Patients Undergoing Resection Of Colorectal Liver Metastases Research Articles

Sarcopenic Obesity Promotes Recurrence in Patients Undergoing Resection for Colorectal Liver Metastases (CRLM).

Sarcopenia, is predictive of a worse outcome after resection for colorectal liver metastases (CRLM). Obesity leads to a metabolic double burden if sarcopenia is as present, prompting malignancy progression, known as sarcopenic obesity (SO). This study aimed to compare sarcopenia and SO in patients undergoing CRLM resection, to prognostic parameters. The skeletal muscle index (SMI) defined sarcopenia using sex specific cut off values (48.4 cm2/m2 for females and 59.1 cm2/m2 for males) by calculating the preoperative muscle mass at the vertebral height L3 using OSIRIX DICOM viewer. SO was determined as sarcopenia in patients showing obesity, as shown via fat percentage measurements on the preoperative CT scan. Established prognostic parameters (KRAS status, TNM classification, inflammatory response) were evaluated against SMI and SO to assess their predictability for postoperative outcomes. A total of 251 patients (62% female, median age 68 years) were included. Sarcopenic patients showed a threefold higher risk for postoperative death as compared to non-sarcopenic patients (p=0.04). Prevalent SO increased this risk to fivefold (p=0.01) compared to non-sarcopenic patients. COX regression analysis revealed SO and KRAS positivity as independent prognostic factors for disease-free survival (SO: p=0.038; KRAS: p=0.041; TNM, tumor size, Charlson Comorbidity Index, platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio all not significant). Patients risk of death in case of KRAS positivity and SO was seven times higher (p=0.03). There seems to be a benefit in merging data on mutational status and muscle wasting in patients with CRLM to facilitate an individual, patient-tailored approach.

Colorectal Liver Micrometastases: Association with RAS/TP53 Co-Mutation and Prognosis after Surgery.

Micrometastases, defined as microscopic cancer cells spatially separated from the macroscopically evident metastasis, are identified in 24% to 56% of resected colorectal liver metastases (CLMs). Somatic gene mutations have emerged as independent prognostic factors in CLM. This study aimed to determine the prognostic impact and risk factors for the presence of micrometastases, including somatic gene mutations. Prospective evaluation for micrometastases was performed at 2 centers in the US and France from 2015 to 2019. CLM specimens were cut radially from the tumor margin to surrounding grossly normal liver for a distance of 2 cm. Depending on CLM size, 3 to 8 specimens per patient were submitted for microscopic analysis. Somatic gene mutations were detected by next-generation sequencing. Among 140 patients undergoing CLM resection in the US (n = 84) and France (n = 56), 36 (26%) patients were found to have micrometastases. Five-year overall and recurrence-free survival rates with micrometastases were 39% and 0%, respectively, compared with 61% and 20% without micrometastases (both p < 0.05). In multivariable analyses, the presence of micrometastases was an independent risk factor for worse overall survival (hazard ratio 2.88, 95% CI 1.46 to 5.70, p = 0.002) and recurrence-free survival (hazard ratio 1.56, 95% CI 1.01 to 2.41, p = 0.046). In binary logistic regression analysis, RAS/TP53 co-mutation was found to significantly increase the risk of micrometastases (odds ratio 2.77, 95% CI 1.15 to 6.71, p = 0.024). Micrometastases are associated with significantly worse survival after CLM resection. RAS/TP53 co-mutation correlated with increased risk of micrometastases. Further studies are needed to determine strategies to eradicate micrometastases.

Preliminary Analysis of Liquid Biopsy after Hepatectomy for Colorectal Liver Metastases

Liquid biopsies are increasingly tested in patients with colorectal cancer to assess tumor burden, response to therapy, and prognosis. The significance of liquid biopsy results after resection of colorectal liver metastases (CLMs) is not well-defined. Sixty-three patients undergoing CLM resection between 2016 and 2018 had plasma drawn postoperatively for liquid biopsy evaluation. Next-generation sequencing analysis was performed to detect somatic mutations in 70 genes. Liquid biopsy after CLM resection was positive in 42 of 63 patients (67%). Eleven patients (18%) had 1 gene mutation, 14 patients (22%) had 2 to 3 mutations, and 17 patients (27%) had 4 or more mutations. The most common mutation was APC, detected in 32 patients (76%), followed by TP53 (74%) and KRAS (38%). Two-year overall survival rate from date of liver resection was significantly worse among patients with a positive liquid biopsy (70% vs 100%; p= 0.005), particularly for those with 4 or more gene mutations detected, whose 2-year overall survival rate was 41%. Sixteen of the 63 patients underwent serial liquid biopsies, resulting in 100 liquid biopsies with matched serum CEA and CT scan results. Metastases were identified in 74 CT scans, which correlated with positive liquid biopsy in 77% of samples (p < 0.001) and CEA > 3 ng/mL in 45% of samples (p < 0.22). Liquid biopsy results provide information about disease burden and prognosis that is complementary to serum CEA and CT imaging. A positive liquid biopsy after CLM resection is associated with worse overall survival, particularly when multiple gene mutations are detected.

The prognostic impact of RAS on overall survival following liver resection in early versus late-onset colorectal cancer patients

BackgroundThe impact of molecular aberrations on survival after resection of colorectal liver metastases (CLM) in patients with early-age-onset (EOCRC) versus late-age-onset colorectal cancer (LOCRC) is unknown.MethodsPatients who underwent liver resection for CLM with known RAS, BRAF and MSI status were retrospectively studied. The prognostic impact of RAS mutations by age was analysed with age as a categorical variable and a continuous variable.ResultsThe study included 573 patients, 192 with EOCRC and 381 with LOCRC. The younger the age of onset of CRC, the greater the negative impact on overall survival of RAS mutations in the LOCRC, EOCRC, and ≤40 years (hazard ratio (HR), 1.64 (95% confidence interval (CI), 1.23–2.20), 2.03 (95% CI, 1.30–3.17), and 2.97 (95% CI, 1.44–6.14), respectively. Age-specific mortality risk and linear regression analysis also demonstrated that RAS mutations had a greater impact on survival in EOCRC than in LOCRC (slope: −4.07, 95% CI −8.10 to 0.04, P = 0.047, R2 = 0.08).ConclusionAmong patients undergoing CLM resection, RAS mutations have a greater negative influence on survival in patients with EOCRC, more so in patients ≤40 years, than in patients with LOCRC and should be considered as a prognostic factor in multidisciplinary treatment planning.

A New Surveillance Algorithm After Resection of Colorectal Liver Metastases Based on Changes in Recurrence Risk and RAS Mutation Status.

The optimal surveillance strategy after resection of colorectal liver metastases (CLM) is unknown. We evaluated changes in recurrence risk after CLM resection and developed a surveillance algorithm. Patients undergoing CLM resection during 1998 to 2015 were identified from a prospectively compiled database and analyzed if they had the potential for follow-up longer than the longest observed time to recurrence in this cohort. Changes in recurrence risk and risk factors for recurrence were evaluated. All statistical tests were 2-sided. Among 2,105 patients who were initially identified and underwent CLM resection, the latest recurrence was observed at 87 months; 1,221 consecutive patients from 1998 through 2011 with the potential for at least 87 months of follow-up were included. The risk of recurrence was highest at 0 to 2 years after CLM resection, lower at 2 to 4 years after CLM resection, and steadily lower after 4 years after CLM resection. Factors associated with increased recurrence risk at the time of surgery were primary lymph node metastasis (hazard ratio [HR], 1.54; 95% CI, 1.21-1.97; P<.001), multiple CLM (HR, 1.31; 95% CI, 1.06-1.63; P=.015), largest liver metastasis diameter >5 cm (HR, 1.64; 95% CI, 1.23-2.19; P<.001), and RAS mutation (HR, 1.29; 95% CI, 1.04-1.59; P=.020). In patients without recurrence at 2 years, the only factor still associated with increased recurrence risk was RAS mutation. In those patients, the recurrence rate at 4 years was 59.3% in patients with RAS mutation versus 27.8% in patients with RAS wild-type (P=.019). For patients who have undergone CLM resection, we propose surveillance every 3 to 4 months during years 0 to 2, every 3 to 4 months (if mutant RAS) versus every 4 to 6 months (if RAS wild-type) during years 2 to 4, and every 6 to 12 months if recurrence-free at 4 years.

Interactions of multiple gene alterations in colorectal liver metastases

The advancements in next generation sequencing have expanded the information available in clinical practice. Alterations of TP53, APC, RAS, PIK3CA, and SMAD4 are present in more than 10% of patients with colorectal liver metastases (CLM). Of these genes, TP53, RAS and SMAD4 were associated with worse survival in patients undergoing CLM resection. Testing multiple gene alterations provides a more precise prognosis for patients undergoing CLM resection and may be useful for better clinical decision making.

Mutation Status of RAS, TP53, and SMAD4 is Superior to Mutation Status of RAS Alone for Predicting Prognosis after Resection of Colorectal Liver Metastases.

Somatic gene mutations have been increasingly recognized to impact prognosis following resection of colorectal liver metastases (CLM). We aimed to determine the impact of combinations of somatic mutations on survival in patients undergoing CLM resection. We identified patients who underwent initial CLM resection during 2007-2017 and had genetic sequencing data available. Risk factors for overall survival (OS) and recurrence-free survival (RFS) were determined using Cox proportional hazards models. Of 1460 patients who underwent CLM resection during the study period, 507 met the inclusion criteria. Multigene testing revealed mutation rates greater than 10% for TP53 (mutated in 70.8% of patients), APC (53.5%), RAS (50.7%), PIK3CA (15.8%), and SMAD4 (11.0%). BRAF was mutated in 2.0% of patients. BRAF, RAS, TP53, and SMAD4 mutations were significantly associated with OS, and RAS, TP53, and SMAD4 mutations were significantly associated with RFS. Coexisting mutations in RAS, TP53, and SMAD4 were associated with significantly worse OS and RFS than coexisting mutations in any 2 of these genes and mutations in 1 or none of these genes. Coexisting mutations in 2 genes conferred significantly worse OS and RFS than single mutation or no mutations. OS and RFS did not differ significantly between patients with RAS mutation and wild-type TP53 and SMAD4 and patients with wild-type RAS (P = 0.858 and 0.729, respectively). RAS mutation status alone is not sufficient for precisely predicting prognosis after CLM resection.

Deleterious Effect of RAS and Evolutionary High-risk TP53 Double Mutation in Colorectal Liver Metastases.

To assess the impact of somatic gene mutations on survival among patients undergoing resection of colorectal liver metastases (CLM). Patients undergoing CLM resection have heterogeneous outcomes, and accurate risk stratification is necessary to optimize patient selection for surgery. Next-generation sequencing of 50 cancer-related genes was performed from primary tumors and/or liver metastases in 401 patients undergoing CLM resection. Missense TP53 mutations were classified by the evolutionary action score (EAp53)-a novel approach that dichotomizes mutations as low or high risk. The most frequent somatic gene mutations were TP53 (65.6%), followed by KRAS (48.1%) and APC (47.4%). Double mutation in RAS/TP53, identified in 31.4% of patients, was correlated with primary tumor location in the right colon (P = 0.006). On multivariable analysis, RAS/TP53 double mutation was an independent predictor of shorter overall survival (hazard ratio 2.62, 95% confidence interval 1.41-4.87, P = 0.002). In patients with co-mutated RAS, EAp53 high-risk mutations were associated with shorter 5-year overall survival of 12.2%, compared with 55.7% for TP53 wild type (P < 0.001). The negative prognostic effects of RAS and TP53 mutations were limited to tumors harboring mutations in both genes. Concomitant RAS and TP53 mutations are associated with decreased survival after CLM resection. A high EAp53 predicts a subset of patients with worse prognosis. These preliminary analyses suggest that surgical resection of liver metastases should be carefully considered in this subset of patients.

Portal vein embolization does not affect the long-term survival and risk of cancer recurrence among colorectal liver metastases patients: A prospective cohort study

BackgroundPrevious studies comparing the survival outcomes of liver resections with and without preoperative portal vein embolization (PVE) for colorectal liver metastases (CLM) have linked PVE to higher rate of tumor progression, lower overall survival (OS) and lower disease-free survival (DFS). The lack of adjusted models to compare these outcomes is a limitation of these studies since patients requiring PVE may differ significantly from the ones receiving upfront surgery. Materials and methodsProspective cohort study of 128 patients undergoing CLM resection. The OS analysis followed an intent-to-treat (ITT) approach. The adjusted impact of PVE on OS and DFS was evaluated using multivariate Cox regression models. ResultsSeventy-one patients underwent PVE before attempting a liver resection while 57 received upfront surgery (NoPVE). All NoPVE patients were resected while 14 PVE participants (19.7%) were not operated (tumor progression = 9/14). PVE patients had a significantly higher preoperative lesions count (3 [1.75–4] vs 1 [1–2.5]; p < 0.001), a higher prevalence of bilateral metastases (23.5% vs 8.8, p = 0.028) and a higher count of neo-adjuvant chemotherapy cycles compared to NoPVE patients. The OS of PVE patients was similar to NoPVE participants (44.7 months [26.9–69.5] vs 49.0 [24.9–64.8], p = 0.761). The DFS of resected PVE patients was higher than NoPVE patients (33.2 months [10.7–54.6] vs 23.4 months [14.1–58.1], p = 0.991). In the adjusted models, preoperative lesions count was the only significant predictor of overall mortality (HR+IC95 = 1.06 (1.02–1.11) p = 0.005) and cancer recurrence (HR+IC95 = 1.14 (1.03–1.27) p = 0.012). ConclusionIn the context of CLM, patients requiring PVE differ significantly from patients receiving upfront surgery. This confirms the need for adjusted models when comparing the clinical outcomes of both groups. Our adjusted analysis suggests that PVE is not a significant predictor of a lower OS or DFS. PVE allowed the resection of 80% of participants with initially unresectable CLM. Institutional protocol number12.106 Study registration numberNCT03168230.

Biomarkers in colorectal liver metastases.

Despite a 5-year overall survival rate of 58 per cent after liver resection for colorectal liver metastases (CLMs), more than half of patients develop recurrence, highlighting the need for accurate risk stratification and prognostication. Traditional prognostic factors have been superseded by newer outcome predictors, including those defined by the molecular origin of the primary tumour. This review synthesized findings in the literature using the PubMed database of articles in the English language published between 1998 and 2017 on prognostic and predictive biomarkers in patients undergoing resection of CLMs. Responses to preoperative chemotherapy define prognosis in patients undergoing CLM resection. There are differences by embryological origin too. Somatic mutations in the proto-oncogenes KRAS and NRAS are associated with positive surgical margins and tumour regrowth after ablation. Other mutations (such as BRAF) and co-occurring mutations in RAS/TP53 and APC/PIK3CA have emerged as important biomarkers that determine an individual patient's tumour biology and may be used to predict outcome after CLM resection. Knowledge of somatic mutations can guide the use of preoperative therapy, extent of surgical margin and selection for ablation alone.

Eradication of Missing Liver Metastases After Fiducial Placement

BackgroundThe risk of colorectal liver metastases (CLM) disappearing on cross-sectional imaging has increased with advances in preoperative chemotherapy, but <50 % of disappearing CLM demonstrate complete pathological response. ObjectiveThe aim of this study was to evaluate the role of fiducial marker placement before potentially curative treatment of CLM at risk of disappearing with chemotherapy. MethodsAll consecutive patients who underwent fiducial placement for tracking of CLM at a tertiary center were reviewed. ResultsAmong 1377 patients undergoing CLM resection between 2005 and 2015, 35 patients underwent fiducial placement. Three patients were excluded due to disease progression. The study population comprised 32 patients who underwent fiducial placement in 41 CLM. Among the 41 marked CLM, 34 (83 %) were located >10 mm deep in the liver parenchyma, 25 (61 %) were in the right liver, and median size was 12 mm (range, 6–20 mm). No complication occurred after fiducial placement. After chemotherapy, 19 (46 %) of the 41 marked metastases disappeared on cross-sectional imaging. All fiducial-tracked CLM were treated with resection (n = 31) or ablation (n = 10). After median follow-up of 14 months (range, 0–64 months), no local recurrences were observed. ConclusionFiducial placement represents a safe procedure that facilitates accurate localization for resection or ablation of small CLM at risk of disappearing with chemotherapy.

Prognostic performance of inflammation-based prognostic indices in patients with resectable colorectal liver metastases.

A range of prognostic cellular indices of the systemic inflammatory response, namely the neutrophil-lymphocyte ratio (NLR), derived NLR (dNLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), combination of platelet count and neutrophil-lymphocyte ratio (COP-NLR) and prognostic nutritional index (PNI), have been developed and found to have prognostic utility across varied malignancies. The current study is the first to examine the prognostic value of these six inflammatory scores in patients with resectable colorectal liver metastases (CRLM). Data from 302 consecutive patients undergoing surgery for resectable CRLM were evaluated. The prognostic influence of clinicopathological variables and the inflammatory scores NLR, dNLR, PLR, LMR, COP-NLR and PNI upon overall survival (OS) and cancer-specific survival (CSS) were determined by log-rank analysis and univariate and multivariate Cox regression analyses. High preoperative NLR was the only inflammatory variable independently associated with shortened OS (HR 1.769, 95 % CI 1.302-2.403, P < 0.001) or CSS (HR 1.927, 95 % CI 1.398-2.655, P < 0.001) following metastasectomy. When NLR was replaced by dNLR in analyses, high dNLR was independently associated with shortened OS (HR 1.932, 95 % CI 1.356-2.754, P < 0.001) and CSS (HR 1.807, 95 % CI 1.209-2.702, P = 0.004). The inflammatory scores PLR, LMR, COP-NLR and PNI demonstrated no independent association with either overall or cancer-specific survival in the study population. Our findings support high preoperative NLR and dNLR as independent prognostic factors for poor outcome in patients undergoing CRLM resection, with prognostic value superior to other cellular-based systemic inflammatory scores.

Exploring Gene Expression Signatures for Predicting Disease Free Survival after Resection of Colorectal Cancer Liver Metastases

Background and ObjectivesThis study was designed to identify and validate gene signatures that can predict disease free survival (DFS) in patients undergoing a radical resection for their colorectal liver metastases (CRLM).MethodsTumor gene expression profiles were collected from 119 patients undergoing surgery for their CRLM in the Paul Brousse Hospital (France) and the University Medical Center Utrecht (The Netherlands). Patients were divided into high and low risk groups. A randomly selected training set was used to find predictive gene signatures. The ability of these gene signatures to predict DFS was tested in an independent validation set comprising the remaining patients. Furthermore, 5 known clinical risk scores were tested in our complete patient cohort.ResultNo gene signature was found that significantly predicted DFS in the validation set. In contrast, three out of five clinical risk scores were able to predict DFS in our patient cohort.ConclusionsNo gene signature was found that could predict DFS in patients undergoing CRLM resection. Three out of five clinical risk scores were able to predict DFS in our patient cohort. These results emphasize the need for validating risk scores in independent patient groups and suggest improved designs for future studies.

Pathologic Response to Preoperative Chemotherapy in Colorectal Liver Metastases: Fibrosis, not Necrosis, Predicts Outcome

Pathologic response to preoperative chemotherapy for colorectal liver metastases (CLM) is associated with survival after hepatectomy. Histologically, dominant response patterns include fibrosis, necrosis and/or acellular mucin, but some of these changes can appear without previous chemotherapy and their individual correlation with outcome is unknown. Pathology slides from patients who underwent CLM resection (irrespective of preoperative chemotherapy status) were rereviewed by a blinded pathologist. Pathologic response was recorded as the summation of percentage necrosis, fibrosis and acellular mucin. Associations between pathologic response, its components, preoperative chemotherapy, and survival were analyzed. Pathology slides were rereviewed in 366 patients undergoing CLM resection from 2003 to 2007. Preoperative chemotherapy was administered in 249 (68 %) patients, who, when compared to no preoperative chemotherapy patients, had higher rates of overall pathologic response (57 vs. 46 %, P < .01), fibrosis (21 vs. 12 %, P < .01) and acellular mucin (6 vs. 3 %, P = .05) but similar rates of necrosis (30 vs. 31 %, P = .30). In patients receiving preoperative chemotherapy, overall pathologic response ≥ 75 % (5 year, 83 vs. 47 %, P < .01) and fibrosis ≥ 40 % (5 year, 87 vs. 51 %, P < .01) independently correlated with disease-specific survival after hepatectomy. Preoperative hepatic artery infusion chemotherapy (P = .04) and bevacizumab (P = .05) were marginally associated with overall pathologic response and fibrosis, respectively. Fibrosis is the predominant chemotherapy-related pathologic alteration driving the association of treatment response with survival after CLM resection. Necrosis in CLM is not related to chemotherapy or outcome.