Hepatectomy versus systemic therapy for liver-limited BRAF V600E-mutated colorectal liver metastases: multicentre retrospective study.

BACKGROUND: To date, only two studies have compared the outcomes of patients with liver-limited BRAF V600E-mutated colorectal liver metastases (CRLMs) managed with resection versus systemic therapy alone, and these have reported contradictory findings. METHODS: In this observational, international, multicentre study, patients with liver-limited BRAF V600E-mutated CRLMs treated with resection or systemic therapy alone were identified from institutional databases. Patterns of recurrence/progression and overall survival were compared using multivariable analyses of the entire cohort and a propensity score-matched cohort. RESULTS: Of 170 patients included, 119 underwent hepatectomy and 51 received systemic treatment. Surgically treated patients had a more favourable pattern of recurrence with most recurrences limited to a single site, whereas diffuse progression was more common among patients who received systemic treatment (19 versus 44%; P = 0.002). Surgically treated patients had longer median overall survival (35 versus 20 months; P < 0.001). Hepatectomy was independently associated with better OS than systemic treatment alone (HR 0.37, 95% c.i. 0.21 to 0.65). In the propensity score-matched cohort, surgically treated patients had longer median overall survival (28 versus 20 months; P < 0.001); hepatectomy was independently associated with better overall survival (HR 0.47, 0.25 to 0.88). CONCLUSION: BRAF V600E mutation should not be considered a contraindication to surgery for patients with resectable, liver-only CRLMs.

Comparing Survival of Perihilar Cholangiocarcinoma After R1 Resection Versus Palliative Chemotherapy for Unresected Localized Disease.

BACKGROUND: Resection of perihilar cholangiocarcinoma (pCCA) is a complex procedure with a high risk of postoperative mortality and early disease recurrence. The objective of this study was to compare patient characteristics and overall survival (OS) between pCCA patients who underwent an R1 resection and patients with localized pCCA who received palliative systemic chemotherapy. METHODS: Patients with a diagnosis of pCCA between 1997-2021 were identified from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) registry. pCCA patients who underwent an R1 resection were compared with patients with localized pCCA (i.e., nonmetastatic) who were ineligible for surgical resection and received palliative systemic chemotherapy. The primary outcome was OS. RESULTS: Overall, 146 patients in the R1 resection group and 92 patients in the palliative chemotherapy group were included. The palliative chemotherapy group more often underwent biliary drainage (95% vs. 66%, p < 0.001) and had more vascular encasement on imaging (70% vs. 49%, p = 0.012) and CA 19.9 was more frequently >200 IU/L (64 vs. 45%, p = 0.046). Median OS was comparable between both groups (17.1 vs. 16 months, p = 0.06). Overall survival at 5 years after diagnosis was 20.0% with R1 resection and 2.2% with chemotherapy. Type of treatment (i.e., R1 resection or palliative chemotherapy) was not an independent predictor of OS (hazard ratio 0.76, 95% confidence interval 0.55-1.07). CONCLUSIONS: Palliative systemic chemotherapy should be considered instead of resection in patients with a high risk of both R1 resection and postoperative mortality.

Is Precision Surgery Applicable to Colorectal Liver Metastases? A Systematic Review and Meta-analysis of Studies that Investigate the Association of Surgical Technique with Outcomes in the Context of Distinct Tumor Biology.

BACKGROUND: Although some data suggest that patients with mutRAS colorectal liver metastases (CRLM) may benefit from anatomic hepatectomy, this topic remains controversial. We performed a systematic review and meta-analysis to determine whether RAS mutation status was associated with prognosis relative to surgical technique [anatomic resection (AR) vs. nonanatomic resection (NAR)] among patients with CRLM. PATIENTS AND METHODS: A systematic review and meta-analysis of studies were performed to investigate the association of AR versus NAR with overall and liver-specific disease-free survival (DFS and liver-specific DFS, respectively) in the context of RAS mutation status. RESULTS: Overall, 2018 patients (831 mutRAS vs. 1187 wtRAS) were included from five eligible studies. AR was associated with a 40% improvement in liver-specific DFS [hazard ratio (HR) = 0.6, 95% confidence interval (CI) 0.44-0.81, p = 0.01] and a 28% improvement in overall DFS (HR = 0.72, 95% CI 0.54-0.95, p = 0.02) among patients with mutRAS tumors; in contrast, AR was not associated with any improvement in liver-specific DFS or overall DFS among wtRAS patients. These differences may have been mediated by the 40% decreased incidence in R1 resection among patients with mutRAS tumors who underwent AR versus NAR [relative risk (RR): 0.6, 95% CI 0.40-0.91, p = 0.02]. In contrast, the probability of an R1 resection was not decreased among wtRAS patients who underwent AR versus NAR (RR: 0.93, 95% CI 0.69-1.25, p = 0.62). CONCLUSIONS: The data suggest that precision surgery may be relevant to CRLM. Specifically, rather than a parenchymal sparing dogma for all patients, AR may have a role in individuals with mutRAS tumors.

The Influence of Hepatic Steatosis and Fibrosis on Postoperative Outcomes After Major Liver Resection of Perihilar Cholangiocarcinoma.

BACKGROUND: Surgical resection for perihilar cholangiocarcinoma (pCCA) is associated with high operative risks. Impaired liver regeneration in patients with pre-existing liver disease may contribute to posthepatectomy liver failure (PHLF) and postoperative mortality. This study aimed to determine the incidence of hepatic steatosis and fibrosis and their association with PHLF and 90-day postoperative mortality in pCCA patients. METHODS: Patients who underwent a major liver resection for pCCA were included in the study between 2000 and 2021 from three tertiary referral hospitals. Histopathologic assessment of hepatic steatosis and fibrosis was performed. The primary outcomes were PHLF and 90-day mortality. RESULTS: Of the 401 included patients, steatosis was absent in 334 patients (83.3%), mild in 58 patients (14.5%) and moderate to severe in 9 patients (2.2%). There was no fibrosis in 92 patients (23.1%), periportal fibrosis in 150 patients (37.6%), septal fibrosis in 123 patients (30.8%), and biliary cirrhosis in 34 patients (8.5%). Steatosis (≥ 5%) was not associated with PHLF (odds ratio [OR] 1.36; 95% confidence interval [CI] 0.69-2.68) or 90-day mortality (OR 1.22; 95% CI 0.62-2.39). Neither was fibrosis (i.e., periportal, septal, or biliary cirrhosis) associated with PHLF (OR 0.76; 95% CI 0.41-1.41) or 90-day mortality (OR 0.60; 95% CI 0.33-1.06). The independent risk factors for PHLF were preoperative cholangitis (OR 2.38; 95% CI 1. 36-4.17) and future liver remnant smaller than 40% (OR 2.40; 95% CI 1.31-4.38). The independent risk factors for 90-day mortality were age of 65 years or older (OR 2.40; 95% CI 1.36-4.23) and preoperative cholangitis (OR 2.25; 95% CI 1.30-3.87). CONCLUSION: In this study, no association could be demonstrated between hepatic steatosis or fibrosis and postoperative outcomes after resection of pCCA.

Impact of sarcopenia on clinical outcomes for patients with resected hepatocellular carcinoma: a retrospective comparison of Eastern and Western cohorts.

BACKGROUND: Patient fitness is important for guiding treatment. Muscle mass, as a reflection thereof, can be objectively measured. However, the role of East-West differences remains unclear. Therefore, we compared the impact of muscle mass on clinical outcomes after liver resection for hepatocellular carcinoma (HCC) in a Dutch [the Netherlands (NL)] and Japanese [Japan (JP)] setting and evaluated the predictive performance of different cutoff values for sarcopenia. METHOD: In this multicenter retrospective cohort study, patients with HCC undergoing liver resection were included. The skeletal muscle mass index (SMI) was determined on computed tomography scans obtained within 3 months before surgery. The primary outcome measure was overall survival (OS). Secondary outcome measures were: 90-day mortality, severe complications, length of stay, and recurrence-free survival. The predictive performance of several sarcopenia cutoff values was studied using the concordance index (C-index) and area under the curve. Interaction terms were used to study the geographic effect modification of muscle mass. RESULTS: Demographics differed between NL and JP. Gender, age, and body mass index were associated with SMI. Significant effect modification between NL and JP was found for BMI. The predictive performance of sarcopenia for both short-term and long-term outcomes was higher in JP compared to NL (maximum C-index: 0.58 vs. 0.55, respectively). However, differences between cutoff values were small. For the association between sarcopenia and OS, a strong association was found in JP [hazard ratio (HR) 2.00, 95% CI [1.230-3.08], P =0.002], where this was not found in NL (0.76 [0.42-1.36], P =0.351). The interaction term confirmed that this difference was significant (HR 0.37, 95% CI [0.19-0.73], P =0.005). CONCLUSIONS: The impact of sarcopenia on survival differs between the East and West. Clinical trials and treatment guidelines using sarcopenia for risk stratification should be validated in race-dependent populations prior to clinical adoption.

Multivariable prediction model for both 90-day mortality and long-term survival for individual patients with perihilar cholangiocarcinoma: does the predicted survival justify the surgical risk?

BACKGROUND: The risk of death after surgery for perihilar cholangiocarcinoma is high; nearly one in every five patients dies within 90 days after surgery. When the oncological benefit is limited, a high-risk resection may not be justified. This retrospective cohort study aimed to create two preoperative prognostic models to predict 90-day mortality and overall survival (OS) after major liver resection for perihilar cholangiocarcinoma. METHODS: Separate models were built with factors known before surgery using multivariable regression analysis for 90-day mortality and OS. Patients were categorized in three groups: favourable profile for surgical resection (90-day mortality rate below 10 per cent and predicted OS more than 3 years), unfavourable profile (90-day mortality rate above 25 per cent and/or predicted OS below 1.5 years), and an intermediate group. RESULTS: A total of 1673 patients were included. Independent risk factors for both 90-day mortality and OS included ASA grade III-IV, large tumour diameter, and right-sided hepatectomy. Additional risk factors for 90-day mortality were advanced age and preoperative cholangitis; those for long-term OS were high BMI, preoperative jaundice, Bismuth IV, and hepatic artery involvement. In total, 294 patients (17.6 per cent) had a favourable risk profile for surgery (90-day mortality rate 5.8 per cent and median OS 42 months), 271 patients (16.2 per cent) an unfavourable risk profile (90-day mortality rate 26.8 per cent and median OS 16 months), and 1108 patients (66.2 per cent) an intermediate risk profile (90-day mortality rate 12.5 per cent and median OS 27 months). CONCLUSION: Preoperative risk models for 90-day mortality and OS can help identify patients with resectable perihilar cholangiocarcinoma who are unlikely to benefit from surgical resection. Tailored shared decision-making is particularly essential for the large intermediate group.

Performance of the 7 th and 8 th Editions of the American Joint Committee on Cancer Staging System in Patients with Intraductal Papillary Mucinous Neoplasm-Associated PDAC : A Multi-institutional Analysis.

OBJECTIVE: To validate the 7 th and 8 th editions of the AJCC staging system for patients with invasive carcinomas arising in association with IPMN (IPMN-associated PDAC). BACKGROUND DATA: Although several studies have validated AJCC systems in patients with conventional PDAC, their applicability to IPMN-associated PDAC has not been assessed. METHODS: Two hundred seventy-five patients who underwent resection for IPMN-associated PDAC between 1996 and 2015 at 3 tertiary centers and had data on the size of the invasive component and lymph node status were identified. Concordance probability estimates (CPE) were calculated and recursive partitioning analysis was employed to identify optimal prognostic cutoffs for T and N. RESULTS: The CPE for the 7 th and 8 th editions of the AJCC schema were relatively good (0.64 for both) and similar for colloid and tubular subtypes (0.64 for both). The 8 th edition introduced T1a sub-staging and a new distinction between N1 and N2. The utility of the former was confirmed, although the latter did not improve prognostic discrimination. The successful validation of the 8th edition of the AJCC criteria in patients with tubular and colloid subtypes allowed us to compare these patients in early vs late T and N stages which showed that with advanced disease, the prognostic superiority of colloid tumors over their tubular counterparts diminishes. CONCLUSIONS: Our findings support the use of the AJCC 8 th edition in the IPMN-associated PDAC population, but suggest that certain cutoffs may need to be revisited. In advanced AJCC stages, patients with colloid vs tubular subtypes have comparable prognosis.

Demystifying BRAF Mutation Status in Colorectal Liver Metastases : A Multi-institutional, Collaborative Approach to 6 Open Clinical Questions.

OBJECTIVE: To investigate the clinical implications of BRAF -mutated (mut BRAF ) colorectal liver metastases (CRLMs). BACKGROUND: The clinical implications of mut BRAF status in CRLMs are largely unknown. METHODS: Patients undergoing resection for mut BRAF CRLM were identified from prospectively maintained registries of the collaborating institutions. Overall survival (OS) and recurrence-free survival (RFS) were compared among patients with V600E versus non-V600E mutations, KRAS/BRAF comutation versus mut BRAF alone, microsatellite stability status (Microsatellite Stable (MSS) vs instable (MSI-high)), upfront resectable versus converted tumors, extrahepatic versus liver-limited disease, and intrahepatic recurrence treated with repeat hepatectomy versus nonoperative management. RESULTS: A total of 240 patients harboring BRAF -mutated tumors were included. BRAF V600E mutation was associated with shorter OS (30.6 vs 144 mo, P =0.004), but not RFS compared with non-V600E mutations. KRAS/BRAF comutation did not affect outcomes. MSS tumors were associated with shorter RFS (9.1 vs 26 mo, P <0.001) but not OS (33.5 vs 41 mo, P =0.3) compared with MSI-high tumors, whereas patients with resected converted disease had slightly worse RFS (8 vs 11 mo, P =0.01) and similar OS (30 vs 40 mo, P =0.4) compared with those with upfront resectable disease. Patients with extrahepatic disease had worse OS compared with those with liver-limited disease (8.8 vs 40 mo, P <0.001). Repeat hepatectomy after intrahepatic recurrence was associated with improved OS compared with nonoperative management (41 vs 18.7 mo, P =0.004). All results continued to hold true in the multivariable OS analysis. CONCLUSIONS: Although surgery may be futile in patients with BRAF -mutated CRLM and concurrent extrahepatic disease, resection of converted disease resulted in encouraging survival in the absence of extrahepatic spread. Importantly, second hepatectomy in select patients with recurrence was associated with improved outcomes. Finally, MSI-high status identifies a better prognostic group, with regard to RFS while patients with non-V600E mutations have excellent prognosis.

Comparison of Hepatic Arterial Infusion Pump Chemotherapy vs Resection for Patients With Multifocal Intrahepatic Cholangiocarcinoma.

Importance: Intrahepatic cholangiocarcinoma (iCCA) is often multifocal (ie, satellites or intrahepatic metastases) at presentation. Objective: To compare the overall survival (OS) of patients with multifocal iCCA after hepatic arterial infusion pump (HAIP) floxuridine chemotherapy vs resection. Design, Setting, and Participants: In this cohort study, patients with histologically confirmed, multifocal iCCA were eligible. The HAIP group consisted of consecutive patients from a single center who underwent HAIP floxuridine chemotherapy for unresectable multifocal iCCA between January 1, 2001, and December 31, 2018. The resection group consisted of consecutive patients from 12 centers who underwent a curative-intent resection for multifocal iCCA between January 1, 1990, and December 31, 2017. Resectable metastatic disease to regional lymph nodes and previous systemic therapy were permitted. Patients with distant metastatic disease (ie, stage IV), those who underwent resection before starting HAIP floxuridine chemotherapy, and those who received a liver transplant were excluded. Data were analyzed on September 1, 2021. Main Outcomes and Measures: Overall survival in the 2 treatment groups was compared using the Kaplan-Meier method and log-rank test. Results: A total of 319 patients with multifocal iCCA were included: 141 in the HAIP group (median [IQR] age, 62 [53-70] years; 79 [56.0%] women) and 178 in the resection group (median [IQR] age, 60 [50-69] years; 91 [51.1%] men). The HAIP group was characterized by a higher percentage of bilobar disease (88.0% [n = 124] vs 34.3% [n = 61]), larger tumors (median, 8.4 cm vs 7.0 cm), and a higher proportion of patients with 4 or more lesions (66.7% [94] vs 24.2% [43]). Postoperative mortality after 30 days was 0.8% (95% CI, 0.0%-2.1%) in the HAIP group vs 6.2% (95% CI, 2.3%-9.7%) in the resection group (P = .01). The median OS for HAIP was 20.3 months vs 18.9 months for resection (P = .32). Five-year OS in patients with 2 or 3 lesions was 23.7% (95% CI, 12.3%-45.7%) in the HAIP group vs 25.7% (95% CI, 17.9%-37.0%) in the resection group. Five-year OS in patients with 4 or more lesions was 5.0% (95% CI, 1.7%-14.3%) in the HAIP group vs 6.8% (95% CI, 1.8%-25.3%) in the resection group. After adjustment for tumor diameter, number of tumors, and lymph node metastases, the hazard ratio of HAIP vs resection was 0.75 (95% CI, 0.55-1.03; P = .07). Conclusions and Relevance: This cohort study found that patients with multifocal iCCA had similar OS after HAIP floxuridine chemotherapy vs resection. Resection of multifocal intrahepatic cholangiocarcinoma needs to be considered carefully given the complication rate of major liver resection; HAIP floxuridine chemotherapy may be an effective alternative option.

Cholangiocarcinoma landscape in Europe: Diagnostic, prognostic and therapeutic insights from the ENSCCA Registry.

BACKGROUND & AIMS: Cholangiocarcinoma (CCA) is a rare and heterogeneous biliary cancer, whose incidence and related mortality is increasing. This study investigates the clinical course of CCA and subtypes (intrahepatic [iCCA], perihilar [pCCA], and distal [dCCA]) in a pan-European cohort. METHODS: The ENSCCA Registry is a multicenter observational study. Patients were included if they had a histologically proven diagnosis of CCA between 2010-2019. Demographic, histomorphological, biochemical, and clinical studies were performed. RESULTS: Overall, 2,234 patients were enrolled (male/female=1.29). iCCA (n = 1,243) was associated with overweight/obesity and chronic liver diseases involving cirrhosis and/or viral hepatitis; pCCA (n = 592) with primary sclerosing cholangitis; and dCCA (n = 399) with choledocholithiasis. At diagnosis, 42.2% of patients had local disease, 29.4% locally advanced disease (LAD), and 28.4% metastatic disease (MD). Serum CEA and CA19-9 showed low diagnostic sensitivity, but their concomitant elevation was associated with increased risk of presenting with LAD (odds ratio 2.16; 95% CI 1.43-3.27) or MD (odds ratio 5.88; 95% CI 3.69-9.25). Patients undergoing resection (50.3%) had the best outcomes, particularly with negative-resection margin (R0) (median overall survival [mOS] = 45.1 months); however, margin involvement (R1) (hazard ratio 1.92; 95% CI 1.53-2.41; mOS = 24.7 months) and lymph node invasion (hazard ratio 2.13; 95% CI 1.55-2.94; mOS = 23.3 months) compromised prognosis. Among patients with unresectable disease (49.6%), the mOS was 10.6 months for those receiving active palliative therapies, mostly chemotherapy (26.2%), and 4.0 months for those receiving best supportive care (20.6%). iCCAs were associated with worse outcomes than p/dCCAs. ECOG performance status, MD and CA19-9 were independent prognostic factors. CONCLUSION: CCA is frequently diagnosed at an advanced stage, a proportion of patients fail to receive cancer-specific therapies, and prognosis remains dismal. Identification of preventable risk factors and implementation of surveillance in high-risk populations are required to decrease cancer-related mortality. LAY SUMMARY: This is, to date, the largest international (pan-European: 26 hospitals and 11 countries) observational study, in which the course of cholangiocarcinoma has been investigated, comparing the 3 subtypes based on the latest International Classification of Diseases 11th Edition (ICD-11) (i.e., intrahepatic [2C12], perihilar [2C18], or distal [2C15] affected bile ducts), which come into effect in 2022. General and tumor-type specific features at diagnosis, risk factors, biomarker accuracy, as well as patient management and outcomes, are presented and compared, outlining the current clinical state of cholangiocarcinoma in Europe.

Mutant KRAS as a prognostic biomarker after hepatectomy for rectal cancer metastases: Does the primary disease site matter?

BACKGROUND: The prognostic implication of mutant KRAS (mKRAS) among patients with primary disease in the rectum remains unknown. METHODS: From 2000 to 2018, patients undergoing hepatectomy for colorectal liver metastases at 10 collaborating international institutions with documented KRAS status were surveyed. RESULTS: A total of 834 (65.8%) patients with primary colon cancer and 434 (34.2%) patients with primary rectal cancer were included. In patients with primary colon cancer, mKRAS served as a reliable prognostic biomarker of poor overall survival (OS) (hazard ratio [HR]: 1.58, 95% CI 1.28-1.95) in the multivariable analysis. Although a trend towards significance was noted, mKRAS was not found to be an independent predictor of OS in patients with primary rectal tumors (HR 1.34, 95% CI 0.98-1.80). For colon cancer, the specific codon impacted in mKRAS appears to reflect underlying disease biology and oncologic outcomes, with codon 13 being associated with particularly poor OS in patients with left-sided tumors (codon 12, HR 1.56, 95% CI 1.22-1.99; codon 13, HR 2.10 95% CI 1.43-3.08;). Stratifying the rectal patient population by codon mutation did not confer prognostic significance following hepatectomy. CONCLUSIONS: While the left-sided colonic disease is frequently grouped with rectal disease, our analysis suggests that there exist fundamental biologic differences that drive disparate outcomes. Although there was a trend toward significance of KRAS mutations for patients with primary rectal cancers, it failed to achieve statistical significance.

Systematic review and meta-analysis of validated prognostic models for resected hepatocellular carcinoma patients.

BACKGROUND: Many prognostic models for Hepatocellular Carcinoma (HCC) have been developed to inform patients and doctors about individual prognosis. Previous reviews of these models were qualitative and did not assess performance at external validation. We assessed the performance of prognostic models for HCC and set a benchmark for biomarker studies. METHODS: All externally validated models predicting survival for patients with resected HCC were systematically reviewed. After selection, we extracted descriptive statistics and aggregated c-indices using meta-analysis. RESULTS: Thirty-eight validated prognostic models were included. Models used on average 7 (IQR:4-9) prognostic factors. Tumor size, tumor number, and vascular invasion were almost always included. Alpha-fetoprotein (AFP) was commonly incorporated since 2007. Recently, the more subjective items ascites and encephalopathy have been dropped. Eight established models performed poor to moderate at external validation, with a pooled C-index below 0.7; including the Barcelona Clinic Liver Cancer (BCLC) system, the American Joint Committee on Cancer (AJCC) 7th edition, the Cancer of the Liver Italian (CLIP) Program, and the Japan Integrated Staging (JIS) score. Out of 24 prognostic models predicting OS, only 6 (25%) had good performance at external validation with pooled C-indices above 0.7; the Li-post (0.77), Li-OS (0.74), Yang-pre (0.74), Yang-post (0.76), Shanghai-score (0.70), and Wang-nomogram (0.71). Models improved over time, but overall performance and study quality remained low. CONCLUSIONS: Six validated prognostic models demonstrated good performance for predicting survival after resection of HCC. These models can guide patients and doctors and are a benchmark for future models incorporating novel biomarkers.