Hepatectomy For Colorectal Liver Metastases Research Articles

6. Two-stage hepatectomy for colorectal liver metastases: A major pathologic response to chemotherapy is associated with longer survival

6. Two-stage hepatectomy for colorectal liver metastases: A major pathologic response to chemotherapy is associated with longer survival

453. The outcomes of hepatectomy for colorectal liver metastases located in the right side of caudate lobe

453. The outcomes of hepatectomy for colorectal liver metastases located in the right side of caudate lobe

Short Chemotherapy-Free Interval Improves Oncological Outcome in Patients Undergoing Two-Stage Hepatectomy for Colorectal Liver Metastases.

In patients undergoing two-stage hepatectomy (TSH) for colorectal liver metastases (CRLM), chemotherapy is discontinued before portal vein occlusion and restarted after curative resection. Long chemotherapy-free intervals (CFI) may lead to tumor progression and poor oncological outcomes. The aim of this study was to investigate the impact of the length of CFI on oncological outcome in patients undergoing TSH for CRLM. Overall, 74 patients suffering from bilobar CRLM who underwent ALPPS (associating liver partition with portal vein ligation for staged hepatectomy; n=43) or conventional TSH (n=31) at two tertiary centers were investigated. The impact of CFI on long-term outcomes was analyzed by univariable and multivariable analysis. Preoperative chemotherapy was administered in 91% (67/74) of patients, and chemotherapy was resumed postoperatively in 69% (44/64) of patients who completed TSH. The use of postoperative chemotherapy was significantly associated with improved mean overall survival (36±3 vs. 13±3months; p<0.001). Overall, the median CFI from surgery to postoperative chemotherapy was 16weeks (interquartile range 11-31) and was significantly shorter in the ALPPS group when compared with the conventional TSH group (10 vs. 21weeks; p<0.001). Multivariable analysis revealed a CFI≤10weeks as an independent factor associated with improved overall survival (p=0.006) and disease-free survival (p=0.010). A short CFI is associated with improved oncological outcome in patients undergoing TSH for CRLM. Decreased interstage intervals after ALPPS may facilitate the timely resumption of chemotherapy.

Prognostic Implication of KRAS Status after Hepatectomy for Colorectal Liver Metastases Varies According to Primary Colorectal Tumor Location.

Right-sided and left-sided colorectal cancer (CRC) is known to differ in their molecular carcinogenic pathways. We sought to investigate the variable prognostic implication of KRAS mutation after hepatectomy for colorectal liver metastases (CRLM) according to the site of primary CRC. A total of 426 patients who underwent a curative-intent hepatic resection and whose KRAS status was available were identified. Clinicopathologic characteristics and long-term outcomes were stratified by KRAS status (wild type vs. mutant type) and primary tumor location (right-sided vs. left-sided). Cecum, right and transverse colon were defined as right-sided, whereas left colon and rectum were defined as left-sided. Among patients with a right-sided CRC, 5-year recurrence-free survival (RFS) and overall survival (OS) were not correlated with KRAS status (wild type: 30.8 and 47.2% vs. mutant type: 38.5 and 49.1%, respectively) (both P>0.05). Specifically, mutant-type KRAS was not associated with either RFS or OS on multivariable analysis (hazard ratio [HR] 1.51, 95% confidence interval [CI] 0.73-3.14, P=0.23 and HR 1.03, 95% CI 0.51-2.08, P=0.95, respectively). In contrast, among patients who underwent resection of CRLM from a left-sided primary CRC, 5-year RFS and OS were worse among patients with mutant-type KRAS (wild type: 23.7 and 57.2% vs. mutant type: 19.6 and 38.2%, respectively) (both P<0.05). On multivariable analysis, mutant-type KRAS remained independently associated with worse RFS and OS among patients with a left-sided primary CRC (HR 1.57, 95% CI 1.01-2.44, P=0.04 and HR 1.81, 95% CI 1.11-2.96, P=0.02, respectively). KRAS status has a variable prognostic impact after hepatic resection for CRLM depending on the site of the primary CRC. Future studies examining the impact of KRAS status on prognosis after hepatectomy should take into account the primary CRC tumor site.

RAS Mutation Is Associated with Decreased Survival in Patients Undergoing Repeat Hepatectomy for Colorectal Liver Metastases

BackgroundThe relationship between RAS mutation status and outcome for patients undergoing repeat hepatectomy (RH) for recurrent colorectal liver metastases (CLM) has not been defined. ObjectiveThe objective of this study was to evaluate the relationship between RAS mutation status and outcome in patients undergoing RH for CLM. MethodsAll patients who underwent RH for CLM with known RAS mutation status between January 2005 and November 2014 were identified, and the outcomes of patients with and without RAS mutations were compared. ResultsNinety-eight patients underwent RH, of whom 34 (35 %) harbored a RAS mutation. Wild-type (WT) and mutant RAS groups had similar clinicopathologic characteristics. Median recurrence-free survival (RFS) for patients with WT and mutant RAS was 12.2 and 6.1 months, respectively (p = 0.03). Median overall survival (OS) for the WT and mutant RAS patients were 42.5 and 26.6 months, respectively (p < 0.01). On multivariate analysis, RAS mutations [hazard ratio (HR) = 1.69, p = 0.04] were associated with worse RFS, while multiple tumors (HR = 1.92, p = 0.045) and RAS mutations (HR = 2.11, p = 0.02) predicted worse OS. ConclusionPatients with recurrent CLM that harbor RAS mutations have worse RFS and OS than patients with WT RAS, and RAS mutations are independently associated with worse RFS and OS. RAS mutation status should be determined prior to RH, as it may impact treatment decisions.

Factors influencing recurrence following initial hepatectomy for colorectal liver metastases.

Data on recurrence patterns following hepatectomy for colorectal liver metastases (CRLMs) and their impact on long-term outcomes are limited in the setting of modern multimodal management. This study sought to characterize the patterns of, factors associated with, and survival impact of recurrence following initial hepatectomy for CRLMs. A retrospective cohort study of patients undergoing initial hepatectomy for CRLMs at 39 institutions (2006-2013) was conducted. Kaplan-Meier methods were used for survival analyses. Overall survival landmark analysis at 12 months after hepatectomy was performed to compare groups based on recurrence. Multivariable Cox and regression models were used to determine factors associated with recurrence. Among 2320 patients, tumours recurred in 47·4 per cent at median of 10·1 (range 0-88) months; 89·1 per cent of recurrences developed within 3 years. Recurrence was intrahepatic in 46·2 per cent, extrahepatic in 31·8 per cent and combined intra/extrahepatic in 22·0 per cent. The 5-year overall survival rate decreased from 74·3 (95 per cent c.i. 72·2 to 76·4) per cent without recurrence to 57·5 (55·0 to 60·0) per cent with recurrence (adjusted hazard ratio (HR) 3·08, 95 per cent c.i. 2·31 to 4·09). After adjusting for clinicopathological variables, prehepatectomy factors associated with increased risk of recurrence were node-positive primary tumour (HR 1·27, 1·09 to 1·49), more than three liver metastases (HR 1·27, 1·06 to 1·52) and largest metastasis greater than 4 cm (HR 1·19; 1·01 to 1·43). Recurrence after CRLM resection remains common. Although overall survival is inferior with recurrence, excellent survival rates can still be achieved.

The influence of chemotherapy-associated sinusoidal dilatation on short-term outcome after partial hepatectomy for colorectal liver metastases: A systematic review with meta-analysis

Summary background dataHepatic sinusoidal dilatation (SD) is a histopathological entity that occurs in up to 75% of patients undergoing oxaliplatin-based chemotherapy for colorectal liver metastases (CRLM). ObjectiveTo study the influence of SD on outcome after partial hepatectomy in patients with CRLM. MethodsMedline, Embase, CENTRAL, LILACS and CINAHL were searched for studies published between 01.01.2004 and 09.06.2015 with keywords: “sinusoidal obstruction syndrome”, “hepatic veno-occlusive disease”, and “Stuart-Bras syndrome”. Studies comprising adults who underwent partial hepatectomy for CRLM with grading of SD and registration of postoperative morbidity and/or mortality were included. Risk of bias and quality of studies were evaluated with the Quality In Prognosis Studies Instrument (QUIPS) and modified GRADE framework. ResultsSearch strategies produced 2007 hits from which 23 and 13 articles were extracted for qualitative and quantitative analyses, respectively. Meta-analysis on the influence of SD grade 2–3 vs. SD grade 0–1 on postoperative overall morbidity showed an odds ratio (OR) of 1.26 [95% CI 0.74, 2.15](p = 0.40), an OR of 1.03 [0.15, 6.89](p = 0.98) for liver failure, an OR of 1.21 [0.23, 6.35](p = 0.82) for overall mortality, and an OR of 3.52 [0.31, 39.91](p = 0.31) for liver-related morbidity. QUIPS showed a low to high risk of bias for studies, and GRADE showed very low quality of evidence per outcome. ConclusionsNo significant effect of SD grade 2–3 on short-term outcome after partial hepatectomy was found. However, the data on which this conclusion was based were not very robust and therefore no solid conclusions could be drawn.

Factors affecting surgical margin recurrence after hepatectomy for colorectal liver metastases.

Hepatic recurrence after resection of colorectal liver metastasis (CLM) occurs in 50% of patients during follow-up, with 2.8% to 13.9% presenting with surgical margin recurrence (SMR). The aim of this study is to analyze factors that related to SMR in patients with CLM undergoing hepatectomy. Demographics, clinical and survival data of patients who underwent hepatectomy were identified from a prospectively maintained, institutional review board (IRB)-approved database between 2000 and 2012. Statistical analysis was performed using univariate Kaplan Meier and Cox proportional hazard model. There were 85 female and 121 male patients who underwent liver resection for CLM. An R0 resection was performed in 157 (76%) patients and R1 resection in 49. SMR was detected in 32 patients (15.5%) followed up for a median of 29 months (range, 3-121 months). A half of these patients had undergone R1 (n=16) and another half R0 resection (n=16). Tumor size, preoperative carcinoembryonic antigen (CEA) level and margin status were associated with SMR on univariate analysis. On multivariate analysis, a positive surgical margin was the only independent predictor of SMR. The receipt of adjuvant chemotherapy did not affect margin recurrence. SMR was an independent risk factor associated with worse disease-free (DFS) and overall survival (OS). This study shows that SMR, which can be detected in up to 15.5% of patients after liver resection for CLM, adversely affects DFS and OS. The fact that a positive surgical margin was the only predictive factor for SMR in these patients underscores the importance of achieving negative margins during hepatectomy.

PWE-039 The Interaction between The Hypoxia Inducible Factor-1Α (HIF-1Α) and ERBB Signalling Pathways in Colorectal Liver Metastases (CRLM)

Introduction Tumour hypoxia is associated with reduced survival by activating multiple molecular pathways such as, but not exclusively, HIF-1α and mTOR/AKT/PI3K pathways. It is also known to cause overexpression of Epidermal Growth Factor (EGFR)/HER1 in human cancer. HER2 (neu) signalling increases the rate of Hypoxia-Inducible Factor 1α (HIF-1α) synthesis. Overexpression of Erbb3/HER3 and Erbb4/HER4 is associated with a higher recurrence rate of stage 2 and 3 colorectal cancer. The aim of this study was to analyse the relationship between the expression of HIF-1α and members of the ErbB pathway in CRLM utilising a novel proteomic based collaborative Enzyme Enhanced Reactive (CEER) immunoassay. Methods Protein lysates of from fresh frozen biopsies and formalin fixed paraffin sections of CRLM from 18 patients who had not undergone neoadjuvant chemotherapy prior to a potentially curative hepatectomy for CRLM were analysed. When multiple metastases were present biopsies and sections were obtained from the largest metastasis. CEER immunoassay was performed on the protein lysates to quantify the phosphorylated and non-phosphorylated forms of receptors; ErbB family receptors (HER1/EGFR, HER2/c-neu, HER3, HER4) and cMET, and phosphorylated downstream ErbB pathway factors AKT, PRAS, RSP6, ERK, and RSK, and CK. Immunostaining was performed on formalin-fixed-paraffin-embedded CRLM sections for HIF-1α. ErbB pathway factor quantification was segregated according to the HIF-1α expression status; HIF-1α +ve and HIF-1α -ve Results HIF-1α was expressed in 15 (83%) of tumours. There was no significant difference between the expression of phosphorylated ‘receptors’, and phosphorylated forms AKT, PRAS, RSP6, ERK, MEK, and PI3K between the HIF-1α +ve and HIF-1α –ve groups. HER3 and IGF1R were higher; (median µm: range; 87 [74–344] vs 222 [60–404]) and (115 [85–206] vs 186 [90–285]) respectively in the HIF-1α +ve group, HER1, HER2, PI3K and CK levels were lower; (108 [40–316] vs 36 [22–46]), (698 [523–870] vs 481 [288–709]), (5338 [3334–6689] vs 2719 [1790–4193]), (5383 [1826–9799] vs 2719 [1789–4193]) respectively in the HIF-1α +ve group. Although a trend was observed, the difference did not reach statistical significance. Conclusion HIF-1α may have a role in the overexpression of HER3 and IGF1R overexpression in CRLM. More research is needed to establish this interrelationship which would help in molecular based therapeutics for CRLM. Disclosure of Interest None Declared

Codon 13 KRAS mutation predicts patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases.

Investigations regarding the impact of tumor biology after surgical management of colorectal liver metastasis have focused largely on overall survival. We investigated the impact of codon-specific KRAS mutations on the rates and patterns of recurrence in patients after surgery for colorectal liver metastasis (CRLM). All patients who underwent curative-intent surgery for CRLM between 2002 and 2015 at Johns Hopkins who had available data on KRAS mutation status were identified. Clinico-pathologic data, recurrence patterns, and recurrence-free survival (RFS) were assessed using univariable and multivariable analyses. A total of 512 patients underwent resection only (83.2%) or resection plus radiofrequency ablation (16.8%). Although 5-year overall survival was 64.6%, 284 (55.5%) patients recurred with a median RFS time of 18.1 months. The liver was the initial recurrence site for 181 patients, whereas extrahepatic recurrence was observed in 162 patients. Among patients with an extrahepatic recurrence, 102 (63%) had a lung recurrence. Although overall KRAS mutation was not associated with overall RFS (P = 0.186), it was independently associated with a worse extrahepatic (P = 0.004) and lung RFS (P = 0.007). Among patients with known KRAS codon-specific mutations, patients with codon 13 KRAS mutation had a worse 5-year extrahepatic RFS (P = 0.01), whereas codon 12 mutations were not associated with extrahepatic (P = 0.11) or lung-specific recurrence rate (P = 0.24). On multivariable analysis, only codon 13 mutation independently predicted worse overall extrahepatic RFS (P = 0.004) and lung-specific RFS (P = 0.023). Among patients undergoing resection of CRLM, overall KRAS mutation was not associated with RFS. KRAS codon 13 mutations, but not codon 12 mutations, were associated with a higher risk for overall extrahepatic recurrence and lung-specific recurrence. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2698-2707. © 2016 American Cancer Society.

Oncological benefit of parenchyma-preserving hepatectomy for colorectal liver metastasis.

3526Background: Occasionally, major hepatectomy (MH), rather than parenchyma-preserving hepatectomy (PH), is performed for solitary colorectal liver metastasis (CLM). It is unclear whether PH has a...

Early Recurrence After Hepatectomy for Colorectal Liver Metastases: What Optimal Definition and What Predictive Factors?

The purpose of this study was to determine the optimal definition and elucidate the predictive factors of early recurrence after surgery for colorectal liver metastases (CRLM). Among 987 patients who underwent curative surgery for CRLM from 1990 to 2012, 846 with a minimum follow-up period of 24 months were eligible for this study. The minimum p value approach of survival after initial recurrence was used to determine the optimal cutoff for the definition of early recurrence. The predictive factors of early recurrence and prognostic factors of survival were analyzed. For 667 patients (79%) who developed recurrence, the optimal cutoff point of early recurrence was determined to be 8 months after surgery. The impact of early recurrence on survival was demonstrated mainly in patients who received preoperative chemotherapy. Among the 691 patients who received preoperative chemotherapy, recurrence was observed in 562 (81%), and survival in patients with early recurrence was significantly worse than in those with late recurrence (5-year survival 18.5% vs. 53.4%, p < .0001). Multivariate logistic analysis identified age ≤57 years (p = .0022), >1 chemotherapy line (p = .03), disease progression during last-line chemotherapy (p = .024), >3 tumors (p = .0014), and carbohydrate antigen 19-9 >60 U/mL (p = .0003) as independent predictors of early recurrence. Salvage surgery for recurrence significantly improved survival, even in patients with early recurrence. The optimal cutoff point of early recurrence was determined to be 8 months. The preoperative prediction of early recurrence is possible and crucial for designing effective perioperative chemotherapy regimens. In this study, the optimal cutoff point of early recurrence was determined to be 8 months after surgery based on the minimum p value approach, and its prognostic impact was demonstrated mainly in patients who received preoperative chemotherapy. Five factors, including age, number of preoperative chemotherapy lines, response to last-line chemotherapy, number of tumors, and carbohydrate antigen 19-9 concentrations, were identified as predictors of early recurrence. Salvage surgery for recurrence significantly improved survival, even in patients with early recurrence. For better selection of patients who could truly benefit from surgery and should also receive strong postoperative chemotherapy, the accurate preoperative prediction of early recurrence is crucial.

Postoperative complications following aggressive repeat hepatectomy for colorectal liver metastasis have adverse oncological outcomes.

Repeat hepatectomy remains the only curative treatment for recurrent colorectal liver metastasis (CLM) after primary hepatectomy. However, the repeat resection rate is still low, and there is insufficient data on the outcomes after repeat hepatectomy. The aim of this study was to investigate the feasibility and prognostic benefit of aggressive repeat hepatectomy for recurrent CLM. Data were reviewed from 282 consecutive patients who underwent primary curative hepatectomy for CLM between January 1994 and March 2015. The short- and long-term outcomes were analyzed. One hundred ninety-three patients (68%) developed recurrence, and repeat hepatectomy was conducted in 62 patients. Overall, 62s, 11 third, 4 fourth, and 1 fifth hepatectomies were performed. The postoperative morbidity and mortality rates were low (11.5 and 1.3%, respectively). The overall survival rates at 3 and 5years after primary hepatectomy for CLM in the repeat hepatectomy group were 79.5 and 57.4%, respectively. A multivariate analysis indicated that postoperative complications were independently associated with overall survival after repeat hepatectomy. Repeat hepatectomy for CLM is feasible, with acceptable rates of perioperative morbidity and mortality, and the potential for long-term survival. However, postoperative complications following aggressive repeat hepatectomy for CLM are associated with adverse oncological outcomes.

Operative morbidity and survival following hepatectomy for colorectal liver metastasis in octogenarians: A modern case matched series

Introduction: Clinical outcomes of octogenarians undergoing hepatectomy for colorectal liver metastases (CRLM) in the modern era are poorly characterized. The current study evaluated operative morbidity, mortality and survival outcomes amongst a contemporary cohort of octogenarians. Methods: Patients undergoing first time hepatectomy for CRLM were identified from institutional databases and those ≥ 80y.o were matched 1:1 to patients<80y.o. Matching criteria included BMI, number of comorbidities, extent of resection, and clinical risk score. Data pertaining to surgical morbidity/mortality, disease recurrence and survival were obtained and compared using standard statistical methods. Results: From 2002–2012, 1391 hepatectomies were performed for CRLM, 55 (4%) in patients ≥80y.o. Major complications occurred twice as frequently among patients ≥80y.o [10 (19%) ≥80y.o vs. 5 (9%)<80y.o, (p = 0.27)]. No patient<80y.o died within 90d of operation, whereas, 4 (7.4%) patients ≥80y.o did, p = 0.13. Median follow-up was significantly longer for the<80y.o. group [44 (1–146) vs. 23 (0–102) months, p = 0.006]. Probability of disease recurrence at 1-, 2- and 3-years was not different between groups (p = 0.13) nor was the cumulative incidence of death from disease (p = 0.37); however, patients ≥80y.o had significantly higher incidence of death from alternative causes (p = 0.01, Figure 1) Conclusions: Hepatectomy for CRLM in octogenarians is associated with clinically significant morbidity and 90d mortality. However, disease recurrence rate and survival outcomes appear comparable to patients<80y.o. Life expectancy of well selected patients ≥80y.o is long; therefore despite considerable operative risk, hepatectomy for CRLM is reasonable and survival outcomes are similar to those observed in younger patients.

Abstract B01: Lymphangiogenic gene expression is associated with lymph node recurrence and poor survival after hepatectomy for colorectal liver metastases

Abstract Expression of the lymphangiogenic growth factors, in particular VEGF-C, are correlated with disease-free and overall survival in primary colorectal cancer (CRC). Moreover, in patients with metastatic CRC (mCRC) lymphatic invasion and lymph node metastases are correlated with worse outcome, but the biology underlying these correlations remains unknown. To study a potential relationship between tumor biology, lymphatic spread from liver metastases and outcome, we compiled a lymph-endothelium gene set the lymphangiogenesis signature comprised of six genes specifically expressed by lymph endothelial cells, or growth factors stimulating them. In primary colorectal cancer, expression of this signature correlated with increased risk of distant metastasis. When used to cluster a cohort of 119 colorectal liver metastases (CRLM) based on gene expression profiles, the signature identified an aggressive poor prognosis subtype of CRLM with mesenchymal gene expression and a stem-like tumor phenotype. RTqPCR analysis of CRLMs with and without lymph node recurrence during follow up showed that VEGF-C and neuropilin-2 were significantly higher expressed by CRLM with onward spread to the lymph nodes. We conclude that CRLM expressing high levels of lymphangiogenic genes are more likely to develop lymph node metastases during follow up and that this correlates with a general aggressive tumor biology (i.e. the mesemcnymal/stem-like phenotype) and poor survival. Post liver resection adjuvant therapy targeting onward spread to the lymph nodes may be beneficial for patients with mesenchymal-type mCRC. Citation Format: Thomas Vellinga, Dieuwke Marvin, Inne Borel Rinkes, Jeroen Hagendoorn, Onno Kranenburg. Lymphangiogenic gene expression is associated with lymph node recurrence and poor survival after hepatectomy for colorectal liver metastases. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B01.

Lymphangiogenic gene expression is associated with lymph node recurrence and poor survival after hepatectomy for colorectal liver metastases

Lymphangiogenic gene expression is associated with lymph node recurrence and poor survival after hepatectomy for colorectal liver metastases

The impact of advancing age and adjuvant chemotherapy on recurrence and survival following major hepatectomy for colorectal liver metastases

The impact of advancing age and adjuvant chemotherapy on recurrence and survival following major hepatectomy for colorectal liver metastases

Major hepatectomy for colorectal liver metastases in patients aged over 80: A propensity score matching analysis

Major hepatectomy for colorectal liver metastases in patients aged over 80: A propensity score matching analysis

The influence of chemotherapy-associated liver injury on outcome after partial hepatectomy for colorectal liver metastases: Results from a multicenter cohort study

The influence of chemotherapy-associated liver injury on outcome after partial hepatectomy for colorectal liver metastases: Results from a multicenter cohort study

Short and long term outcomes of older patients undergoing hepatectomy for colorectal liver metastasis

Short and long term outcomes of older patients undergoing hepatectomy for colorectal liver metastasis