Resection Of Colorectal Cancer Liver Metastases Research Articles

Tumour-agnostic circulating tumour DNA analysis for improved recurrence surveillance after resection of colorectal liver metastases: A prospective cohort study

PurposeNearly 50% of patients recur within two years after curatively intended resection of colorectal cancer liver metastasis (CRLM). The optimal surveillance strategy is unknown due to the lack of evidence. Here, we explored the potential for improving postoperative CRLM surveillance by performing serial circulating tumour DNA (ctDNA) assessments parallel to standard-of-care surveillance. Experimental design499 prospectively collected serial plasma samples from 96 patients undergoing CRLM resection were analysed using the tumour-agnostic methylation multiplex droplet-digital PCR test ‘TriMeth’. ResultsPatients with ctDNA postoperatively or post adjuvant chemotherapy experienced a significant lower recurrence-free survival than patients without ctDNA (hazard ratio (HR) 4.5; P < 0.0001 and HR 8.4, P < 0.0001). ctDNA status was a stronger predictor of recurrence than standard clinical risk factors and carcinoembryonic antigen. Serial TriMeth analysis detected ctDNA before radiological recurrence in 55.6% of ctDNA-positive patients, with up to 10.6 months lead-time (median 3.1 months). During surveillance, 24% of patients had inconclusive CT scans, which was associated with a significant delay in recurrence diagnosis (median 3.5 months versus 1.0 month, P < 0.0001). Uniquely, ctDNA status at the time of inconclusive CT scans predicted recurrence with positive and negative predictive values of 100%, and 75% (P = 0.0003). Serial TriMeth analysis allowed ctDNA growth rate assessment and revealed that fast ctDNA growth was associated with poor overall survival (HR: 1.6, P = 0.0052). ConclusionsSerial postoperative ctDNA analysis has a strong prognostic value and is more sensitive for recurrence detection than standard-of-care CRLM surveillance tools. Altogether, TriMeth provides several opportunities for improving postoperative surveillance of CRLM patients.

Impact of microscopic incomplete resection for colorectal liver metastases on surgical margin recurrence: R1-Contact vs R1

Several studies highlighted an inferior outcome of R1 resection for colorectal cancer liver metastases (CRLM); it is still unclear whether directly involved margins (R1-contact) are associated with a poorer outcome compared to R1<1mm. The aim of this study is to analyze the impact on surgical margin recurrence (SMR) of R1-contact vs R1<1mm patients. Patients who underwent surgery for CRLM between 2009-2018 with both R1 resections on final histology were included and compared in terms of recurrence and survival. Factors associated with SMR were assessed by univariate and multivariate analysis. Out of 477, 77 (17.2%) patients showed R1 resection (53 R1-Contact and 24 R1<1mm). Overall recurrence rate was 79.2% (R1<1mm = 70.8% vs R1-contact group = 83%, P=.222). Median disease-free survival (DFS) and disease-specific survival (DSS) were significantly higher in R1<1mm vs R1-contact group (93 vs 55months; P=.025 and 69 vs 46months; P=.038, respectively). The SMR rate was higher in R1-contact compared to R1<1mm group (30.2% vs 8.3%; P=.036). At univariate analysis, age, number of metastases, open surgical approach, RAS status, and R1-contact were associated with SMR. At multivariate analysis, R1-contact margin was the only factor independently associated with higher SMR (OR = 5.6; P=.046). R1-contact margin is independently associated with SMR after liver resection for CRLM. Patients with R1-contact margin will also experience poorer DFS and DSS.

Prognostic implications of adaptive immune features in MMR-proficient colorectal liver metastases classified by histopathological growth patterns.

After resection, colorectal cancer liver metastases (CRLM) surrounded by a desmoplastic rim carry a better prognosis than the metastases replacing the adjacent liver. However, these histopathological growth patterns (HGPs) are insufficient to guide clinical decision-making. We explored whether the adaptive immune features of HGPs could refine prognostication. From 276 metastases resected in 176 patients classified by HGPs, tissue microarrays were used to assess intratumoral T cells (CD3), antigen presentation capacity (MHC class I) and CD73 expression producing immunosuppressive adenosine. We tested correlations between these variables and patient outcomes. The 101 (57.4%) patients with dominant desmoplastic HGP had a median recurrence-free survival (RFS) of 17.1 months compared to 13.3 months in the 75 patients (42.6%) with dominant replacement HGP (p = 0.037). In desmoplastic CRLM, high vs. low CD73 was the only prognostically informative immune parameter and was associated with a median RFS of 12.3 months compared to 26.3, respectively (p = 0.010). Only in dominant replacement CRLM, we found a subgroup (n = 23) with high intratumoral MHC-I expression but poor CD3+ T cell infiltration, a phenotype associated with a short median RFS of 7.9 months. Combining the assessments of HGP and adaptive immune features in resected CRLM could help identify patients at risk of early recurrence.

Colorectal cancer liver metastases: current state of the problem, priority treatment approaches

The review is devoted to the world trends in epidemiology of colorectal cancer and treatment of colorectal cancer liver metastases. The authors analyze the effectiveness of traditional (resection) and modern minimally invasive methods of local destruction (radiofrequency thermoablation, microwave ablation, cryoablation), stereotactic radiotherapy, radiosurgery, targeted therapy and endovascular techniques (chemoinfusion, chemoembolization, radioembolization). It was emphasized that searching for new chemotherapeutic and targeted drugs is one of the reserve ways to improve treatment outcomes in patients with potentially resectable colorectal cancer liver metastases. The possibilities and prospects of liver transplantation as a priority treatment strategy for patients with unresectable bilobar colorectal cancer liver metastases are highlighted.

Proteomics in Colorectal Cancer Liver Metastases and Related Prognosis

Introduction: The identification of liver metastasis-related factors is important for the treatment and prognosis of colon cancer. There is no specific biomarker for disease recurrence. Proteomics helps to reveal new therapeutic opportunities and for these reasons the aim of this study is to describe the proteins that have been identified in liver metastasis that could potentially be studied as biomarkers and are related to surveillance and disease-free survival. Methods: A systematic search was made in PubMed of all the publications made from 1972 to 2021. 748 articles were identified, of which 701 were excluded based on the following criteria: not english-language articles, experimental studies, case reports, studies not included in medline. After an exhaustive review, 23 additional articles were excluded, finally leaving a number of 24 articles for a systematic review. Results: In the 24 articles selected for this systematic review, we identified 39 proteins associated with colorectal cancer liver metastasis (CRCLM); with different cell localization, multiple functions and related with all varieties of genes. Only 5 articles described proteins related with surveillance and/or disease free-survival, and at the same with statistical significance, which are: TGF-a, EGFR, p53, PRL3, Maspin, AURKA, MMP9 and PTGS2 (Table nº1). Conclusion: Potential biomarkers of resected CRCLM may be helpful not also for prediction of metastases, but potential target treatments.Tabled 1Table no 1Protein localizationProteinDisease free survivalSurveillanceAuthor, YearEstromaTGFaN/AElevated TGFa in the CRCLM in relation to the primary tumor, is related to a survival of 25 months. Low TGFa had a median survival of 60 months (p <0.036).De Jong et al., 1998MaspinMaspin expression was 2.1 times higher in tumours of patients with a short time to recurrence (<6 months) vs tumours in patients with a prolonged time to recurrence (> 6 months) (p = 0.01).The 2-year recurrence-free survival probability of patients with Maspin-high tumours is an estimated 0.10 (95% CI = 0.00–0.20) compared with 0.39 (95% CI = 0.18–0.60) in patients with Maspin-low tumours (Cox regression analysis p = 0.007, HR = 2.65, 95% CI = 1.307–5.380).High levels of Maspin are significantly correlated with disease-specific (p = 0.005) and overall survival (p = 0.029) in primary stage IV CRC patients.Snoeren et al., 2013MMP9N/AThe resulting classifier was based on AURKA, PTGS2 and MMP9 expression and was associated with OS (HRR 2.79, p < .001), also after multivariate analysis (HRR 3.57, p < .001). The prognostic value of the biomarker-based classifier was superior to the clinicopathological model (p = .001). Prognostic value was highest for colon cancer patients (HRR 5.71, p < .001) and patients not treated with systemic therapy (HRR 3.48, p < .01).Goos et al., 2016NuclearP53The presence of p53 was related to increased survival at 5 years. (p <0.03). One of the best predictors of disease-free survival after resection (RR: 2.33)The presence of p53 presented a higher survival rate, 95% vs 50% at 2 years (p <0.03)De Jong et al., 1998PTGS2N/AThe resulting classifier was based on AURKA, PTGS2 and MMP9 expression and was associated with OS (HRR 2.79, p < .001), also after multivariate analysis (HRR 3.57, p < .001). The prognostic value of the biomarker-based classifier was superior to the clinicopathological model (p = .001). Prognostic value was highest for colon cancer patients (HRR 5.71, p < .001) and patients not treated with systemic therapy (HRR 3.48, p < .01).Goos et al., 2016TBL1XR1High expression of TBL1XR1 in either primary tumor tissues (p = 0.014,) or liver metastases (p = 0.041) was correlated with poor DFS.N/ALiu et al., 2017MembraneEGFROne of the best predictors of disease-free survival after resection (RR: 2.38)N/ADe Jong et al., 1998PRL-3N/APRL-3 expression was significantly associated with the liver metastasis of colorectal cancer (p = 0,004) and tended to shorten survival time (p =0,0145).Peng et al., 2003CytoplasmAURKAN/AThe resulting classifier was based on AURKA, PTGS2 and MMP9 expression and was associated with OS (HRR 2.79, p < .001), also after multivariate analysis (HRR 3.57, p < .001). The prognostic value of the biomarker-based classifier was superior to the clinicopathological model (p = .001). Prognostic value was highest for colon cancer patients (HRR 5.71, p < .001) and patients not treated with systemic therapy (HRR 3.48, p < .01).Goos et al., 2016 Open table in a new tab

Primary Colorectal Cancer Histopathology Predicts the Histopathological Growth Pattern of Corresponding Liver Metastasis

Introduction: Histopathological growth patterns (HGPs) are a prognostic and predictive biomarker in the surgical management of colorectal cancer liver metastasis (CRLM); the desmoplastic HGP marks good prognosis whereas the non-desmoplastic HGP predicts favourable chemotherapy response. Clinical applicability is however limited as determination requires resection. This study investigates whether primary colorectal cancer (CRC) histopathology may predict the HGP of corresponding CRLM. Method: A retrospective cohort study was performed in treatment-naive patients undergoing CRLM resection. Thirteen distinct histopathology features were determined on H&E sections of resected CRC and compared between desmoplastic and non-desmoplastic CRLM; tumour sidedness, pT & pN stage, tumour grade, tumour deposits, perineural- (lympho-)vascular- and extramural venous invasion, peritumoural budding, stroma type, CRC growth pattern, Crohn’s-like lymphoid reaction, and tumour-infiltrating lymphocyte (TIL) density. A point-based score (table) was calculated, assigning a point for each unfavourable feature. Multivariable logistic regression was performed using this score and TIL density as predictors. Results: 180 patients were included, of which 150 (83%) had non-desmoplastic CRLM. Unfavourable histopathology was more frequent in non-desmoplastic CRLM for all individual CRC features evaluated (figure), and significantly so for a lower TIL density and a “non-mature” stroma (both p<0.03). This was confirmed by the point-based score, which revealed a significant association between unfavourable CRC histopathology and non-desmoplastic CRLM (median [IQR]: 4 [2;5] vs 1 [1;3] unfavourable features, p<0.001). Multivariable logistic regression achieved good discriminatory performance to predict the HGP (AUC=0.74). Conclusions: The current study observes an association in treatment-naive patients between CRC histopathology and the HGP of corresponding CRLM.Tabled 1CRC histopathology featurePointsCRC histopathology featurePointsRight-sided tumour+1Perineural invasion+1Poorly differentuiated+1(Lympho-)vascular invasion+1pT4 tumour+1Extramural venous invasion+1Positive lymph node(s)+1Peritumoural buddig (II or III)+1Tumour deposit(s)+1Non-mature stroma type+1Absent Chron's-like lymphoid reaction+1Infiltrative CRC growth pattern+1 Open table in a new tab

Treatment strategy for resectable colorectal cancer liver metastases from the viewpoint of time to surgical failure

The efficacy of pre or postoperative chemotherapy for resectable colorectal cancer liver metastases (CRLM) is disputed. This study aimed to examine the risk factors for time to surgical failure (TSF) and analyze the efficacy of pre or postoperative chemotherapy prior to liver resection for CRLM. The clinicopathological factors of 567 patients who underwent initial hepatectomy for CRLM at 7 university hospitals between April 2007 and March 2013 were retrospectively analyzed. The prognostic factors were identified and then stratified into two groups according to the number of preoperative prognostic factors: the high-score group (H-group, score 2-4) and the low-score group (L-group, score 0 or 1). Patients who experienced unresectable recurrence within 12months after initial treatment had a significantly shorter prognosis than other patients (p < 0.001). Multivariate analysis identified age ≥ 70 (p = 0.001), pT4 (p = 0.015), pN1 (p < 0.001), carbohydrate antigen 19-9 ≥ 37 U/ml (p = 0.002), Clavien-Dindo grade ≥ IIIa (p = 0.013), and postoperative chemotherapy (p = 0.006) as independent prognostic factors. In the H-group, patients who received chemotherapy had a better prognosis than those who did not (p = 0.001). Postoperative chemotherapy is beneficial in colorectal cancer patients with more than two of the following factors: age ≥ 70, carbohydrate antigen 19-9-positivity, pT4, and lymph node metastasis.

Characterization of Biomarkers in Colorectal Cancer Liver Metastases as a Prognostic Tool.

Background: Unfortunately, the majority of patients with colorectal cancer liver metastases (CRCLM) experience disease recurrence following hepatic surgery. The key challenge is therefore optimal patient selection, which currently relies on anatomical and clinical parameters. Exploring a potential molecular signature may be predictive for seeing a clinical benefit from CRCLM resection. Methods: Consecutive patients who underwent CRCLM resection at our medical center between 2006 and 2016 were divided into cohorts of “good prognosis” (GP) or “poor prognosis” (PP) based on the time interval between their resection and disease recurrence. Proteomic analysis was performed on the surgical specimen and correlation analysis was carried out with demographics and clinical outcomes. Results: Proteomic analysis revealed 99 differentially expressed proteins of which a third were associated with extracellular matrix (ECM) pathways as the matrix metalloproteinases (MMPs). Multivariate analysis yielded a statistically differential proteomic pattern between the cohort regardless of perioperative treatment. Conclusion: Our results indicate a different proteomic landscape in the cohort of patients who had a clinical benefit from CRCLM resection which appears to be correlated with ECM pathways. Further prospective studies are needed to define the role of ECM pathways in prognostics and patient selection for surgical procedures for CRCLM.

Role of hepatic surgery in colorectal cancer multiple liver metastasis

Colorectal cancer liver metastasis can be categorized as initially resectable and initially unresectable liver metastasis. Patients with initially resectable colorectal cancer liver metastases may benefit from hepatic surgery significantly,while those with initially unresectable metastases also have an opportunity to be treated radically by liver surgery after conversion therapy,so as to have a prolonged survival time. It is crucial to choose the right time and right way of surgical intervention. The timing depends on determination of tumor resectability,controlling of pre-operative systemic therapy and evaluation of liver function after systemic treatment. The selection of right way contains the election between synchronous operation and staged operation, resection margin and using of technologies such as laparoscope and associating liver partition and portal vein ligation for staged hepatectomy. This paper aims to explore the optimal timing for operation and the approaches of surgical method based on the research progress worldwide for prolonging the survival time of patients with colorectal cancer multiple liver metastases.

Incidence and Risk Factors of Venous Thromboembolism Following Hepatectomy for Colorectal Metastases: A Population-Based Retrospective Cohort Study.

Incidence of venous thromboembolism (VTE) following hepatectomy for colorectal cancer (CRC) metastases is unclear. These patients may represent a vulnerable population due to increased tumour burden. We aim to identify the risk of VTE development in routine clinical practice among patients with resected CRC liver metastases, the associated risk factors, and its impact on survival. We conducted a population-based retrospective cohort study of Ontario patients undergoing hepatectomy for CRC metastases between 2002 and 2009 using linked universal healthcare databases. Multivariable logistic regression was used to estimate the association between patient characteristics and VTE risk at 30 and 90-days after surgery. Cox proportional-hazards regression was used to estimate the association between VTE and adjusted cancer specific (CSS) and overall survival (OS). 1310 patients were included with a mean age of 63 ± 11. 62% were male. 51% had one metastatic deposit. Major hepatectomy occurred in 64%. VTE occurred in 4% within 90days of liver resection. Only longer length of stay was associated with VTE development (OR 6.88 (2.57-18.43), p <0.001 for 15-21days versus 0-7days). 38% of VTEs were diagnosed after discharge, comprising 1.52% of the total cohort. VTE was not associated with inferior CSS or OS. Risk of VTE development in this population is similar to those undergoing hepatectomy for other indications, and to the risk following other cancer site resections where post-operative extended VTE prophylaxis is currently recommended. The number of VTEs occurring after discharge suggests there may be a role for extended VTE prophylaxis.

Neoadjuvant chemotherapy for patients with resectable colorectal cancer liver metastases: A systematic review and meta-analysis

BACKGROUNDIn recent years, neoadjuvant chemotherapy (NAC) has been increasingly used in patients with resectable colorectal liver metastases. However, the efficacy and safety of NAC in the treatment of resectable colorectal liver metastases (CRLM) are still controversial.AIMTo assess the efficacy and application value of NAC in patients with resectable CRLM.METHODSWe searched PubMed, Embase, Web of Science, and the Cochrane Library from inception to December 2020 to collect clinical studies comparing NAC with non-NAC. Data processing and statistical analyses were performed using Stata V.15.0 and Review Manager 5.0 software. RESULTSIn total, 32 studies involving 11236 patients were included in this analysis. We divided the patients into two groups, the NAC group (that received neoadjuvant chemotherapy) and the non-NAC group (that received no neoadjuvant chemotherapy). The meta-analysis outcome showed a statistically significant difference in the 5-year overall survival and 5-year disease-free survival between the two groups. The hazard ratio (HR) and 95% confidence interval (CI) were HR = 0.49, 95%CI: 0.39-0.61, P = 0.000 and HR = 0.48 95%CI: 0.36-0.63, P = 0.000. The duration of surgery in the NAC group was longer than that of the non-NAC group [standardized mean difference (SMD) = 0.41, 95%CI: 0.01-0.82, P = 0.044)]. The meta-analysis showed that the number of liver metastases in the NAC group was significantly higher than that in the non-NAC group (SMD = 0.73, 95%CI: 0.02-1.43, P = 0.043). The lymph node metastasis in the NAC group was significantly higher than that in the non-NAC group (SMD = 1.24, 95%CI: 1.07-1.43, P = 0.004).CONCLUSIONWe found that NAC could improve the long-term prognosis of patients with resectable CRLM. At the same time, the NAC group did not increase the risk of any adverse event compared to the non-NAC group.

P-193 Final results of hepatectomy followed by adjuvant chemotherapy with 3-month capecitabine plus oxaliplatin for colorectal cancer liver metastases: A multicenter phase 2 study

The role of neoadjuvant and adjuvant chemotherapy in the management of initially resectable colorectal cancer liver metastases (CLM) is still unclear. We evaluated the feasibility of 3-month adjuvant treatment with capecitabine plus oxaliplatin in combination (CAPOX) for post curative resection of CLM.

Hepatectomy Followed by Adjuvant Chemotherapy with 3-Month Capecitabine Plus Oxaliplatin for Colorectal Cancer Liver Metastases.

Lessons Learned Three‐month adjuvant capecitabine plus oxaliplatin in combination (CAPOX) appeared to reduce recurrence, with mild toxicity in postcurative resection of colorectal cancer liver metastases (CLM).Recurrence in patients who underwent the 3‐month adjuvant CAPOX after resection of CLM was most commonly at extrahepatic sites. BackgroundThe role of neoadjuvant and adjuvant chemotherapy in the management of initially resectable colorectal cancer liver metastases (CLM) is still unclear. We evaluated the feasibility of 3‐month adjuvant treatment with capecitabine plus oxaliplatin in combination (CAPOX) for postcurative resection of CLM.MethodsPatients received one cycle of capecitabine followed by four cycles of CAPOX as adjuvant chemotherapy after curative resection of CLM. Oral capecitabine was given as 1,000 mg/m2 twice daily for 2 weeks in a 3‐week cycle, and CAPOX consisted of oral capecitabine plus oxaliplatin 130 mg/m2 on day 1 in a 3‐week cycle. Primary endpoint was the completion rate of adjuvant chemotherapy. Secondary endpoints included recurrence‐free survival (RFS), overall survival (OS), dose intensity, and safety.ResultsTwenty‐eight patients were enrolled. Median age was 69.5 years, 54% of patients had synchronous metastases, and 29% were bilobar. Mean number of lesions resected was two, and mean size of the largest lesion was 31 mm. Among patients, 20 (71.4%; 95% confidence interval, 53.6%–89.3%) completed the protocol treatment and met its primary endpoint. The most common grade 3 or higher toxicity was neutropenia (29%). Five‐year recurrence‐free survival and overall survival were 65.2% and 87.2%, respectively.ConclusionThree‐month adjuvant treatment with CAPOX is tolerable and might be a promising strategy for postcurative resection of CLM.

Expression and prognostic value of epithelial-to-mesenchymal transition and cancer stem cellmarkersin primary lesions and liver metastases of colorectal cancers.

Cancer stem cells (CSCs) and epithelial mesenchymal transition (EMT) markers are considered useful indicators associated with metastasis and prognosis of colorectal cancers (CRCs). However, only a few studies have focused on the expression of these useful markers in metastases. Metastasectomy is widely used in advanced CRCs, and thus the postoperative prognostic factors are worth investigating. The present study investigated the consistency and differences of target proteins between primary and metastatic lesions of colorectal cancer, and discussed the prognostic indicators following resection of colorectal liver metastases. Clinical data of 56 patients with liver metastases from colorectal cancer were collected and the expression levels of target proteins (Ki-67, CD133, CD44, Snail, E-cadherin and β-catenin) were detected in primary tumor and matched liver metastases via immunohistochemistry analysis. Paired comparison between both tissue types was performed. The prognostic values of the target proteins for resectable colorectal cancer liver metastases were assessed. No significant differences were observed between the primary tissues and metastatic tissues. The consistency rates of these protein expression levels ranged from 51.8–78.6%. The maximum diameter of the liver metastases was <5 cm. Low Snail expression in metastases was associated with a longer overall survival (OS) time following resection of colorectal liver metastases. Furthermore, N0 stage and low carcinoembryonic antigen levels were associated with a longer progression-free survival time. Notably, no significant differences were observed in expression levels of the target proteins between the primary tumors and liver metastases. Taken together, the results of the present study suggest that Snail expression in liver metastases may be used as a novel independent prognostic factor for OS following resection of colorectal liver metastases.

Different Forms of Tumor Vascularization and Their Clinical Implications Focusing on Vessel Co-option in Colorectal Cancer Liver Metastases.

In modern anti-cancer therapy of metastatic colorectal cancer (mCRC) the anti-angiogenic treatment targeting sprouting angiogenesis is firmly established for more than a decade. However, its clinical benefits still remain limited. As liver metastases (LM) represent the most common metastatic site of colorectal cancer and affect approximately one-quarter of the patients diagnosed with this malignancy, its treatment is an essential aspect for patients' prognosis. Especially in the perioperative setting, the application of anti-angiogenic drugs represents a therapeutic option that may be used in case of high-risk or borderline resectable colorectal cancer liver metastases (CRCLM) in order to achieve secondary resectability. Regarding CRCLM, one reason for the limitations of anti-angiogenic treatment may be represented by vessel co-option (VCO), which is an alternative mechanism of blood supply that differs fundamentally from the well-known sprouting angiogenesis and occurs in a significant fraction of CRCLM. In this scenario, tumor cells hijack pre-existing mature vessels of the host organ independently from stimulating new vessels formation. This represents an escape mechanism from common anti-angiogenic anti-cancer treatments, as they primarily target the main trigger of sprouting angiogenesis, the vascular endothelial growth factor A. Moreover, the mechanism of blood supply in CRCLM can be deduced from their phenotypic histopathological growth pattern (HGP). For that, a specific guideline has already been implemented. These HGP vary not only regarding their blood supply, but also concerning their tumor microenvironment (TME), as notable differences in immune cell infiltration and desmoplastic reaction surrounding the CRCLM can be observed. The latter actually serves as one of the central criteria for the classification of the HGP. Regarding the clinically relevant effects of the HGP, it is still a topic of research whether the VCO-subgroup of CRCLM results in an impaired treatment response to anti-angiogenic treatment when compared to an angiogenic subgroup. However, it is well-proved, that VCO in CRCLM generally relates to an inferior survival compared to the angiogenic subgroup. Altogether the different types of blood supply result in a relevant influence on the patients' prognosis. This reinforces the need of an extended understanding of the underlying mechanisms of VCO in CRCLM with the aim to generate more comprehensive approaches which can target tumor vessels alternatively or even other components of the TME. This review aims to augment the current state of knowledge on VCO in CRCLM and other tumor entities and its impact on anti-angiogenic anti-cancer therapy.

Infiltrative Tumor Borders in Colorectal Liver Metastasis: Should We Enlarge Margin Size?

Surgery is the only potentially curative treatment for colorectal cancer liver metastases (CRLMs). Despite an improvement in results following resection, recurrence rates remain high. Many histopathological features have been reported as prognostic factors. Infiltrative borders are known to be associated with worse prognosis; however, margin size has never been evaluated together with the type of tumor border. In the present study, we analyzed the prognosis of patients with resected CRLM according to tumor growth pattern (TGP) and whether a larger margin size would bring any prognostic benefit. Medical records from a prospective database of 645 patients who underwent hepatic resection for CRLM between January 2004 and December 2019 at a single center were reviewed, and 266 patients were included in the analytic cohort. TGP (pushing or infiltrative) was evaluated regarding the impact in overall and disease-free survival. The impact of margin size (≤ or > 1 cm) on survival and hepatic recurrence according to TGP was also evaluated. TGP was defined as infiltrative in 182 cases (68.4%) and pushing in 84 patients (31.6%). Patients with infiltrative-type border presented worse overall survival and disease-free survival, as well as higher intrahepatic recurrence (p < 0.05). Larger margin size did not impact the prognosis of patients with infiltrative borders. Patients with infiltrative-type border present worse prognosis and higher intrahepatic recurrence. Larger margin size (> 1 cm) does not change the prognosis in patients with infiltrative border, showing that tumor biology is the most important factor for survival.

Preoperative nomogram to predict survival following colorectal cancer liver metastasis simultaneous resection.

Simultaneous resection for patients with synchronous colorectal cancer liver metastases (CRLM) remains an optimal option for the sake of curability. However, few studies so far focus on outcome of this subgroup of patients (who receive simultaneous resection for CRLM). Substantial heterogeneity exists among such patients and more precise categorization is needed preoperatively to identify those who may benefit more from surgery. In this study, we formulated this internally validated scoring system as an option. Clinicopathological and follow-up data of 234 eligible CRLM patients undergoing simultaneous resection from January 2010 to March 2019 in our center were included for analysis. Patients were randomized to either a training or validation cohort. We performed multivariable Cox regression analysis to determine preoperative factors with prognostic significance using data in training cohort, and a nomogram scoring system was thus established. Time-dependent receiver operating characteristic (ROC) curve and calibration plot were adopted to evaluate the predictive power of our risk model. In the multivariable Cox regression analysis, five factors including presence of node-positive primary defined by enhanced CT/MR, preoperative CEA level, primary tumor location, tumor grade and number of liver metastases were identified as independent prognostic indicators of overall survival (OS) and adopted to formulate the nomogram. In the training cohort, calibration plot graphically showed good fitness between estimated and actual 1- and 3-year OS. Time-dependent ROC curve by Kaplan-Meier method showed that our nomogram model was superior to widely used Fong's score in prediction of 1- and 3-year OS (AUC 0.702 vs. 0.591 and 0.848 vs. 0.801 for 1- and 3-year prediction in validation cohort, respectively). Kaplan-Meier curves for patients stratified by the assessment of nomogram showed great discriminability (P<0.001). In this retrospective analysis we identified several preoperative factors affecting survival of synchronous CRLM patients undergoing simultaneous resection. We also constructed and validated a risk model which showed high accuracy in predicting 1- and 3-year survival after surgery. Our risk model is expected to serve as a predictive tool for CRLM patients receiving simultaneous resection and assist physicians to make treatment decision.

Comparative study on prognosis of neoadjuvant chemotherapy followed by hepatic surgery versus upfront surgery in patients with synchronous colorectal liver metastasis

Objective: To compare the survival outcome in patients with synchronous colorectal cancer liver metastasis receiving neoadjuvant chemotherapy followed by hepatic surgery versus upfront surgery strategies. Methods: A retrospective cohort study was carried out. Data of patients undergoing surgery at the Department of Hepatopancreatobiliary Surgery Unit I of Peking University Cancer Hospital from January 2008 to December 2018 for initially resectable synchronous colorectal liver metastasis were retrospectively collected. A total of 282 cases were enrolled, including 244 in the neoadjuvant chemotherapy group, 38 in the upfront surgery first group. The overall survival (OS) and progression-free survival (PFS) of the two groups were compared. A propensity score risk adjustment was used to eliminate potential bias between groups, and the covariates including sex, age, location of primary tumor, T stage, clinical risk score (CRS), RAS gene status, adjuvant chemotherapy, and resection margin status were included for adjustment. Results: In the neoadjuvant chemotherapy group, 244 cases received 4 (1-15) cycles of chemotherapy before hepatic resection, among whom 207 cases received oxaliplatin-based regimens, 37 cases received irinotecan-based regimens, and 90 cases received combined targeted agents in the first line treatment. The median follow-up time was 30 (5-134) months, and loss of follow-up was 1%. Before adjustment, Kaplan-Meier survival analysis showed that the 1-year and 3-year OS rates in the neoadjuvant chemotherapy group (95.1% and 66.4%) were better than those in the upfront surgery first group (94.7% and 51.5%, P=0.026); 1-year and 3-year PFS rates in neoadjuvant chemotherapy group (51.0% and 23.4%) were also better than those in surgery first group (39.5% and 11.5%, P=0.039). After propensity score risk adjustment, Cox multivariate analysis indicated that neoadjuvant chemotherapy was an independent protective factor of PFS (HR=0.664, 95% CI: 0.449-0.982, P=0.040), however, neoadjuvant chemotherapy was not an independent protective factor of OS (HR=0.651, 95% CI: 0.393-1.079, P=0.096). Subgroup analysis showed that the 1-year and 3-year OS rates in the patients with response to the first line treatment (194, including complete remission, partial remission and reduction but not partial remission) (96.9% and 67.1%) were better than those in the upfront surgery group (94.7% and 51.5%, P=0.026) after adjustment. However, the 1-year and 3-year OS rates in the patients without response to the first line treatment (50, including tumor progression or enlargement) were 90.0% and 63.3%, respectively, which were not significantly different with 94.7% and 51.5% in the upfront surgery group (P=0.310) after adjustment. Conclusions: For patients with resectable synchronous colorectal cancer liver metastasis, liver resection after neoadjuvant chemotherapy can provide longer PFS than upfront surgery. Although the whole OS benefit is not significant, patients with effective neoadjuvant first-line chemotherapy have better OS than those undergoing upfront surgery.

Histopathological Growth Patterns and Survival After Resection of Colorectal Liver Metastasis: An External Validation Study.

BackgroundAfter resection of colorectal cancer liver metastases (CRLM), 2 main histopathological growth patterns can be observed: a desmoplastic and a nondesmoplastic subtype. The desmoplastic subtype has been associated with superior survival. These findings require external validation.MethodsAn international multicenter retrospective cohort study was conducted in patients treated surgically for CRLM at 3 tertiary hospitals in the United States and the Netherlands. Determination of histopathological growth patterns was performed on hematoxylin and eosin–stained sections of resected CRLM according to international guidelines. Patients displaying a desmoplastic histopathological phenotype (only desmoplastic growth observed) were compared with patients with a nondesmoplastic phenotype (any nondesmoplastic growth observed). Cutoff analyses on the extent of nondesmoplastic growth were performed. Overall survival (OS) and disease-free survival (DFS) were estimated using Kaplan-Meier and multivariable Cox analysis. All statistical tests were 2-sided.ResultsIn total 780 patients were eligible. A desmoplastic phenotype was observed in 19.1% and was associated with microsatellite instability (14.6% vs 3.6%, P = .01). Desmoplastic patients had superior 5-year OS (73.4%, 95% confidence interval [CI] = 64.1% to 84.0% vs 44.2%, 95% CI = 38.9% to 50.2%, P < .001) and DFS (32.0%, 95% CI = 22.9% to 44.7% vs 14.7%, 95% CI = 11.7% to 18.6%, P < .001) compared with their nondesmoplastic counterparts. A desmoplastic phenotype was associated with an adjusted hazard ratio for death of 0.36 (95% CI = 0.23 to 0.58) and 0.50 (95% CI = 0.37 to 0.66) for cancer recurrence. Prognosis was independent of KRAS and BRAF status. The cutoff analyses found no prognostic relationship between either OS or DFS and the extent of nondesmoplastic growth observed (all P > .1).ConclusionsThis external validation study confirms the remarkably good prognosis after surgery for CRLM in patients with a desmoplastic phenotype. The extent of nondesmoplastic growth does not affect prognosis.

How successful is liver resection for colorectal cancer liver metastases in patients over 75 years old?

Backgrounds/AimsAs populations age, an increased incidence of colorectal cancer will generate an increase in colorectal cancer liver metastases (CRLM). In order to guide treatment decisions, this study aimed to identify the contemporary complication rates of elderly patients undergoing liver resection for CRLM in a, centralised, UK centre.MethodsAll patients undergoing operative procedures for CRLM between January 2013 and January 2019 were included. Patient, tumour and operative data were analysed, including the prognostic marker; tumour burden score.Results339 operations were performed on 289 consecutive patients with CRLM (272 patients <75 years old, 67 patients ≥75 years old). Median age was 66 years (range 20-93). There was no difference in major complication rates between the two age cohorts (6.65 vs. 6.0%, p=0.847) or operative mortality (1.1% vs. 1.4%, p=0.794). Younger patients had higher R1 resection rates (20.4% vs. 4.5%, p=0.002) and post-operative chemotherapy rates (60.3% vs. 35.8%, p< 0.001). The 1, 3 and 5-year OS was 90.2%, 70.5% and 52.3% respectively, median 70 months, with no difference between age cohorts (p=0.772). Tumour Burden score and operation type were independent predictors of overall survival.ConclusionsLiver resection for CRLM in patients 75 years and older is feasible, safe and confers a similar 5-year survival rate to younger patients. The current outcomes from surgery are better than historical datasets.