increase in OS at 61-90 d (adjusted HR = 0.34, 95% CI: 0.21-0.54) and after 90 d (HR = 0.23, 95% CI: 0.21-0.27) of treatment initiation. CONCLUSIONS: For patients with localized BTC, surgical resection alone is associated with improved long-term survival outcomes compared to multiagent chemotherapy alone.

Understanding surgical attrition for "resectable" pancreatic cancer.

OBJECTIVES: We used a novel combined analysis to evaluate various factors associated with failure to undergo surgery in non-metastatic pancreatic cancer. METHODS: We identified rates of surgery and reasons for surgical attrition from clinical trials, which studied neoadjuvant therapy in resectable pancreatic cancer. Next, we queried the National Cancer Database (NCDB) for Stage I-III, T1-3 pancreatic adenocarcinoma patients. We investigated the rates and factors associated with the receipt of surgery. Finally, we evaluated variable importance predicting the receipt of surgery. RESULTS: In clinical trials, 25-30 % of patients did not undergo surgery, mostly due to disease progression. In the NCDB, the overall surgical rate was only 49 %, but increased to 67 % in a curated cohort meant to mirror clinical trial patients. Patients treated at low-volume institutions (OR = 0.64, 95 % CI: 0.61-0.67) and who were uninsured (OR = 0.56, 95 % CI: 0.52-0.62) and Medicaid-insured (OR = 0.67, 95 % CI: 0.64-0.71) were less likely to receive potentially curative surgery. CONCLUSION: We have identified a realistic target surgery rate of 70%-75 % in potentially-resectable pancreatic cancer. While attrition to pancreatic cancer surgery is mostly due to tumor biology, our study identified the most important non-medical barriers, such as facility volume and insurance, affecting pancreatic cancer surgery.

Understanding Disparities in Receipt of Complex Gastrointestinal Cancer Surgery at a Small Geographic Scale.

OBJECTIVE: To define neighborhood-level disparities in the receipt of complex cancer surgery. BACKGROUND: Little is known about the geographic variation of receipt of surgery among patients with complex gastrointestinal (GI) cancers, especially at a small geographic scale. METHODS: This study included individuals diagnosed with 5 invasive, nonmetastatic, complex GI cancers (esophagus, stomach, pancreas, bile ducts, liver) from the Ohio Cancer Incidence Surveillance System during 2009 and 2018. To preserve patient privacy, we combined US census tracts into the smallest geographic areas that included a minimum number of surgery cases (n=11) using the Max-p-regions method and called these new areas "MaxTracts." Age-adjusted surgery rates were calculated for MaxTracts, and the Hot Spot analysis identified clusters of high and low surgery rates. US Census and CDC PLACES were used to compare neighborhood characteristics between the high- and low-surgery clusters. RESULTS: This study included 33,091 individuals with complex GI cancers located in 1006 MaxTracts throughout Ohio. The proportion in each MaxTract receiving surgery ranged from 20.7% to 92.3% with a median (interquartile range) of 48.9% (42.4-56.3). Low-surgery clusters were mostly in urban cores and the Appalachian region, whereas high-surgery clusters were mostly in suburbs. Low-surgery clusters differed from high-surgery clusters in several ways, including higher rates of poverty (23% vs. 12%), fewer married households (40% vs. 50%), and more tobacco use (25% vs. 19%; all P <0.01). CONCLUSIONS: This improved understanding of neighborhood-level variation in receipt of potentially curative surgery will guide future outreach and community-based interventions to reduce treatment disparities. Similar methods can be used to target other treatment phases and other cancers.

Assessing the use of Extended Venous Thromboembolism Prophylaxis on the Rates of Venous Thromboembolism and Postpancreatectomy Hemorrhage Following Pancreatectomy for Malignancy.

OBJECTIVE: To compare rates of venous thromboembolism (VTE) and postpancreatectomy hemorrhage (PPH) in patients with pancreatic or periampullary malignancy preimplementation and postimplementation of routine extended VTE prophylaxis. BACKGROUND: Guidelines recommend up to 28 days of VTE prophylaxis following major abdominal cancer operations. There is a paucity of data examining rates of VTE and PPH in patients who receive extended VTE prophylaxis following pancreatectomy. METHODS: Single-institution analysis of patients who underwent pancreatectomy for malignancy (2004-2021). VTE and PPH rates within 90 days of discharge were compared based on receipt of extended VTE prophylaxis with enoxaparin. RESULTS: A total of 478 patients were included. Twenty-two (4.6%) patients developed a postoperative VTE, 12 (2.5%) of which occurred postdischarge. Twenty-five (5.2%) patients experienced PPH, 13 (2.7%) of which occurred postdischarge. There was no associated difference in the development of postdischarge VTE between patients who received extended VTE prophylaxis and those who did not (2.3% vs 2.8%, P =0.99). There was no associated difference in the rate of postdischarge PPH between patients who received extended VTE prophylaxis and those who did not (3.4% vs 1.9%, P =0.43). In the subset of patients on antiplatelet agents, the addition of enoxaparin did not appear to be associated with higher VTE (3.9 vs. 0%, P =0.31) or PPH (3.0 vs. 4.5%, P =0.64) rates. CONCLUSIONS: Extended VTE prophylaxis following pancreatectomy for malignancy was not associated with differences in postdischarge VTE and PPH rates. These data suggest extended VTE prophylaxis is safe but may not be necessary for all patients following pancreatectomy.

Discordance Between Conventional and Detailed Lymph Node Analysis in Resected, Node-negative Pancreatic or Ampullary Adenocarcinomas and Association With Adverse Survival Outcomes: A Single-institution Analysis.

OBJECTIVE: To assess the frequency of occult metastases (OM) in patients with resected pancreatic ductal adenocarcinoma (PDAC) or ampullary adenocarcinoma (AA) discovered on detailed pathologic examination on lymph nodes (LNs) previously considered negative by conventional analysis and to examine the association between OM and overall survival (OS). BACKGROUND: Poor prognosis of patients with no pathologic evidence of LN metastases may be due to OM that is not detected on conventional LN analysis. METHODS: Patients with LN-negative resected PDAC or AA (2010-2020) were identified from our institutional database. Original hematoxylin and eosin ( H and E ) slides were reanalyzed. In addition, selected LN were analyzed by H and E (3 sections/LN) and pan-cytokeratin (AE1-AE3/PCK26) immunohistochemistry. RESULTS: A total of 598 LNs from 74 LN-negative patients were reexamined. Nineteen patients (25.7%) had OM; 9 (47.4%) were found with immunohistochemistry but not on H and E . The number of positive LNs ranged from 1 to 3. No clinicodemographic, pathologic, or treatment-related factors were associated with OM. On conventional LN analysis, 3/19 patients (15.8%) had stage IA, 9/34 (26.5%) had stage IB, and 7/19 (36.8%) had stage IIA. On detailed LN analysis, 11/19 patients (57.9%) were upstaged to IIB, whereas 8/19 (42.1%) had isolated tumor cells only (N0i+). OM was associated with shorter OS (median OS: 22.3 vs 50.5 months; hazard ratio=3.95, 95% CI: 1.58-9.86). CONCLUSIONS: There is a 26% discordance rate between conventional and detailed LN pathologic analysis in resected PDAC and AA. The presence of OM is associated with shorter OS.

Why the Treatment Sequence Matters: Interplay Between Chemotherapy Cycles Received, Cumulative Dose Intensity, and Survival in Resected Early-stage Pancreas Cancer.

OBJECTIVE: To define the optimal threshold of perioperative chemotherapy completion and relative dose intensity (RDI) for patients with resected pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Many patients who undergo pancreatectomy for PDAC fail to initiate or complete recommended perioperative chemotherapy. The association between the amount of perioperative chemotherapy received and overall survival (OS) is not well-defined. METHODS: Single-institution analysis of 225 patients who underwent pancreatectomy for stage I/II PDAC (2010-2021). Associations between OS, chemotherapy cycles completed, and RDI were analyzed. RESULTS: Regardless of treatment sequence, completion of ≥67% of recommended cycles was associated with improved OS compared with no chemotherapy [median OS: 34.5 vs 18.1 months; hazard ratio (HR): 0.43; 95% CI: 0.25-0.74] and <67% of cycles (median OS: 17.9 months; HR: 0.39; 95% CI: 0.24-0.64). A near-linear relationship existed between cycles completed and the RDI received (ß = 0.82). A median RDI of 56% corresponded to the completion of 67% of cycles. Receipt of ≥56% RDI was associated with improved OS compared with no chemotherapy (median OS: 35.5 vs 18.1 months; HR: 0.44; 95% CI: 0.23-0.84) and <56% RDI (median OS: 27.2 months; HR: 0.44; 95% CI: 0.20-0.96). Neoadjuvant chemotherapy is associated with increased odds of receiving ≥67% of recommended cycles (odds ratio: 2.94; 95% CI: 1.45-6.26) and ≥56% RDI (odds ratio: 4.47; 95% CI: 1.72-12.50). CONCLUSIONS: Patients with PDAC who received ≥67% of recommended chemotherapy cycles or ≥56% cumulative RDI had improved OS. Neoadjuvant therapy was associated with increased odds of receiving ≥67% of cycles and ≥56% cumulative RDI and should be considered in all patients with resectable PDAC.

Trends in and Prognostic Significance of Time to Treatment in Pancreatic Cancer: A Population-Based Study.

INTRODUCTION: The association of time to treatment (TTT) with survival remains unclear in pancreatic adenocarcinoma (PDAC). In this study, we evaluate the recent trends in TTT, causes for delay, and its effect on survival. METHODS: We included patients with PDAC of all stages from the National Cancer Database (2004-2020) who underwent either surgery or chemotherapy/radiotherapy (CT/RT). TTT was defined as the duration between tissue diagnosis and first treatment. Linear regression (ß) was used to study the temporal trends in time delay. RESULTS: A total of 239,638 patients were included. The median TTT was 25 days. Using multivariable analysis, we found that increasing age (OR 1.48), female gender (OR 1.04), Black race (OR 1.3), lower educational status (OR 1.2), Medicaid, Medicare insurance, and uninsured (OR 1.2, 1.5, and 1.2, respectively), treatment at academic centers (OR 1.3), higher Charlson-Deyo comorbidity index (OR 1.2), and CT/RT (OR 1.5) were associated with increased TTT. There was a steady rise in median TTT from 21 to 28 days between 2004 and 2020 (ß = 0.3), suggestive of a worsening trend. Concurrently, there was an increasing trend in utilization of neoadjuvant CT/RT between 2004 and 2020 in early-stage PDAC. On Cox regression, TTT delay was associated with poor overall survival in stage I-IV patients (HR 1.1, 1.1, 1.09, and 1.53, respectively). CONCLUSIONS: Delayed treatment approaching 2 months was observed in 10% of the population. The rising temporal trend in TTT may be attributed to the increasing shift toward neoadjuvant CT/RT in early-stage PDAC and/or the increasing use of tissue biopsy prior to surgery.

Management of adenocarcinoma of the pancreatic tail in the elderly.

INTRODUCTION: Elderly patients with adenocarcinoma of the pancreatic head can achieve reasonable survival with multimodal therapy. An analysis specific to cancers of the pancreatic tail has not been published. METHODS: We identified patients ≥65 years with localized adenocarcinoma of the pancreatic tail in the National Cancer Database (2011-2017). Patients were grouped by age (65-79 and ≥80 years) and categorized by treatment regimen. Postoperative outcomes and survival were analyzed using propensity score matching and multivariable logistical regression. RESULTS: 2168 patients were included: 73.9% were 65-79 years and 26.1% were ≥80 years. 34.1% of octogenarians did not receive any treatment, relative to 15.9% of younger patients (p < 0.001). Thirty-day mortality rates were similar in operatively managed patients; however, the 90-day mortality rate among octogenarians was greater (3.0% vs. 7.8%, p < 0.001; odds ratio [OR] = 1.85, 95% confidence interval [CI] = 1.07-3.19). Age ≥ 80 was not associated with survival on multivariable hazards regression (hazard ratio [HR] = 1.08, 95% CI = 0.95-1.24). After propensity matching, the addition of chemotherapy was not associated with improved survival relative to distal pancreatectomy alone among octogenarians (HR = 1.09, 95% CI = 0.72-1.65). CONCLUSIONS: Management of adenocarcinoma of the pancreatic tail varies based on patient age. Resection appears to play a key role in management, but there is substantial upfront risk. Shared decision making should be employed to balance the chance for long-term survival with the risk of early mortality.

Disparities in guideline-compliant care for patients with pancreatic ductal adenocarcinoma at minority-versus non-minority-serving hospitals.

BACKGROUND: We examined disparities in guideline-compliant care at minority-serving hospitals (MSH) versus non-MSH among patients with localized or metastatic pancreatic adenocarcinoma (PDAC). METHODS: Patients with PDAC were identified within the National Cancer Database (2004-2018). Guideline-compliant care was defined as surgery + chemotherapy ± radiation therapy for localized and chemotherapy for metastatic disease. Facilities in the top decile of minority patients treated were considered MSH. RESULTS: A total of 190,950 patients were identified and most (59.6%) had metastatic disease. Overall, 6.4% of patients with localized and 8.2% of patients with metastatic disease were treated at MSH. Patients treated at MSH were less likely to receive guideline-compliant care (localized: OR = 0.78, 95% CI: 0.67-0.91; metastatic: OR = 0.77, 95% CI: 0.67-0.88). Minority patients were less likely to receive guideline-compliant care at non-MSH (localized: OR = 0.71, 95% CI: 0.67-0.75; metastatic: OR = 0.85, 95% CI: 0.82-0.89) or MSH (localized: OR = 0.85, 95% CI: 0.74-0.98; metastatic: OR = 0.91, 95% CI: 0.82-0.99). Patients treated at non-MSH or MSH who received guideline-compliant care were more likely to have higher OS regardless of stage or race. CONCLUSIONS: MSH patients were less likely to receive guideline-compliant care and minority patients were less likely to receive guideline-compliant care regardless of MSH status. Guideline-compliant care was associated with improved OS.

Trends and disparities in the utilization of systemic chemotherapy in patients with metastatic hepato-pancreato-biliary cancers.

BACKGROUND: We described trends and disparities in utilization of systemic chemotherapy in metastatic hepato-pancreato-biliary (HPB) cancers. METHODS: We queried the National Cancer Database for metastatic HPB cancers [hepatocellular carcinoma (HCC), biliary tract cancers (BTC), pancreatic adenocarcinoma (PDAC)]. We used multivariable analysis to examine the factors associated with utilization of systemic chemotherapy. We utilized marginal structural logistic models to estimate the effect of health insurance, facility type, or facility volume on utilization of systemic chemotherapy. RESULTS: We identified 162,283 patients with metastatic HPB cancers: 23,923 (14.7%) had HCC, 26,766 (16.5%) had BTC, and 111,594 (68.8%) had PDAC. A total of 37.2% patients with HCC, 55.6% with BTC, and 56.4% with PDAC received chemotherapy. Age ≥70 years and Charlson-Deyo score ≥2 were associated with lower likelihood of receiving chemotherapy across all cancers. Patients with private health insurance had higher receipt of chemotherapy. Receiving treatment at academic facilities had no effect on the receipt of chemotherapy. Treatment of patients with HCC or PDAC at high-volume facilities resulted in higher receipt of chemotherapy. CONCLUSION: A significant proportion of patients with metastatic HPB cancers do not receive systemic chemotherapy. Several disparities in administration of chemotherapy for metastatic HPB cancers exist.

The Role of the Microbiome in Gastroentero-Pancreatic Neuroendocrine Neoplasms (GEP-NENs).

Gut microbiome balance plays a key role in human health and maintains gut barrier integrity. Dysbiosis, referring to impaired gut microbiome, is linked to a variety of diseases, including cancers, through modulation of the inflammatory process. Most studies concentrated on adenocarcinoma of different sites with very limited information on gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In this study, we have analyzed the gut microbiome (both fungal and bacterial communities) in patients with metastatic GEP-NENs. Fecal samples were collected and compared with matched healthy control samples using logistic regression distances utilizing R package MatchIt (version 4.2.0, Daniel E. Ho, Stanford, CA, USA). We examined differences in microbiome profiles between GEP-NENs and control samples using small subunit (SSU) rRNA (16S), ITS1, ITS4 genomic regions for their ability to accurately characterize bacterial and fungal communities. We correlated the results with different behavioral and dietary habits, and tumor features including differentiation, grade, primary site, and therapeutic response. All tests are two-sided and p-values ≤ 0.05 were considered statistically significant. Gut samples of 34 patients (12 males, 22 females, median age 64 years) with metastatic GEP-NENs (22 small bowel, 10 pancreatic, 1 gall bladder, and 1 unknown primary) were analyzed. Twenty-nine patients had well differentiated GEP-neuroendocrine tumors (GEP-NETs), (G1 = 14, G2 = 12, G3 = 3) and five patients had poorly differentiated GEP-neuroendocrine carcinomas (GEP-NECs). Patients with GEP-NENs had significantly decreased bacterial species and increased fungi (notably Candida species, Ascomycota, and species belonging to saccharomycetes) compared to controls. Patients with GEP-NECs had significantly enriched populations of specific bacteria and fungi (such as Enterobacter hormaechei, Bacteroides fragilis and Trichosporon asahii) compared to those with GEP-NETs (p = 0.048, 0.0022 and 0.034, respectively). In addition, higher grade GEP-NETs were associated with significantly higher Bacteroides fragilis (p = 0.022), and Eggerthella lenta (p = 0.00018) species compared to lower grade tumors. There were substantial differences associated with dietary habits and therapeutic responses. This is the first study to analyze the role of the microbiome environment in patients with GEP-NENs. There were significant differences between GEP-NETs and GEP-NECs, supporting the role of the gut microbiome in the pathogenesis of these two distinct entities.

Weight Tracking as a Novel Prognostic Marker After Pancreatectomy.

BACKGROUND: Objective measures of post-pancreatectomy weight change for pancreatic ductal adenocarcinoma (PDAC) have not been extensively studied for long-term outcomes. We used weight measurements in our institutional medical record to analyze trends in post-pancreatectomy weight and determine the association with disease status. METHODS: Pancreatectomies for PDAC (n = 315) and benign indications (n = 111) were identified. Preoperative baseline, minimum postoperative (Min #1), and subsequent postoperative maximum (Max) weights were abstracted. Multivariable Cox hazards regression was conducted to analyze the association between weight change and survival. RESULTS: Median weight loss postoperatively in each group was > 20 lbs. PDAC patients gained 10 lbs after Min #1 compared to 15 lbs in the benign cohort (p < 0.001). Few patients returned to their preoperative weight (29.8% PDAC vs. 40.5% benign, p = 0.04). Patients with early PDAC recurrence (< 13 months) lost more weight (18.0% vs. 13.3% vs. 10.9%, p < 0.001) and gained less weight (2.1% vs. 12.0% vs. 7.9%, p < 0.001) compared with those with late cancer recurrence (≥ 13 months) or no evidence of active disease, respectively. PDAC patients lost 11.2 lbs in the year preceding recurrence diagnosis. Weight loss was not associated with survival; however, weight gain was associated with improved survival. CONCLUSIONS: Resections for PDAC are complicated by a similar degree of weight loss as patients with benign disease, and there is no association with survival. However, failure to gain weight is especially ominous. Weight loss after weight recovery foreshadows disease recurrence. These data suggest that rigorous weight tracking is an untapped surveillance strategy in patients with PDAC.

Prodromal depression and anxiety are associated with worse treatment compliance and survival among patients with pancreatic cancer.

OBJECTIVE: To determine the frequency of depression or anxiety preceding a diagnosis of pancreatic cancer (PC). Further, to examine the association of PC-associated depression or anxiety with treatment compliance and survival. METHODS: 856 patients with PC from a single institution were identified using International Classification of Diseases (ICD) codes. For each case, two non-cancer age- and sex-matched controls were included. Dates of depression or anxiety diagnosis identified using ICD codes were compared to the date of PC diagnosis. The medical record was queried to further explore psychiatric symptoms. Multivariable analyses were performed to examine if prediagnosis depression or anxiety was associated with receipt of treatment or survival. RESULTS: A greater proportion of patients with PC experienced depression or anxiety in the year preceding diagnosis than the overall frequency in controls (4.6% vs. 2.6%, p = 0.005) based on ICD codes. Patients with PC exhibited signs of prodromal depression or anxiety based on ICD codes, clinical documentation of psychiatric symptoms, or initiation of new psychiatric medications more often than controls (20.7% vs. 6.7%, p < 0.001). Prediagnosis depression or anxiety was associated with a reduced likelihood of receiving chemotherapy (OR = 0.58, p = 0.04). There was an associated decrease in overall survival among patients with metastatic disease who experienced depression or anxiety before PC diagnosis (HR = 1.32, p = 0.04). CONCLUSIONS: The frequency of depression or anxiety among patients with PC was higher than the general population. Prediagnosis psychiatric symptoms were associated with reduced chemotherapy utilization and worse overall survival. Thus, timely identification and treatment of these symptoms may improve outcomes.

Time to Neoadjuvant Chemotherapy Initiation Is not Associated With Survival in Pancreatic Cancer.

INTRODUCTION: Not all patients with pancreatic adenocarcinoma (PDAC) tolerate multiagent neoadjuvant chemotherapy (NAC). We utilized institutional data and the National Cancer Database (NCDB) to investigate if time from diagnosis to NAC initiation is associated with survival. METHODS: Patients who received NAC and underwent pancreatectomy at our institution (2010-2021) or within the NCDB (2010-2016) were identified. Time from diagnosis to NAC was grouped: <21, 21-35, and >35 d. Recurrence-free (RFS) and overall survival (OS) was compared. RESULTS: At our institution, 122 patients received NAC before pancreatectomy (<21 d: n = 36; 21-35 d: n = 61; >35 d: n = 25). Demographics, performance status, and anatomic resectability were similar. There was no difference in RFS (13.3 versus 12.4 versus 11.9 mo) or OS (26.7 versus 25.8 versus 26.1 mo) based on NAC timing. Patients who received FOLFIRINOX had an improvement in RFS (14.4 versus 12.2 versus 6.8 mo, P = 0.05) and OS (39.2 versus 21.4 versus 17.3 mo, P = 0.01) compared to gemcitabine with nab-paclitaxel or other regimens. Within the NCDB, 6713 patients were included (<21 d: n = 2087; 21-35 d: n = 2656; >35 d: n = 1970). There was no difference in OS (21.6 versus 20.9 versus 22.2 mo). Multiagent NAC was associated with improved OS compared to single-agent (22.6 versus 18.8 mo, P < 0.001). CONCLUSIONS: Delay in NAC initiation for PDAC is not associated with survival. Patient optimization could be considered with the goal of improving tolerance of multiagent chemotherapy.

Facility type and size-stratified analysis of management patterns and outcomes of patients with localized non-functional pancreatic neuroendocrine tumors.

BACKGROUND: Non-functional neuroendocrine tumors of the pancreas (NF-pNETs) are uncommon. Consensus guidelines have conflicting recommendations. We performed a nationwide analysis of patterns in management and outcomes based on facility type and tumor size. METHODS: The National Cancer Database (2004-2016) was queried for patients with localized NF-pNETs (<1 cm, 1-2 cm, >2 cm) stratified by facility type. Management decisions, operative outcomes, and survival were compared. RESULTS: A total of 7170 patients were included in the analysis (<1 cm = 916; 1-2 cm = 2180; >2 cm = 4074). Most patients were treated at academic facilities (62.8%). Over 67% of patients with tumors <1 cm underwent resection, independent of facility type (p = 0.443). There was no association between facility type and operative vs non-operative management of patients with NF-pNETs 1-2 cm in size. Patients treated at academic facilities were more likely to undergo resection for tumors >2 cm compared to other facility types. Resection was associated with improved survival among patients with tumors 1-2 cm (HR = 0.43,p < 0.001) and >2 cm (HR = 0.32,p < 0.001), but not <1 cm (HR = 0.64,p = 0.054), as compared to non-operative management. CONCLUSION: There is heterogeneity in management of NF-pNETs across facility types. Treatment at academic facilities appears to be associated with higher resection rates for tumors >2 cm. There appears to be an independent association between operative management and improved survival for tumors ≥1 cm in size.

Racial disparities in operative management of localized, non-functional pancreatic neuroendocrine tumors in surgically fit patients.

BACKGROUND: Guidelines recommend resection of non-functional neuroendocrine tumors of the pancreas (NF-pNETs) that are ≥2 cm in size. We compared utilization of surgery based on race. METHODS: We identified non-Hispanic White and Black patients with localized NF-pNETs ≥2 cm and Charlson-Deyo score 0-1 in the NCDB (2004-2016). We compared utilization of surgery by race, adjusting for clinicodemographic variables. Overall survival was compared based on management. RESULTS: A total of 3459 patients were included (White = 3005; Black = 454). Black patients were younger (58vs63 years) and more often treated at academic facilities (65.3%vs60.3%). Overall, Black and White patients underwent surgery at similar rates (77.3%vs79.6%). When stratified by primary site, Black patients with body/tail tumors were less likely to undergo surgery (78.5%vs84.7%). On multivariable analysis, Black race was associated with a lower likelihood of surgery overall (OR 0.74,p = 0.034) and in patients with body/tail tumors (OR 0.56,p = 0.001). Non-operative management was associated with a higher risk of death (HR 3.19,p < 0.001). CONCLUSION: In a national cohort of patients with NF-pNETs meeting criteria for resection, Black race is associated with lower frequency of surgery. Operative intervention is associated with prolonged survival. Persistent racial disparities in management of a surgically curable disease should be targeted for improvement.

A nationwide analysis of clinical trial participation for common hepato-pancreato-biliary malignancies demonstrates survival advantages for subsets of trial patients but disparities in and infrequency of enrollment.

BACKGROUND: We describe factors associated with trial enrollment for patients with hepato-pancreato-biliary (HPB) malignancies. We analyzed the association and effect of trial enrollment on overall survival (OS). METHODS: The National Cancer Database (2004-2017) was queried for common HPB malignancies (pancreatic adenocarcinoma [PDAC] & neuroendocrine tumors, hepatocellular carcinoma [HCC], biliary tract cancers [BTC]). Multivariable logistic regression was used to identify factors associated with trial enrollment. OS was analyzed by multivariable Cox regression. Inverse-probability-weighted Cox regression was utilized to determine the effect of trial enrollment on OS. RESULTS: A total of 1573 (0.3%) of 511,639 patients were enrolled in trials; pancreatic malignancy: 1214 (0.4%); HCC: 217 (0.14%); BTC: 106 (0.15%). HCC and BTC were associated with lower likelihood of enrollment compared with pancreatic malignancy. Black and Hispanic patients were less likely to be enrolled compared to White patients. Treatment at academic facilities and metastatic disease were associated with higher likelihood of enrollment. Enrollment was associated with higher OS for PDAC, metastatic HCC, and metastatic BTC. Trial enrollment exhibited an OS advantage for PDAC and metastatic HCC. CONCLUSION: Nationally, fewer than 1% of patients with HPB malignancies were enrolled in clinical trials. There are racial, sociodemographic, and facility-based disparities in trial enrollment.

Multimodal therapy with or without irreversible electroporation for unresectable locally advanced pancreatic adenocarcinoma: a systematic review and meta-analysis.

BACKGROUND: Irreversible electroporation (IRE) is used as a locoregional treatment modality for patients with locally advanced pancreatic cancer (LAPC), but is non-curative and is associated with postoperative morbidity and mortality. We performed a systematic review and meta-analysis comparing survival outcomes of multimodal therapy with or without IRE. METHODS: Separate searches were performed for multimodal therapy + IRE and multimodal therapy alone given the lack of comparative literature using PubMed, SCOPUS, and Cochrane Library in 3/2021. We determined overall survival (OS) and progression-free survival (PFS) from diagnosis and time of IRE. Treatment-related morbidity and mortality was determined. RESULTS: Of 585 published articles, 48 met inclusion criteria for IRE (n = 27) and without IRE (n = 21) with data for 1420 (IRE) and 1348 (without IRE) patients. The 6/12/24 months OS with IRE was 99%/84%/28%. The 6/12/24 months OS without IRE was 99%/80%/12%. At 12 months from IRE, OS was 55% and PFS was 12%. The mean major complication and 90-day mortality rates for IRE were 17.95% and 2.65%. CONCLUSION: Multimodal therapy alone is associated with similar OS to multimodal therapy + IRE in patients with LAPC. Most patients progress and nearly half die within 1 year of the IRE procedure. Given the lack of quality prospective data, IRE should remain experimental and be used with caution in LAPC.

Medicaid expansion is associated with a higher likelihood of early diagnosis, resection, transplantation, and overall survival in patients with hepatocellular carcinoma.

BACKGROUND: We examined the association between Medicaid expansion (ME) and the diagnosis, treatment, and survival of patients with hepatocellular carcinoma (HCC). METHODS: We identified patients with HCC <65yrs with Medicaid or without insurance within the National Cancer Database before (2010-2013) or after (2015-2017) ME with early (cT1) or intermediate/advanced (cT2-T4 or M1) disease. RESULTS: We identified 4848 patients with HCC before and 4526 after ME. Prior to ME, there was no association between future ME status and diagnosis of early HCC (34.5% vs. 32.9%). There was no association between future ME status and treating early HCC with ablation, resection, or transplantation. Patients with early HCC in future ME states were less likely to die (HR = 0.81, 95% CI: 0.67-0.98). After ME, patients in ME states were more likely to be diagnosed with early HCC (39.2% vs. 32.1%). Patients with early disease in ME states were more likely to undergo resection (OR=1.78, 95% CI: 1.16-2.75) or transplantation (OR=3.20, 95% CI: 1.40-7.33). There was a further associated decrease in the hazard of death (HR=0.68, 95% CI: 0.54-0.86). CONCLUSION: ME was associated with early diagnosis of HCC. For early HCC, ME was associated with increased utilization of resection and transplantation and improvement in survival.