Resection versus resection with ablation: Analysis from the colorectal liver operative metastasis international collaborative.

BACKGROUND: Thermal ablation has recently become a key therapy for the treatment of colorectal liver metastasis (CLM). However, the role of ablation in combination with resection has not yet been firmly established. We hypothesize that in patients with CLM, those who undergo liver resection with ablation (RA) have similar outcomes compared with those who undergo liver resection only. METHODS: We reviewed a multicenter international database of 906 surgical procedures for CLM from 5 high volume hepatobiliary surgical units. Patients undergoing RA (n = 63) were matched based on the number of lesions and tumor size using a 1:1 balanced propensity score analysis with those having resection only (n = 63). Our primary outcomes were overall survival (OS) and disease-free survival (DFS). RESULTS: The mean age of our cohort was 58 ± 11 years, with 43% females. With a median follow-up of 70.8 months, patients in the resection and RA group had a median OS of 45.1 and 54.8 months (p = 0.71), respectively. The median DFS was 22.7 and 14.2 months (p = 0.045), respectively. Using a multivariate Cox proportional hazards regression model, the treatment approach was not associated with OS (p = 0.94) or DFS (p = 0.059). A higher number of lesions is independently associated with worse DFS (hazard ratio: 1.12, p < 0.01). When there was disease recurrence, the region of recurrence was similar between the RA versus resection only groups (p = 0.27), but there was a shorter time to recurrence in the RA group (p = 0.002). CONCLUSION: For CLM, the treatment approach was not significantly associated with OS or DFS, while tumor biology likely played an important role. Prospective research on the quality and effectiveness of thermal ablation combined with hepatic resection is warranted.

Prognostic implications of margin status in association with systemic treatment in a cohort study of patients with resection of colorectal liver metastases.

BACKGROUND: This study investigates the impact of margin status after colorectal liver metastasis (CLM) resection on outcomes of patients after neoadjuvant treatment versus those who underwent upfront resection. METHODS: An international collaborative database of CLM patients who underwent surgical resection was used. Proportional hazard regression models were created for single and multivariable models to assess the relationship between independent measures and median overall survival (mOS). RESULTS: R1 was associated with worse OS in the neoadjuvant group (mOS: 51.8 m for R0 vs. 26.0 m for R1; HR: 2.18). In the patients who underwent upfront surgery, R1 was not associated with OS. (mOS: 46.7 m for R0 vs. 42.6 m for R1). When patients with R1 in each group were stratified by adjuvant treatment, there was no significant difference in the neoadjuvant group, while in the upfront surgery group with R1, adjuvant treatment was associated with significant improvement in OS (mOS: 42.6 m for adjuvant vs. 25.0 m for no adjuvant treatment; HR: 0.21). CONCLUSION: R1 is associated with worse outcomes in the patients who receive neoadjuvant treatment with no significant improvement with the addition of adjuvant therapy, likely representing an aggressive tumor biology. R1 did not impact OS in patients with upfront surgery who received postoperative chemotherapy.

Survival Outcomes of Optimally Treated Colorectal Metastases: The Importance of R0 Status in Surgical Treatment of Hepatic and Peritoneal Surface Disease.

BACKGROUND: Although colorectal hepatic metastases (HM) and peritoneal surface disease (PSD) are distinct biologic diseases, they may have similar long-term survival when optimally treated with surgery. METHODS: This study retrospectively reviewed prospectively managed databases. Patients undergoing R0 or R1 resections were analyzed with descriptive statistics, the Kaplan-Meier method, and Cox regression. Survival was compared over time for the following periods: 1993-2006, 2007-2012, and 2013-2020. RESULTS: The study enrolled 783 HM patients undergoing liver resection and 204 PSD patients undergoing cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). Compared with PSD patients, HM patients more often had R0 resections (90.3% vs. 32.4%), less often had pre-procedure chemotherapy (52.4% vs. 92.1%), and less often were functionally independent (79.7% vs. 95.6%). The 5-year overall survival for HM was 40.9%, with a median survival period of 45.8 months versus 25.8% and 33.4 months, respectively, for PSD (p < 0.05). When stratified by resection status, R0 HM and R0 PSD did not differ significantly in median survival (49.0 vs. 45.4 months; p = 0.83). The median survival after R1 resection also was similar between HM and PSD (32.6 vs. 26.9 months; p = 0.59). Survival between the two groups again was similar over time when stratified by resection status. The predictors of survival for HM patients were R0 resection, number of lesions, intraoperative transfusion, age, and adjuvant chemotherapy. For the PSD patients, the predictors were peritoneal cancer index (PCI) score, estimated blood loss (EBL), and female gender. CONCLUSION: The study showed that R0 resections are associated with improved outcomes and that median survival is similar between HM and PSD patients when it is achieved. Surveillance and treatment strategies that facilitate R0 resections are needed to improve results, particularly for PSD.

Conditional Survival After Hepatectomy for Colorectal Liver Metastasis: Results from the Colorectal Liver Operative Metastasis International Collaborative (COLOMIC).

INTRODUCTION: Complete resection of colorectal liver metastasis (CLM) improves long-term survival in colorectal cancer. However, there is limited recent data on conditional survival (CS) as postoperative survival milestones are achieved post-hepatectomy. METHODS: A retrospective analysis was performed on the penta-institutional Colorectal Liver Operative Metastasis International Collaborative (COLOMIC), with 906 consecutive CLM hepatectomy cases. CS was calculated using Bayes' theorem and Kaplan-Meier analysis. Additional CS analyses were performed on additional clinicopathologic risk factors, including colon cancer laterality, KRAS mutation status, and extrahepatic disease. RESULTS: The 5-year CS was 40.6%, 45.3%, 52.8%, and 65.3% at 0, 1, 2, and 3 years postoperatively, with significant improvements each year (p < 0.005). CS was not significantly different between right-sided and left-sided colorectal cancers by 3 years postoperatively. Patients with KRAS mutations had worse CS at all timepoints (p < 0.001). Extrahepatic disease was a poor prognostic factor for OS and CS (p < 0.001). However, CS for patients with KRAS mutations or extrahepatic disease improved significantly as 2-year, postoperative survival was achieved (p < 0.05). CONCLUSIONS: Five-year CS after hepatectomy for CLM improved with each passing year of survival postoperatively. Although extrahepatic disease and KRAS mutations are poor prognostic factors for OS, these populations still had improved CS after 2 years postoperatively.

Perioperative chemotherapy for resectable colorectal liver metastases: Analysis from the Colorectal Operative Liver Metastases International Collaborative (COLOMIC).

BACKGROUND: Chemotherapy has been increasingly combined with surgery as multimodality treatment for resectable colorectal-liver metastases (CLM). There is paucity of clinical data addressing optimal timing of chemotherapy relative to surgery. We examined outcomes of patients undergoing hepatectomy for resectable CLM. METHODS: Seven hundred and eighteen patients treated with hepatectomy for CLM were analyzed from five hepatobiliary institutions between 2000 and 2018. Overall survival (OS) was measured from time of hepatectomy for patients receiving: surgery alone, neoadjuvant, adjuvant, and neoadjuvant-plus-adjuvant (perioperative) chemotherapy. Kaplan-Meier analysis was performed to detect differences in OS between treatment groups. Single- and multi-variable analysis with Cox proportional hazards were run for OS between groups. RESULTS: One hundred and thirty-seven patients (19.08%) received surgery, 104 (14.48%) received neoadjuvant-only, 214 (29.81%) received adjuvant-only, and 263 (36.63%) received perioperative chemotherapy; with median OS of 48.20, 46.83, 56.27, and 49.93 months, respectively. No differences in median OS were seen between groups on Kaplan-Meier analysis. No significant difference in Charlson-Deyo comorbidity status was seen between groups (p = 0.853), while significant difference was seen in maximum tumor size (p = 0.0023). On multivariate analysis, adjuvant (p = 0.010) and perioperative (p = 0.020) chemotherapy were independently associated with OS compared to surgery alone. DISCUSSION: Despite group differences, chemotherapy after surgery was independently associated with improved OS in CLM.

Outcomes after repeat hepatectomy for colorectal liver metastases from the colorectal liver operative metastasis international collaborative (COLOMIC).

BACKGROUND: Resection of colorectal liver metastasis (CLM) is beneficial when feasible. However, the benefit of second hepatectomy for hepatic recurrence in CLM remains unclear. METHODS: The Colorectal Liver Operative Metastasis International Collaborative retrospectively examined 1004 CLM cases from 2000 to 2018 from a total of 953 patients. Hepatic recurrence after initial hepatectomy was identified in 218 patients. Kaplan-Meier analysis was performed for overall survival (OS) and recurrence-free survival (RFS). Propensity score matching (PSM) was performed to offset selection bias. Cox proportional-hazards regression was performed to identify risk factors associated with OS. RESULTS: A total of 51 patients underwent second hepatectomy. Unadjusted median OS was 60.1 months in repeat-hepatectomy versus 38.3 months in the single-hepatectomy group (p = 0.015). In the PSM population, median OS remained significantly better in the repeat-hepatectomy group (60.1 vs. 33.1 months; p = 0.0023); median RFS was 12.4 months for the repeat-hepatectomy group, versus 9.8 months in the single-hepatectomy group (p = 0.0050). Repeat hepatectomy was associated with lower risk of death (hazard ratio: 0.283; p = 0.000012). Obesity, tobacco use, and high intraoperative blood loss were associated with significant risk of death (p < 0.05). CONCLUSION: In CLM with hepatic recurrence, second hepatectomy was beneficial for OS. With PSM, the OS benefit of performing a second hepatectomy remained significant.

Association of primary tumor laterality with surgical outcomes for colorectal liver metastases: results from the Colorectal Liver Operative Metastasis International Collaborative (COLOMIC).

BACKGROUND: Primary laterality of colorectal cancer is thought to be associated with differences in outcomes. Liver metastasis is the most common site of solitary colorectal cancer spread. However, how primary colorectal cancer laterality affects outcomes in colorectal liver metastasis remains unclear. METHODS: The Colorectal Liver Operative Metastasis International Collaborative (COLOMIC) of operative hepatectomy cases for colorectal liver metastasis was compiled from five participating institutions. This included consecutive cases from 2000 to 2018 at all sites. A total of 884 patients were included in this study. Univariate, multivariate, and Kaplan-Meier analyses were performed. RESULTS: Patients with left-sided versus right-sided cancers had significantly better overall survival: 49.4 vs. 41.8 months (p < 0.05). Patients with KRAS mutations had significantly worse median overall survival compared to KRAS wild-type (43.6 vs 56.1 months; p < 0.001). In left-sided cancers, KRAS mutations were associated with significantly worse median overall survival compared to KRAS wild-type cancers (43.6 vs 56.6 months; p < 0.01). This association was absent in patients with right-sided primary tumors. Multivariate Cox regression analysis revealed different variable sets (non-overlapping) were associated with overall survival, when comparing left-sided and right-sided cancers. CONCLUSION: Understanding how primary tumor laterality and related biological aspects affect long-term outcomes can potentially inform treatment decisions for patients with colorectal liver metastases.

APC mutational patterns in gastric adenocarcinoma are enriched for missense variants with associated decreased survival.

Adenomatous polyposis coli (APC) mutations are causally associated with familial adenomatous polyposis (FAP) and are recurrent somatic events across numerous tumor types, including gastric adenocarcinoma. Severity of disease in FAP correlates with specific APC mutations, but the impact of given mutations on phenotype in gastric cancer is not well studied. Sequencing data from the Genomic Data Commons (GDC) demonstrate an APC mutational pattern in gastric cancer that differs dramatically from that seen in colon cancer. Exome sequencing data from APC-mutant colon and gastric adenocarcinomas in GDC was filtered for single nucleotide variants (SNVs) using MuTect2 Variant Aggregation and Masking pipeline, Somatic Aggregation Workflow. APC mutations were found in 57/441 gastric (12.9%) and 309/433 colon adenocarcinomas (71.4%). There was a significant difference in the proportion of stopgain, frameshift, and missense mutations between tumor types(P < .00001). Colon tumors were predominated by frameshift and stopgains, comprising 47.7% and 35.7%, respectively. In contrast, 47.1% of gastric mutations were missense. Gastric tumors harboring missense mutations showed decreased overall survival relative to other mutational subtypes(P = .008). In the gastric samples, 25.9% of frameshift and stopgain mutations are in the 3' portion of the gene, compared to 1.4% of colon samples. APC mutations demonstrate different distributions in gastric and colon adenocarcinoma, with a shift toward missense variants in gastric tumors and worse survival in gastric tumors harboring them. As different mutations confer variable degrees of protein dysfunction and resultant clinical manifestation, expanded investigation of specific mutational patterns will prove integral to future-risk stratification strategies.

Intrahepatic Cholangiocarcinoma: Socioeconomic Discrepancies, Contemporary Treatment Approaches and Survival Trends from the National Cancer Database.

OBJECTIVE: The aim of this study was to evaluate socioeconomic discrepancies in current treatment approaches and survival trends among patients with intrahepatic cholangiocarcinoma (ICC). METHODS: The 2004-2015 National Cancer Database was retrospectively analyzed for histopathologically proven ICC. Treatment predictors were evaluated using multinomial logistic regression and overall survival via multivariable Cox models. RESULTS: Overall, 12,837 ICC patients were included. Multiple factors influenced treatment allocation, including age, education, comorbidities, cancer stage, grade, treatment center, and US state region (multivariable p < 0.05). The highest surgery rates were observed in the Middle Atlantic (28.7%) and lowest rates were observed in the Mountain States (18.4%). Decreased ICC treatment likelihood was observed for male African Americans with Medicaid insurance and those with low income (multivariable p < 0.05). Socioeconomic treatment discrepancies translated into decreased overall survival for patients of male sex (vs. female; hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.16-1.26, p < 0.001), with low income (< $37,999 vs. ≥ $63,000 annually; HR 1.07, 95% CI 1.01-1.14, p = 0.032), and with Medicaid insurance (vs. private insurance; HR 1.13, 95% CI 1.04-1.23, p = 0.006). Both surgical and non-surgical ICC management showed increased survival compared with no treatment, with the longest survival for surgery (5-year overall survival for surgery, 33.5%; interventional oncology, 11.8%; radiation oncology/chemotherapy, 4.4%; no treatment, 3.3%). Among non-surgically treated patients, interventional oncology yielded the longest survival versus radiation oncology/chemotherapy (HR 0.73, 95% CI 0.65-0.82, p < 0.001). CONCLUSIONS: ICC treatment allocation and outcome demonstrated a marked variation depending on socioeconomic status, demography, cancer factors, and US geography. Healthcare providers should address these discrepancies by providing surgery and interventional oncology as first-line treatment to all eligible patients, with special attention to the vulnerable populations identified in this study.

Pancreatic Adenocarcinoma, Version 1.2019.

The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights discuss important updates to the 2019 version of the guidelines, focusing on postoperative adjuvant treatment of patients with pancreatic cancers.

Exome analysis of the evolutionary path of hepatocellular adenoma-carcinoma transition, vascular invasion and brain dissemination.

Hepatocellular adenoma (HCA) is a rare benign liver tumor, predominantly seen in young women. Its major complications are malignant transformation, spontaneous hemorrhage, and rupture. We describe a case of a young female with no underlying liver disease who presented with acute abdominal pain and was found to have a 17cm heterogeneous mass in the left lobe of the liver. She underwent left hepatectomy and pathology revealed a 14cm moderately differentiated hepatocellular carcinoma (HCC) arising in a shell of a HCA. At that time, vascular invasion was already present. She rapidly developed recurrent multifocal hepatic lesions and subsequent spread to the brain, leading to her death 18months after surgery. To investigate the underlying genetic events occurring during hepatocellular adenoma-carcinoma transition and extra-hepatic dissemination, we performed whole exome sequencing of DNA isolated from peripheral blood leucocytes, HCA, HCC, tumor thrombus and brain metastasis. Our data show a step-wise addition of somatic mutations and copy number variations with disease progression, suggesting a linear tumor evolution, which is supported by clonality analysis. Specifically, using a model based clustering of somatic mutations, one single founding clone arising in the HCA, which included catenin beta 1 (CTNNB1) and IL6ST driver mutations, was identified and displayed an increasing clonality rate in HCC, tumor thrombus and brain metastasis. Our data highlight the feasibility of performing whole exome capture, sequencing and analysis using formalin-fixed paraffin-embedded (FFPE) samples, and we describe the first genomic longitudinal study of hepatocellular adenoma-carcinoma transition, vascular invasion and brain metastasis with detailed clinicopathologic annotation.

Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology.

Ductal adenocarcinoma and its variants account for most pancreatic malignancies. High-quality multiphase imaging can help to preoperatively distinguish between patients eligible for resection with curative intent and those with unresectable disease. Systemic therapy is used in the neoadjuvant or adjuvant pancreatic cancer setting, as well as in the management of locally advanced unresectable and metastatic disease. Clinical trials are critical for making progress in treatment of pancreatic cancer. The NCCN Guidelines for Pancreatic Adenocarcinoma focus on diagnosis and treatment with systemic therapy, radiation therapy, and surgical resection.

Final analysis of a phase II study of modified FOLFIRINOX in locally advanced and metastatic pancreatic cancer.

BACKGROUND: Modifications of FOLFIRINOX are widely used despite the absence of prospective data validating efficacy in metastatic disease (metastatic pancreatic cancer (MPC)) or locally advanced pancreatic cancer (LAPC). We conducted a multicentre phase II study of modified FOLFIRINOX in advanced pancreatic cancer to assess the impact of dose attenuation in MPC and efficacy in LAPC. METHODS: Patients with untreated MPC or LAPC received modified FOLFIRINOX (irinotecan and bolus 5-fluorouracil reduced by 25%). Adverse events (AEs) were compared with full-dose FOLFIRINOX. Response rate (RR), median progression-free survival (PFS) and median overall survival (OS) were determined. RESULTS: In total, 31 and 44 patients with LAPC and MPC were enrolled, respectively. In MPC, efficacy of modified FOLFIRINOX was comparable with FOLFIRINOX with RR 35.1%, OS 10.2 months (95% CI 7.65-14.32) and PFS 6.1 months (95% CI 5.19-8.31). In LAPC, efficacy was notable with RR 17.2%, resection rate 41.9%, PFS 17.8 months (95% CI 11.0-23.9) and OS 26.6 months (95% CI 16.7, NA). Neutropenia (P<0.0001), vomiting (P<0.001) and fatigue (P=0.01) were significantly decreased. [(18)F]-Fluorodeoxyglucose positron emission tomography imaging response did not correlate with PFS or OS. CONCLUSIONS: In this first prospective study of modified FOLFIRINOX in MPC and LAPC, we observed decreased AEs compared with historical control patients. In MPC, the efficacy appears comparable with FOLFIRINOX. In LAPC, PFS and OS were prolonged and support the continued use of FOLFIRINOX in this setting.

Resection of oligometastatic lung cancer to the pancreas may yield a survival benefit in select patients--a systematic review.

OBJECTIVES: To conduct a systematic review of the existing literature regarding surgical therapy for oligometastatic lung cancer to the pancreas. METHODS: Data was collected on patients with singular pancreatic metastases from lung cancer from papers published between January 1970 and June 2014. This was performed following the Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) guidelines. Kaplan-Meier and Cox Regression analyses were then used to determine and compare survival. RESULTS: There were 27 papers that fulfilled the search criteria, from which data on 32 patients was collected. Non-small cell lung cancer (NSCLC) was the most prevalent type of primary lung malignancy, and metachronous presentations of metastases were most common. Lesions were most frequently located in the pancreatic head and consequently the most common curative intent metastasectomy was pancreaticoduodenectomy. There was a statistically significant survival benefit for patients whose metastasis were discovered incidentally by surveillance CT as opposed to those whose metastasis were discovered during a work up for new somatic complaints (p = 0.024). The overall median survival for patients undergoing curative intent resection was 29 months, with 2-year and 5-year survivals of 65% and 21% respectively. Palliative surgery or medical only management was associated with a median survival of 8 months and 2-year and 5-year survivals of 25% and 8% respectively. CONCLUSIONS: Curative intent resection of isolated pancreatic metastasis from lung cancer may be beneficial in a select group of patients.

The novel tumor angiogenic factor, adrenomedullin-2, predicts survival in pancreatic adenocarcinoma.

BACKGROUND: Tumor angiogenesis has been demonstrated to have an important role in the development, progression, and metastasis of pancreas cancer. Adrenomedullin-2 (ADM2) is a calcitonin gene-related peptide that has recently been shown to be a novel tumor angiogenesis factor, acting via mitogen-activated protein kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinase/Akt, and vascular endothelial growth factor/vascular endothelial growth factor-2 signaling pathways. Through the use of tissue microarray (TMA) technology, we hypothesize that ADM2 is an important tumor angiogenesis factor in pancreatic cancer. METHODS: Multiple TMAs were created using tissue from pancreatic cancer patients resected between January 1996 and December 2006. Core tissue samples of formalin-fixed, paraffin-embedded blocks of pancreatic cancer tissue were collected through an institutional review board-approved protocol and linked to available clinicopathologic data. Two TMAs consisting of 112 and 60 patients with pancreatic adenocarcinoma were studied for ADM2 protein expression using a quantitative, automated immunofluorescent microscopy system, a technology that removes potential observer bias in TMA analysis. The results were analyzed using independent Student t-test, chi-square, log-rank regression, and Kaplan-Meier methods. RESULTS: One hundred sixteen patients were identified for complete analysis, and 56 patients had complete survival data. Median follow-up for survivors was 14.5 mo. Total cellular levels of ADM2 were found to be a predictor of survival in pancreatic cancer. Low ADM2 levels were associated with a higher 5-y survival compared with high ADM2 levels (18% versus 6%, P = 0.05). Median survival was also worse in high ADM2 expressers (18.7 versus 8.6 mo). In accordance with prior-published pancreatic cancer data, a worse histologic grade (P = 0.001), tumor (T) stage (P = 0.009), and overall disease stage (P = 0.004), all portended a worse survival. CONCLUSIONS: For the first time, we have demonstrated that high levels of ADM2 expression predict a poorer survival in patients with pancreatic adenocarcinoma. This suggests a possible role of ADM2 in pancreas cancer and as a novel biomarker that predicts poorer survival. Additional study of ADM2 in pancreatic cancer will help reveal its true angiogenic role in pancreas cancer and its potential role as a novel therapeutic target.

Hepatocellular carcinoma: a comprehensive overview of surgical therapy.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with a rising incidence in the United States. The increase in medical and locally ablative therapies have improved prognosis, however surgery, either liver resection or transplantation, remains the mainstay of therapy. An increased understanding of liver anatomy, improved imaging modalities and refinements of surgical technique have all led to improved outcomes after surgery. Both resection and transplantation may be used in a complementary manner. Resection remains the treatment of choice for HCC when feasible. Liver transplantation, which removes both the tumor and the underlying diseased liver offers excellent outcomes in patients that meet the Milan criteria. While both these modalities have relatively well defined roles, the treatment of these patients must be tailored individually, using a multidisciplinary approach, to maximize survival, quality of life and allocation of scarce organs.

Perioperative Modified FOLFIRINOX for Resectable Pancreatic Cancer: A Nonrandomized Controlled Trial.

Importance: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor, and durable disease control is rare with the current standard of care, even for patients who undergo surgical resection. Objective: To assess whether neoadjuvant modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) leads to early control of micrometastasis and improves survival. Design, Setting, and Participants: This open-label, single-arm, phase 2 nonrandomized controlled trial for resectable PDAC was conducted at the Yale Smilow Cancer Hospital from April 3, 2014, to August 16, 2021. Pancreatic protocol computed tomography was performed at diagnosis to assess surgical candidacy. Data were analyzed from January to July 2023. Interventions: Patients received 6 cycles of neoadjuvant mFOLFIRINOX before surgery and 6 cycles of adjuvant mFOLFIRINOX. Whole blood was collected and processed to stored plasma for analysis of circulating tumor DNA (ctDNA) levels. Tumors were evaluated for treatment response and keratin 17 (K17) expression. Main Outcomes and Measures: The primary end point was 12-month progression-free survival (PFS) rate. Additional end points included overall survival (OS), ctDNA level, tumor molecular features, and K17 tumor levels. Survival curves were summarized using Kaplan-Meier estimator. Results: Of 46 patients who received mFOLFIRINOX, 31 (67%) were male, and the median (range) age was 65 (46-80) years. A total of 37 (80%) completed 6 preoperative cycles and 33 (72%) underwent surgery. A total of 27 patients (59%) underwent resection per protocol (25 with R0 disease and 2 with R1 disease); metastatic or unresectable disease was identified in 6 patients during exploration. Ten patients underwent surgery off protocol. The 12-month PFS was 67% (90% CI, 56.9-100); the median PFS and OS were 16.6 months (95% CI, 13.3-40.6) and 37.2 months (95% CI, 17.5-not reached), respectively. Baseline ctDNA levels were detected in 16 of 22 patients (73%) and in 3 of 17 (18%) after 6 cycles of mFOLFIRINOX. Those with detectable ctDNA levels 4 weeks postresection had worse PFS (hazard ratio [HR], 34.0; 95% CI, 2.6-4758.6; P = .006) and OS (HR, 11.7; 95% CI, 1.5-129.9; P = .02) compared with those with undetectable levels. Patients with high K17 expression had nonsignificantly worse PFS (HR, 2.7; 95% CI, 0.7-10.9; P = .09) and OS (HR, 3.2; 95% CI, 0.8-13.6; P = .07). Conclusions and Relevance: This nonrandomized controlled trial met its primary end point, and perioperative mFOLFIRINOX warrants further evaluation in randomized clinical trials. Postoperative ctDNA positivity was strongly associated with recurrence. K17 and ctDNA are promising biomarkers that require additional validation in future prospective studies. Trial Registration: ClinicalTrials.gov Identifier: NCT02047474.

Surgical therapy for hepatocellular carcinoma: formulating a rational approach.

Hepatocellular carcinoma is one of the most common malignancies worldwide, and its incidence continues to rise in the United States. Partial hepatectomy and liver transplantation remains the mainstay of treatment for localized disease and provides significant improvement in long-term survival, as well as the potential for cure. The indications and criteria for resection and transplantation are well established, but continue to undergo significant modification over time. Surgical resection is the primary therapeutic modality in patients with well-compensated liver disease, and transplantation is highly effective in early-stage tumors in patients with severe underlying liver disease. The relative role for each of these modalities must be tailored to individual patients based on a rational approach designed to balance quality of life, organ allocation, and patient survival.