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.

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.

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.

Combined multiagent chemotherapy and radiotherapy is associated with prolonged overall survival in patients with non-operatively managed stage II-III pancreatic adenocarcinoma.

BACKGROUND: Most patients with pancreatic adenocarcinoma (PDAC) do not undergo surgical resection. The role of radiotherapy (RT) in non-operatively managed localized pancreatic adenocarcinoma is unclear. METHODS: The National Cancer Database (2010-2016) was queried for patients with clinical stage II-III PDAC treated with multiagent systemic chemotherapy (CT) +/- RT but not surgery. Factors associated with the receipt of RT and overall survival were compared after adjusting for patient demographics and clinical characteristics. RESULTS: A total of 14,921 patients were included, of whom 9279 received CT and 5382 received CT + RT. Patients treated with CT + RT were more likely to be younger (65vs66yrs), treated at non-academic facilities (48.8%vs46.7%), have private insurance (40.3%vs36.5%), and have clinical T4 tumors (53.6%vs48.7%). Most patients who were treated with RT received external beam radiotherapy (89.3%), and the median dose was 5,000 cGy. Median time to start of RT was 129 days. CT + RT was associated with longer overall survival (15.9vs11.8mos,p < 0.001), and remained associated with survival on multivariable analysis (HR 0.74, 95%CI 0.70-0.78). On a 4-month conditional survival analysis, combined CT + RT remained associated with improved survival compared to CT alone (16.0vs13.1mos,p < 0.001). CONCLUSIONS: In patients with non-operatively managed localized pancreatic adenocarcinoma, combined radiotherapy and multiagent systemic chemotherapy is associated with improved overall survival compared to chemotherapy alone.

Average treatment effect of facility hepatopancreatobiliary cancer volume on survival of non-resected pancreatic adenocarcinoma.

BACKGROUND: To examine the average treatment effect of hepato-pancreato-biliary (HPB) cancer volume on survival outcomes of patients with non-resected pancreatic adenocarcinoma (PDAC). METHODS: We queried the National Cancer Database (2004-2018) for patients with HPB malignancies (PDAC, pancreatic neuroendocrine neoplasms, hepatocellular carcinoma, biliary tract cancers). We determined the 25th, 50th, and 75th percentiles based on the total annual HPB volume. We then identified patients with non-resected PDAC. We utilized inverse probability (IP)-weighted Cox regression to estimate the effect of facility volume on overall survival (OS). RESULTS: We identified 710,988 patients with HPB malignancies. The 25th, 50th, and 75th percentiles of total annual HPB volume were 32, 71, and 177 cases/year, respectively. We included a total of 196,150 patients with non-resected PDAC. Patients treated at ≥25th, ≥50th, and ≥75th percentile facilities had improved median OS compared to those treated at facilities below these thresholds (5.8 vs. 4.2months, 6.5 vs. 4.5months, 7.5 vs. 4.8months, respectively; p < 0.001 for all). Treatment at facilities ≥25th, ≥50th, and ≥75th percentile resulted in lower hazards of death than treatment at lower-percentile facilities (HR: 0.87, 95% CI: 0.84-0.90; HR: 0.87, 95% CI: 0.83-0.91; HR: 0.85, 95% CI: 0.79-0.91, respectively). CONCLUSION: Our data suggest that consolidation of care of patients with PDAC to high-volume centers may be beneficial even in the nonoperative setting.

Neoadjuvant chemotherapy is associated with improved survival in patients with left-sided pancreatic adenocarcinoma.

BACKGROUND: Neoadjuvant chemotherapy is used infrequently in the management of distal pancreatic cancers. We investigated outcomes associated with neoadjuvant chemotherapy or up-front surgery in patients undergoing distal pancreatectomy. METHODS: The National Cancer Database (2004-2016) was queried for patients with pancreas cancer who underwent distal pancreatectomy. Demographics, clinical characteristics, postoperative outcomes, pathologic outcomes, and overall survival were analyzed by univariate and multivariate analysis. RESULTS: Six thousand five-hundred and twenty-three patients were included, including 5,643 who underwent up-front distal pancreatectomy and 880 who received neoadjuvant therapy. Factors associated with receipt of neoadjuvant chemotherapy included care at academic/research programs, higher education level, higher clinical T stage, higher clinical N stage, and elevated carbohydrate antigen 19-9 level. Patients who received neoadjuvant therapy had fewer positive lymph nodes, higher margin-negative resection rate, lower 30-day readmission rate, and lower 90-day mortality rate. Patients who received neoadjuvant therapy had longer median overall survival (28.8 vs 22.0 months; P < .001). On multivariate analysis, neoadjuvant therapy remained independently associated with improved survival (hazards ratio, 0.72; 95% confidence inteval, 0.63-0.82; P < .001). CONCLUSIONS: Neoadjuvant therapy in patients with left-sided pancreatic cancers is associated with improved pathologic outcomes as well as longer overall survival. Neoadjuvant therapy should be considered in all patients with PDAC regardless of tumor location.

Circulating Tumor DNA Predicts Early Recurrence Following Locoregional Therapy for Oligometastatic Colorectal Cancer.

(1) Background: Local therapies offer a potentially curative approach for patients with oligometastatic colorectal cancer (CRC). An evidence-based consensus recommendation for systemic therapy following definitive locoregional therapy is lacking. Tumor-informed circulating tumor DNA (ctDNA) might provide information to help guide management in this setting. (2) Methods: A multi-institutional retrospective study was conducted, including patients with CRC that underwent curative-intent locoregional therapy to an isolated site of metastatic disease, followed by tumor-informed ctDNA assessment. The Kaplan-Meier method and log-rank tests were used to compare disease-free survival based on ctDNA results. ctDNA test performance was compared to carcinoembryonic antigen (CEA) test results using McNemar's test. (3) Results: Our study cohort consisted of 87 patients treated with locoregional interventions who underwent ctDNA testing. The initial ctDNA test post-intervention was positive in 28 patients and negative in 59 patients. The median follow-up time was 14.0 months. Detectable ctDNA post-intervention was significantly associated with early disease recurrence, with a median disease-free survival (DFS) of 6.63 months compared to 21.30 months in ctDNA-negative patients (p < 0.001). ctDNA detected a numerically higher proportion of recurrences than CEA (p < 0.097). Post-intervention systemic therapy was not associated with improved DFS (p = 0.745). (4) Conclusions: ctDNA results are prognostically important in oligometastatic CRC, and further prospective studies are urgently needed to define its role in guiding clinical decisions.

Neoadjuvant Radiotherapy is Associated With Improved Pathologic Outcomes and Survival in Resected Stage II-III Pancreatic Adenocarcinoma Treated With Multiagent Neoadjuvant Chemotherapy in the Modern Era.

BACKGROUND: Neoadjuvant chemotherapy (CT) is being utilized more frequently in patients diagnosed with localized pancreatic cancer. The role of additional neoadjuvant radiotherapy (RT) remains undefined. We explored outcomes associated with neoadjuvant RT in the modern era. METHODS: The National Cancer Database (2010-2017) was queried for patients with clinical stage II-III pancreatic adenocarcinoma who received neoadjuvant multiagent systemic CT +/- RT. Demographics, pathologic outcomes, postoperative outcomes, and overall survival were compared. RESULTS: A total of 5245 patients were included, of whom 3123 received CT and 1941 received CT + RT. Use of RT decreased over the 8-year study period. On multivariable analysis, treatment at academic facilities (odds ratio (OR) = 1.52, P < .001) and clinical T4 tumors (OR = 1.68, P < .001) were independently associated with receipt of RT. Patients treated with CT + RT had a higher frequency of ypT0-T2 tumors (35.8% vs. 22.7%) and a lower rate of ypT3-T4 tumors (57.3% vs. 72.8%; P < .001), lower rate of node-positive disease (36.6% vs. 59.8%, P < .001), and margin-positive resections (13.8% vs. 20.2%, P < .001), but slightly higher 90-day postoperative mortality (4.9% vs. 3.6%, P = .04). Neoadjuvant chemotherapy+ RT was associated with longer overall survival (32.7 vs. 29.8 months, P = .008), and remained independently associated with survival on multivariable analysis (HR = .85, P < .001). DISCUSSION: In patients with stage II-III pancreatic adenocarcinoma, the addition of neoadjuvant RT to multiagent neoadjuvant CT may be associated with increased rates of node-negative and margin-negative resection, as well as improved overall survival.