Undergoing Liver Metastasectomy Research Articles

1195 The Outcomes of Liver Resection for Metastatic Liver Disease from Melanoma: A Systematic Review and Meta-Analysis

Abstract Aim There remains controversy in the literature regarding the choice of treatment of melanoma metastases to the liver. This systematic review aims to compare the survival and morbidity rates of patients undergoing liver metastasectomy with patients undergoing medical treatment. Method A literature search was conducted from inception until June 2022 using Ovid, Medline, Embase and the Cochrane library. Snowball and hand searches were also carried out. Included studies compared survival outcomes between patients undergoing metastasectomy to those undergoing medical management. Meta-analyses were performed comparing the survival at 6 months, 1, 3 and 5 years as well as overall survival. A sub-analysis was performed comparing the overall survival between surgically and medically treated patients which exclusively uveal melanoma hepatic metastases. Results 25 studies with a total of 2990 participants were included in our study. All studies were found to have some degree of risk of bias. Mean Overall survival was 44.31 (SD 46.25) and 21.59 (SD 24.31) in surgically and medically treated patients respectively. Meta-analysis showed a statistically significant benefit overall in favour of surgically treated patients (OR = 1.33, 95% CI 0.29 to 2.3, p =0.01, I²=0). This was also the case at 6 months, 1, 3 and 5 years. Meta-analysis showed no significant differences in survival between surgically and medically treated patients which exclusively uveal melanoma metastases. Conclusions This review demonstrates improved survival in patients undergoing hepatic metastatectomy for melanoma metastases compared to those undergoing medical treatment, but this may not be the case for those with uveal metastases.

Simultaneous laparoscopic colectomy and liver metastasectomy with natural orifice specimen extraction: A proof-of-concept study

Background, Natural orifice specimen extraction (NOSE) via the anus or vagina is an alternative to conventional transabdominal specimen extraction in laparoscopic colorectal cancer surgery. NOSE has been shown to be safe and effective, resulting in decreased postoperative pain, analgesia use, and improved recovery, without oncological compromise. We aimed to demonstrate the feasibility of NOSE for combined colectomy with liver metastasectomy.Methods, From July 2022 to April 2024, all cases of laparoscopic colorectal cancer resection and synchronous liver metastasectomy with NOSE were included in the study. Selection criteria included a maximum specimen diameter of less than 5 cm and patient body mass index of less than 35 kg/m2.Results, Over the 22-month duration, four consecutive patients (two males, two females) underwent combined resection with NOSE. Mean age and BMI were 74.8 (range 63–81) years and 20.9 (range 19.5–22.3) kg/m2 respectively. Patient A and D underwent anterior resection for sigmoid cancer, Patient B underwent D3 right hemicolectomy for cecal cancer, and Patient C underwent subtotal colectomy for synchronous cecal and descending colon cancer. All patients underwent liver metastasectomy at the same sitting. Patient A and D had transanal NOSE while Patients B and C underwent transvaginal NOSE. Mean operative time and blood loss was 416 (range 330–535) minutes and 338 (range 50–500) ml respectively. All patients recovered gastrointestinal function within the first two postoperative days. Infected seroma of the liver bed occurred in one patient requiring percutaneous drainage. The average maximum colon tumor diameter was 2.9 (range 1.3–4.0) cm. All resection margins were clear. Mean duration of follow-up was 7.5 (range 2–12) months.Conclusions, Simultaneous colectomy and liver metastasectomy with NOSE for colorectal cancer is feasible and safe in highly selected patients, resulting in good postoperative outcomes. This proof-of-concept analysis paves the way for larger studies to draw definitive conclusions.

Adjuvant systemic chemotherapy with or without hepatic arterial infusion of floxuridine in patients following colorectal cancer liver metastases resection (HARVEST): A prospective, randomized controlled trial.

3516 Background: Several retrospective studies have previously demonstrated that a combination of adjuvant systemic chemotherapy and hepatic arterial infusion (HAI) could benefit patients following colorectal cancer liver metastases (CRLM) resection. This prospective clinical study aimed to determine whether adding HAI to adjuvant systemic chemotherapy could reduce the risk of recurrence following CRLM resection. Methods: The HARVEST study is an investigator-initiated, prospective, randomized controlled trial investigating the efficacy and safety of adjuvant intravenous chemotherapy with or without HAI floxuridine (FUDR) in CRLM patients that underwent liver metastasectomy. Patients in the systemic chemotherapy plus HAIC arm (HAI group) received systemic FOLFOX (q2w) plus HAI (FUDR, d1-14, q4w) for up to 6 months, while the systemic chemotherapy group without HAI (non-HAI group) received intravenous FOLFOX only. The primary study endpoint is the relapse-free survival in the modified intention-to-treat (mITT) population. Blood samples at different time points were also collected and circulating tumor DNA (ctDNA) was tested for NPY and SEPT9 methylation. Results: The study was prematurely terminated due to FUDR production halt in China. Ninety-two patients were randomized and seventy-seven patients (38 in the HAI group and 39 in the non-HAI group) were eventually included in our mITT analysis. After a median follow-up of 35.8 months, there were 22 (57.9%) and 25 (64.1%) recurrences in the HAI and non-HAI groups, respectively. The median relapse-free survival was 20.0 months in the HAI group and 11.7 months in the non-HAI group (p = 0.14; HR 0.65; 95% confidence interval [CI] 0.37 to 1.16). No significant difference was found in terms of overall survival between the two groups (p = 0.461). Our subgroup analysis revealed that patients with multiple liver metastases (p < 0.01) and RAS/BRAF mutation (p < 0.01) could benefit from adjuvant HAI treatment. Based on ctDNA status, patients with positive postoperative ctDNA methylation benefited from adjuvant HAI treatment (p < 0.01), while those with negative postoperative ctDNA methylation status (p = 0.95) did not. Chemotherapy-related adverse events were comparable between the two groups. Conclusions: Adjuvant chemotherapy intensification using HAI did not significantly reduce recurrence following CRLM resection. However, patients with multiple liver metastases, RAS/BRAF mutation and those with positive postoperative ctDNA might benefit from adjuvant HAI treatment. Clinical trial information: NCT03500874 .

Pathological Evaluation of Resected Colorectal Liver Metastases: mFOLFOX6 Plus Bevacizumab versus mFOLFOX6 Plus Cetuximab in the Phase II ATOM Trial.

Simple SummaryWe compared the pre-planned histopathological responses, such as tumor regression grade (TRG), modified TRG, and dangerous halo (DH) of resected liver metastases, in patients who received modified FOLFOX6 plus bevacizumab and modified FOLFOX6 plus cetuximab for liver-limited colorectal metastases from the ATOM trial. We clarified the difference between bevacizumab and cetuximab in terms of histological response. TRG is a useful marker for determining prognosis in both treatments. We also showed, for the first time, that DH is associated with prognosis.We compared the preplanned histopathological responses of resected liver metastases from patients who received modified FOLFOX6 plus bevacizumab or modified FOLFOX6 plus cetuximab for liver-limited colorectal metastases in the ATOM trial. Fibrosis and viable tumor cells in tumor regression grade (TRG), infarct-like necrosis in modified TRG (mTRG), and dangerous halo (DH) were assessed. Fifty-five patients (28 and 27 patients in the bevacizumab and cetuximab arms, respectively) were divided into the low (viable tumor cells ≤ 50%) and high (>50%) TRG or mTRG groups. DH was characterized as absent/rare or focal/diffuse. Compared to the bevacizumab arm, the cetuximab arm was more effective, with respect to low TRG (13 vs. 23 patients) and absent/rare DH (14 vs. 19 patients), respectively. Low mTRG was similarly observed in both arms. Low TRG/mTRG and absent/rare DH showed better relapse-free survival (RFS) than high TRG/mTRG and focal/diffuse DH. In the bevacizumab arm, a significant difference in RFS existed between the low and high TRG groups, while in the cetuximab arm, for TRG, mTRG, and DH, the low and absent/rare groups demonstrated significantly longer RFS than the high and focal/diffuse groups, respectively. TRG could estimate RFS in patients who underwent liver metastasectomy after bevacizumab or cetuximab chemotherapy.

Development of a Risk Score to Predict Post-Discharge Rehabilitation Care After Liver Metastasectomy

IntroductionNeed for discharge to intermediate care (DCIC) can increase length of stay and be a source of stress to patients. Estimating risk of DCIC would allow earlier involvement of case managers, improve length of stay and patient satisfaction by setting realistic expectations. The aim was to use National Surgical Quality Improvement Program dataset to develop a prediction model for DCIC after undergoing liver metastasectomy. MethodsData were obtained from National Surgical Quality Improvement Program 2011-2018 covering liver metastasectomy. Recursive partitioning narrowed potential predictors and identified thresholds for categorization of continuous variables. Logistic regression identified a predictive model, internally validated by using 200 bootstrap samples with replacement. A risk score was derived using Framingham Study methodology by dividing all regression coefficients by the smallest model coefficient. Receiver operating characteristic analysis identified the score that maximized sensitivity/specificity, defining low/high risk. Finally, recursive partitioning identified categories low/medium/high. ResultsThe most parsimonious model predicting DCIC area under the curve (, 0.722, 95%CI: 0.705-0.739) identified five independent predictors including age >60, procedure type, hypertension requiring medication, albumin <3.5 mg/dL and hematocrit <30%. Internal validation resulted in expected bias-corrected area under the curve of 0.717, 95% CI: 0.698-0.732. The maximum score was 17.9 and 5.8 maximized sensitivity (sn) and specificity (sp) [sn = 81%, sp = 51%) predicting DCIC. Stratified into three groups, a score ≥9.5 identified highest risk (12.8%), ≥4.3 medium (6.1%) and <4.3 lowest risk (1.5%). ConclusionsDetermining risk of DCIC benefits shared decision making and patient care. This evidence may enhance discharge planning after liver metastasectomy expediting the process. Age >60 contributed the most weight to the score, but the use of additional variables in three groups allowed further discrimination between patients.

Association of Liver Resection and Visiting More Than One Commission on Cancer Hospital for Colorectal Cancer With Liver Metastasis

IntroductionDespite the advances in treatment, there are low rates of liver metastasectomy for colorectal cancer with liver metastasis (CRLM) in the United States. The aim of this study was to investigate the association between likelihood of liver metastasectomy for CRLM and seeking care at >1 versus 1 Commission on Cancer (CoC) hospital. MethodsWe performed a retrospective analysis of the National Cancer Database (2011-2017) for patients with CRLM. Patients were grouped based on seeking care at 1 CoC hospital or >1 CoC hospital. An adjusted multivariable Poisson regression interaction analysis was used to evaluate likelihood of liver metastasectomy for CRLM according to race and whether care was sought at >1 CoC hospital. ResultsWe identified 25,956 patients with CRLM without extra-hepatic disease. 23,088 (89.0%) patients visited 1 CoC hospital and 2868 (11.1%) visited >1 CoC hospital. Black patients were less likely to seek care at >1 CoC hospital (relative risk [RR] 0.68, confidence intervalCI 0.60-0.76, P < 0.001). Undergoing liver metastasectomy was associated with higher likelihood of seeking care at >1 CoC hospital (RR 1.27, CI 1.26-1.52, P < 0.001). Among patients who sought care at >1 CoC hospital, there was no significant difference between White and Black patients undergoing liver metastasectomy (RR 0.86, 95% CI 0.71-1.04, P = 0.11). ConclusionsPatients with CRLM who sought care at >1 CoC hospital were more likely to undergo a liver metastasectomy. Among White and Black patients who sought care at >1 CoC hospital, there was no difference in likelihood of undergoing a liver metastasectomy.

Does pulmonary metastasectomy of colorectal metastases translate to better survival? A systematic review

Surgical resection of the primary and metastatic tumour is increasingly recommended in suitable patients with metastatic colorectal cancer (CRC). While the role of metastasectomy is well studied and established in colorectal liver metastasis, evidence remains limited in pulmonary metastases. This systematic review was conducted to examine the current evidence on the role of lung metastasectomy (LUM) in CRC. Three databases were systematically searched, to identify studies that compared survival outcomes of LUM, and factors that affected decision for LUM. From a total of 5,477 records, 6 studies were eventually identified. Two papers reported findings from one randomised controlled trial and 4 were retrospective reviews. There was no clear survival benefit in patients who underwent LUM compared to those who did not. When compared against patients who underwent liver metastasectomy, there was also no clear survival benefit. Patients who underwent LUM were also more likely to have a single pulmonary tumour, and metachronous disease. The evidence suggests a role for LUM, but is limited by inherent selection bias in retrospective reviews, and the single randomised clinical trial performed was not completed. More prospective studies are required to understand the true effect of LUM on outcomes in metastatic CRC.

Clinical Outcome of Patients Submitted to Liver Resection in the Context of Metastatic Breast Cancer: A Study of a Tertiary Hospital Center.

Introduction: Breast cancer is the most incident cancer in the world, accounting for 25% of new cancers per year in females. It is the most frequent malignancy in women, being the fifth cause of death from cancer worldwide. Approximately 5 to 10% of patients already present with metastases at diagnosis, and the liver is the site of metastases in half of these cases. Liver metastasis (LM) resection, performed after neoadjuvant systemic treatment, has been reported to increase median overall survival in this population. Aim: The aim of this analysis is to assess the outcomes of patients undergoing breast cancer liver metastasis surgical resection, including impact on survival, compared to patients where metastasectomy was not performed. Methods: retrospective review of 55 female patients with breast cancer liver metastases, diagnosed and treated in a single tertiary university hospital from January 2011 to December 2016 was performed. Results: In 32/55 patients (58.2%), multi-organ metastases were identified (the most common sites being bone, lungs, and lymph nodes). Of the remaining 23 patients, the liver was the unique metastatic site; thirteen patients had diffuse bilobar hepatic metastases. The remaining ten patients were proposed for surgical treatment; three of them had peritoneal carcinomatosis identified during surgery, and no hepatic metastasectomy was performed. As a result, only seven (12.7%) patients underwent liver metastasectomy. Overall survival was higher in patients who had LM surgery (65 months [Interquartile Range (IQR) 54–120]), in comparison to those diagnosed with diffuse bilobar hepatic metastases (17.5 months [IQR 11–41]), and with those showing concurrent liver and bone metastases (16.5 months [IQR 6–36]) (p = 0.012). In univariable analysis, the latter two groups showed worse overall survival outcomes (Hazard Ratio (HR) = 3.447, 95%CI: 1.218–9.756, p = 0.02 and HR = 3.855, 95% Confidence Interval (CI): 1.475–10.077, p = 0.006, respectively) when compared to patients with LM. Conclusion: In our series, patients submitted to metastasectomy had a median overall survival after diagnosis of LM three times greater than the non-operated patients with isolated LM, or concurrent LM and bone metastases (65 vs. 17.5 and 16.5 months, respectively). As is vastly known for colorectal cancer liver metastasis, resection of breast cancer liver metastasis may reduce tumor burden, and therefore may improve patient outcome.

P-191 Prognostic factors of colorectal cancer liver metastasectomy

In selected patients with metastatic colorectal cancer (MCRC), resection of liver metastases may offer the possibility of cure. The aim of this study was to evaluate possible preoperative prognostic factors for survival in patients with MCRC undergoing liver metastasectomy in order to select the ideal patient for this procedure. Retrospective analysis of 121 patients with MCRC followed at our center, who underwent liver metastasectomy with curative intent and who underwent primary chemotherapy between March 2004 and June 2017. Survival analyses was estimated through Kaplan-Meier method and multivariate analyses through Cox regression. The median age at diagnosis was 58 (19-79) and 61% were men. The median follow-up time was 53 months (10-143). The recurrence rate after the first metastasectomy was 73.6%. The median DFS after the first liver metastasectomy was 13 months (95% CI, 10.3-15.6). The median OS was 63 months (95% CI, 48.6-77.4). The preoperative factors which gave the worst prognosis in the analysis for OS and DFS were: the presence of ≥3 metastatic liver lesions (median OS: 101 months, CI 95% 57.4-144.6 vs 51 months, CI 95% 42.0-59.9, p = 0.010; DFS median: 18 months, CI 95% 0.0-36.9 vs 10 months, CI 95% 7.2-12.8, p = 0.013), extrahepatic metastasis (median OS: 71 months, CI 95% 58.4-83.6 vs 37 months, CI 95% 22.6-51.4, p = 0.001; median DFS: 15 months, CI 95% 12.2-17.8 vs 7 months, CI 95% 4.3-9.7, p = 0.002), pT4 (median OS: 65 months, CI 95% 50.2-79.8 vs 34 months, CI 95% 25.4-42.6, p = 0.008; Median DFS: 14 months, CI 95% 10.9-17.1 vs 5 months, CI 95% 2.9-7.1, p = 0.011), size of metastases ≥60 mm (median OS: 80 months, CI 95% 63.7-96.3 vs 51 months, CI 95% 42.8-59.2, p = 0.020; DFS median: 16 months, CI 95% 11.9-20.1 vs 10 months, CI 95% 7.4-12.6, p = 0.020). The factors which maintained a negative impact in the multivariate analysis for OS and DFS were pT4 (OS: p = 0.020, HR 1.98, CI 95% 1.1-3.5; DFS: p = 0.007, HR 2.11, CI 95% 1.2-3.6) and extrahepatic metastasis (OS: p = 0.011, HR 2.05, CI 95% 1.2-3.6; DFS: p = 0.024, HR 1.85, CI 95% 1.1-3.2). The presence of ≥3 metastatic liver lesions, extrahepatic metastasis, pT4 and the size of metastases ≥60 mm had a negative impact on OS and DFS.

Association between race, hospital volume of major liver surgery and access to metastasectomy for colorectal liver metastases

Presenter: Annabelle Jones MD | Brigham and Women's Hospital Background: In select patients with colorectal cancer liver metastases (CRLM), liver metastasectomy with curative-intent has been found to be associated with a 5-year overall survival that is greater than 50%. Despite recent advancements, it is estimated that only half of potentially resectable patients with CRLM are undergoing liver metastasectomy. Previous studies have demonstrated that non-White patients were significantly less likely to undergo liver metastasectomy as compared to White patients. Additionally, hospital variation in access to liver metastasectomy is associated with hospital volume of surgery and medical care for the primary colorectal site. The aim of this study is to evaluate differences in access to metastasectomy for CRLM according to hospital-year volume of liver surgery (HVLS). We hypothesized that access to metastasectomy would be associated with HVLS, and that racial differences in access to metastasectomy would be lower in hospitals with the highest HVLS. Methods: The National Cancer Database (NCDB) Colon, Rectosigmoid Junction and Rectum data (2011-2017) were used to identify patients with a confirmed histology of colorectal adenocarcinoma who underwent primary site surgical resection and had confirmed liver metastases without evidence of extra-hepatic disease. Using the 2011-2017 Liver NCDB, hospitals were stratified into quartiles according to HVLS that included formal and extended hepatectomy and liver transplants. A Poisson regression model adjusted for age, gender, Charlson-Deyo score, insurance type, facility type, facility income quartiles, treatment at multiple facilities, and margin, nodal, and systemic therapy status for the primary colorectal cancer was used to evaluate the interaction between race and HVLS hospital quartiles (lowest and highest) and access to liver metastasectomy. Results: We identified 27,342 patients (median age 60, IQR 51-70, 55.6% male, 82.9% White, 17.2% non-White) with CRLM. The majority of patients did not undergo a liver metastasectomy (n = 20,714, 76%). Of the 6,628 patients treated with a liver metastasectomy, 45.4% (n = 3,009) underwent the liver metastasectomy at a hospital that did not perform any major liver surgery. Overall, non-White patients were less likely to undergo a liver metastasectomy compared to White patients after adjusting for potential confounders (RR 0.88, 95% CI 0.82-0.95, p = 0.001). Additional patient factors that were significantly associated with a lower likelihood of undergoing a liver metastasectomy included Medicaid insurance, being uninsured, and a positive margin status of the primary colorectal cancer. Among patients treated at the highest quartile HVLS hospitals, non-White patients were significantly less likely to undergo a liver metastasectomy for CRLM compared to White patients (RR 0.84, 95% CI 0.73-0.97, p = 0.017, Table). White and non-White patients treated at the lowest quartile HVLS hospitals had the lowest likelihood of undergoing a liver metastasectomy (Table). Conclusion: Undergoing a liver metastasectomy for CRLM was associated with where patients received their cancer care. Although patients who received their care at hospitals with the highest HVLS had a greater likelihood of undergoing a liver metastasectomy, this did not translate into equal access between White and non-White patients. Racial disparities persist in access to liver metastasectomy for CRLM, and future research is needed to develop innovative strategies that address this racial disparity in accessing liver metastasectomy.

Efficacy of liver metastasectomy in pancreatic cancer

Background: Standard treatment for metastatic pancreatic cancer is systemnic chemotherapy. Significance of liver metastasectomy in pancreatic cancer remains unknown. This study aims to investigate efficacy of liver metastasectomy in pancreatic cancer. Methods: Between 2001 and 2019, 14 cases who underwent liver metastasectomy for pancreatic cancer at Tohoku University Hospital, including 7 synchronous metastasis cases and 7 metachronous metastasis cases, were retrospectively investigated. Results: Synchronous metastasis: Simultaneous resection of primary pancreatic tumor and liver metastases was performed in 5 cases, including 4 cases with neoadjuvant therapy and one cases with upfront surgery. Two-stage resection, which means prior metastasectomy and subsequent resection of primary tumor after chemotherapy, was performed in 2 cases. The number of metastatic tumors was within 3 in 6 cases. Median survival time (MST) after surgery, which was calculated from the primary tumor resection date in two-stage resection, was 12.5 months. One case with two-stage resection has been alive without recurrence for 81 months after surgery. Metachronous metastasis: The median time between primary tumor resection and liver metastases was 10.7 months. All cases were treated with systemic chemotherapy before liver metastasectomy. Duration of chemotherapy before metastasectomy was 3 months in 1 case, 6-12 months in 4 cases, and 12-24 months in 2 cases. The number of metastatic tumors was within 2 in all cases. MST after metastasectomy was 19.8 months. Conclusion: There are cases who has benefit of metastasectomy in liver metastasis of pancreatic cancer.

The Level of Preoperative Plasma KRAS Mutations and CEA Predict Survival of Patients Undergoing Surgery for Colorectal Cancer Liver Metastases.

Colorectal cancer (CRC) belongs to the most common cancers. The liver is a predominant site of CRC dissemination. Novel biomarkers for predicting the survival of CRC patients with liver metastases (CLM) undergoing metastasectomy are needed. We examined KRAS mutated circulating cell-free tumor DNA (ctDNA) in CLM patients as a prognostic biomarker, independently or in combination with carcinoembryonic antigen (CEA). Thereby, a total of 71 CLM were retrospectively analyzed. Seven KRAS G12/G13 mutations was analyzed by a ddPCR™ KRAS G12/G13 Screening Kit on QX200 Droplet Digital PCR System (Bio-Rad Laboratories, Hercules, CA, USA) in liver metastasis tissue and preoperative and postoperative plasma samples. CEA were determined by an ACCESS CEA assay with the UniCel DxI 800 Instrument (Beckman Coulter, Brea, CA, USA). Tissue KRAS positive liver metastases was detected in 33 of 69 patients (47.8%). Preoperative plasma samples were available in 30 patients and 11 (36.7%) were KRAS positive. The agreement between plasma- and tissue-based KRAS mutation status was 75.9% (22 in 29; kappa 0.529). Patients with high compared to low levels of preoperative plasma KRAS fractional abundance (cut-off 3.33%) experienced shorter overall survival (OS 647 vs. 1392 days, p = 0.003). The combination of high preoperative KRAS fractional abundance and high CEA (cut-off 3.33% and 4.9 µg/L, resp.) best predicted shorter OS (HR 13.638, 95%CI 1.567–118.725) in multivariate analysis also (OS HR 44.877, 95%CI 1.59–1266.479; covariates: extend of liver resection, biological treatment). KRAS mutations are detectable and quantifiable in preoperative plasma cell-free DNA, incompletely overlapping with tissue biopsy. KRAS mutated ctDNA is a prognostic factor for CLM patients undergoing liver metastasectomy. The best prognostic value can be reached by a combination of ctDNA and tumor marker CEA.

P-364 Higher amount of KRAS mutations in pre-operative plasma cell-free DNA predicts shorter survival after liver metastasectomy in colorectal cancer patients

The liver is the most common site of colorectal cancer metastasis. Liver metastasectomy provides potentially curative treatment for a certain portion of patients with liver metastases. Novel biomarkers predicting patient survival in this specific clinical scenario are urgently needed. Determination of circulating cell-free tumor DNA (ctDNA) can be used as a liquid biopsy method for minimally invasive assessment of the disease course. In this study, we assessed the possibility of liquid biopsy based on KRAS-oncogene mutated ctDNA from peripheral blood to predict survival of colorectal cancer patients undergoing liver metastasectomy.

Immune Cell Infiltration in the Microenvironment of Liver Oligometastasis from Colorectal Cancer: Intratumoural CD8/CD3 Ratio Is a Valuable Prognostic Index for Patients Undergoing Liver Metastasectomy.

Background: A comprehensive investigation into immune cell infiltration provides more accurate and reliable prognostic information for patients with colorectal liver oligometastases (CLO) after liver metastasectomy. Methods: Simultaneous detection of the immune constituents CD3+, CD8+, Foxp3+ T, and α-SMA+ cells in the liver oligometastasis of 133 patients was conducted using a four-colour immunohistochemical multiplex technique. Immune cells were quantified, and tumour-infiltrating lymphocyte (TIL) ratios were subsequently calculated. Correlation analysis was performed using Pearson’s correlation. Recurrence-free survival (RFS) and overall survival (OS) for TIL ratios were analysed using the Kaplan–Meier method and Cox regression models. Results: Significantly fewer CD3+, CD8+, and Foxp3+ T cells were observed in the intratumoural region than in the peritumoural region of liver metastases. CD3+, CD8+, Foxp3+ T, and α-SMA+ cells showed significantly positive correlations with each other both in the intratumoural and peritumoural regions of liver metastases. Only the CD8/CD3 TIL ratio demonstrated a positive correlation between intratumoural and peritumoural regions of liver metastases (r = 0.541, p < 0.001). Patients with high intratumoural CD8/CD3 ratios had significantly longer 3-year RFS (59.0% vs. 47.4%, p = 0.035) and 3-year OS rates (83.3% vs. 65.8%, p = 0.007) than those with low intratumoural CD8/CD3 ratios. Multivariate analyses revealed that the intratumoural CD8/CD3 ratio was independently associated with RFS (HR = 0.593; 95% CI = 0.357–0.985; p = 0.043) and OS (HR = 0.391; 95% CI = 0.193–0.794; p = 0.009). Conclusion: These findings offer a better understanding of the prognostic value of immune cell infiltration on liver oligometastasis from colorectal cancer.

EP1.15-13 Prognosis of Colorectal Cancer Cases That Underwent Lung and Liver Metastasectomy and Therapeutic Outcomes of Brain Metastasis

The resectability is often debated in cases of lung and liver metastases. Further, we had reported previously that the incidence of brain metastasis is significantly higher in colorectal cancer with lung metastasis than cases with liver metastasis (lung: 7.7%, liver: 1.6%). We compared and investigated the therapeutic outcomes of cases of lung, liver and brain metastasis. Between 2002 and 2013, we retrospectively studied the prognosis of 90 cases of colorectal cancer cases that underwent lung metastasectomy, and 148 cases that underwent liver metastasectomy. The course of treatment in 8 cases of subsequent brain metastasis was also evaluated. The 5-year survival rate (5-SR)for 90 cases of lung metastasectomy overall was 66.7%. 63 cases were initial metastasis and the 5-SR was 66.7%. Out of these, there were 7 cases of synchronous metastasis with a 5-SR of 57.1%, and 56 cases of metachronous metastasis with a 5-SR of 67.9%, indicating no significant difference. The regions of secondary recurrence after lung resection were as follows: lung: 28 (cases), liver: 7, brain: 3, mediastinal lymph nodes: 5, other: 5. The 5-SR for 148 cases of liver metastasectomy overall was 54.7%. 141 cases were initial metastasis and the 5-SR was 55.3%. Cases who underwent lung metastasectomy had a significantly higher survival rate (p=0.0068). Out of these, 70 cases were synchronous metastasis with a 5-SR of 35.7%, and 71 cases were metachronous metastasis with a significantly higher 5-SR of 67.9% (p=0.011). The regions of secondary recurrence after liver resection were as follows: lung: 47 (cases), liver: 66,brain: 2, abdominal lymph nodes: 9, dissemination: 6, other: 7. While there were 5 cases of subsequent brain metastasis after lung resection, no subsequent brain metastasis was found after liver resection. All but one of the 8 cases of brain metastasis after lung resection were treated with surgery or CyberKnife. The total survival period was 1141 - 3848 days (median: 1913.5 days), and the survival period after detection of brain metastasis was 15 - 852 days (median: 401 days). In addition, all cases were experiencing associated symptoms when brain metastasis was detected, and only one patient was undergoing regular examinations to detect brain metastasis. While appropriate surgical intervention is recommended in cases of lung metastasis and metachronous liver metastasis,it is debatable in cases of synchronous liver metastasis. Cases of lung metastasis should give attention to brain metastasis and recieve early detection and intervention.

Immune Cell Infiltration in Liver Oligometastasis Microenvironment from Colorectal Cancer: Intratumoral CD8/CD3 Ratio Represents a Valuable Prognostic Index for Patients Undergoing Liver Metastasectomy

Background: The overview of the tumor microenvironment on liver oligometastasis from colorectal cancer remains largely unclear. A comprehensive investigation on the immune cell infiltration and its constituent ratio might provide a more accurate and reliable prognostic information for the patients with colorectal liver oligometastasis (CLO) after liver metastasectomy. Methods: A simultaneous detection of immune constituents CD3+, CD8+, Foxp3+ T cells, and α-SMA fibroblast on the liver oligometastasis of 133 patients were conducted by using a five-color immunohistochemical multiplex technique. The immune cells were quantified and tumor-infiltrating lymphocytes (TILs) ratios were subsequently calculated. Correlation analysis was performed using Pearson's correlation. Recurrence-free survival (RFS) and overall survival (OS) for TIL ratios were analyzed using the Kaplan-Meier method and Cox regression models. Results: The number of CD3+, CD8+, and Foxp3+ T cells were significantly fewer in the intratumoral subsection by compared to the peritumoral subsection of metastases. CD3+, CD8+, Foxp3+ T cells, and α-SMA+ fibroblast showed a significantly positive correlation between each other both in the intratumoral and peritumoral subsection of liver metastases. As to the correlation of TIL ratios, only the CD8/CD3 ratio demonstrated a positive correlation in intratumoral and peritumoral metastases (r=0.541, P<0.001). Patients with high intratumoral CD8/CD3 ratio had a significantly higher 3-year RFS (59.0% vs. 47.4%, P = 0.035) and 3-year OS rate (83.3% vs. 65.8%, P = 0.007) than those with low intratumoral CD8/CD3 ratio. Multivariate analyses revealed that intratumoral CD8/CD3 ratio was independently associated with RFS (HR 0.572; 95% CI 0.346-0.948; P = 0.030). Conclusions The current study showed a novel insight into the tumor microenvironment on CLO. The intratumoral CD8/CD3 ratio was found to be a valuable prognostic index for CLO undergoing liver metastasectomy. Funding: This work was supported by grants from the National Natural Science Foundation of China (grant No.81772595), Sun Yat-sen University Clinical Research 5010 Program (grant No. 2015024), Sun Yat-sen University Clinical Research 5010 Program (grant No. 2013013), and Guangzhou Science and Technology Plan Projects (Health Medical Collaborative Innovation Program of Guangzhou) (grant No. 201803040019). Declaration of Interest: The authors declare that they have no conflict of interest. Ethical Approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the Institutional Research Ethics Committee of Sun Yat-sen University Cancer Center (Approval number: GZR2017-006). Informed consents for using tissue samples before the initial treatment were obtained from the patients.

Type of adjuvant chemotherapy and treatment frequency in survival outcome of patients with colorectal liver metastases who underwent liver metastasectomy: an 8-year cohort study in Taiwan.

The role of adjuvant chemotherapy (ACT) in treating patients who have colorectal liver metastases (CLM) and undergo liver metastasectomy (LMS) is unclear in this patient population. We aimed to compare the mortality of patients receiving different ACT (i.e., oxaliplatin-based, irinotecan-based, and 5-fluorouracil-only (5FU)) and different treatment frequencies. We included 2583 patients with CLM who underwent LMS (including synchronous LMS [SLMS] and metachronous LMS [MLMS]) in this retrospective cohort study. We used Cox proportional hazard model to obtain hazard ratios (HRs) for mortality. The reference group was 5FU-only ACT when comparing ACT type and the reference group was treatment for ≤ 3 times when comparing ACT frequency. In SLMS patients, oxaliplatin-based ACT (HR = 0.78) and receiving ACT for ≥ 4 times (4-6 times, HR = 0.61; 7-9 times, HR = 0.69; 10-12 times, HR = 0.66) were associated with lower risk of mortality. In MLMS patients, oxaliplatin-based ACT (HR = 0.52), irinotecan-based ACT (HR = 0.64), and receiving ACT for 10-12 times (HR = 0.65) were associated with lower risk of mortality. In SLMS and MLMS patients, patients who received oxaliplatin-based ACT were more likely to survive than patients who received 5FU-only ACT. In MLMS patients, patients who received irinotecan-based ACT were also more likely to survive than those who received 5FU-only ACT. We recommend a course of at least four to six times of ACT after LMS in this patient population.

Clinical outcome after liver resection for colorectal versus non-colorectal metastasis: a comparative study

Background: Liver resection is the only curative treatment option for specific types of metastatic neoplasms. Comparative studies on the clinical outcome of liver resection for colorectal liver metastasis (CRLM) and non CRLM (N-CRLM) in Egypt remain inadequate.Methods: Medical records of patients who underwent liver metastasectomy (April 2013-May 2017) at Sohag University Hospital were reviewed. Patients were categorized according to the origin of the primary tumor into CRLM versus N-CRLM. Demographic, clinical, operative and histopathologic data, postoperative surgical complications and survival were analyzed.Results: Twenty-six patients (15 CRLM and 11 N-CRLM) were retrospectively enrolled. N-CRLM group comprised metastatic gall bladder (6), pancreas (2), breast (1) lung (1) and recurrent ovarian (1) cancers. There was no significant difference regarding age or gender predilection. The complication score in CRLM group was not significantly different compared with N-CRLM patients. However, subgroups of multivisceral resections showed significantly higher grades of postoperative complications compared with sole liver resection in both groups. Elderly patients (&gt;70-year-old) exhibited high risk of morbidity compared with younger patients. Early post-operative mortality within the first month was 7.7% (2 patients died, one per each group). After a mean follow up of 32 months, the overall survival rate among patients with CRLM and N-CRLM was 75% and 64% respectively.Conclusions: Liver resection for CRLM and N-CRLM can be safely accomplished. Multivisceral resection and advanced age were associated with increased severity of postoperative complications irrespective of the location of primary neoplasm.

Somatic mutation detection using various targeted detection assays in paired samples of circulating tumor DNA, primary tumor and metastases from patients undergoing resection of colorectal liver metastases

Assessing circulating tumor DNA (ctDNA) is a promising method to evaluate somatic mutations from solid tumors in a minimally-invasive way. In a group of twelve metastatic colorectal cancer (mCRC) patients undergoing liver metastasectomy, from each patient DNA from cell-free DNA (cfDNA), the primary tumor, metastatic liver tissue, normal tumor-adjacent colon or liver tissue, and whole blood were obtained. Investigated was the feasibility of a targeted NGS approach to identify somatic mutations in ctDNA. This targeted NGS approach was also compared with NGS preceded by mutant allele enrichment using synchronous coefficient of drag alteration technology embodied in the OnTarget assay, and for selected mutations with digital PCR (dPCR). All tissue and cfDNA samples underwent IonPGM sequencing for a CRC-specific 21-gene panel, which was analyzed using a standard and a modified calling pipeline. In addition, cfDNA, whole blood and normal tissue DNA were analyzed with the OnTarget assay and with dPCR for specific mutations in cfDNA as detected in the corresponding primary and/or metastatic tumor tissue. NGS with modified calling was superior to standard calling and detected ctDNA in the cfDNA of 10 patients harboring mutations in APC, ATM, CREBBP, FBXW7, KRAS, KMT2D, PIK3CA and TP53. Using this approach, variant allele frequencies in plasma ranged predominantly from 1 to 10%, resulting in limited concordance between ctDNA and the primary tumor (39%) and the metastases (55%). Concordance between ctDNA and tissue markedly improved when ctDNA was evaluated for KRAS, PIK3CA and TP53 mutations by the OnTarget assay (80%) and digital PCR (93%). Additionally, using these techniques mutations were observed in tumor-adjacent tissue with normal morphology in the majority of patients, which were not observed in whole blood. In conclusion, in these mCRC patients with oligometastatic disease NGS on cfDNA was feasible, but had limited sensitivity to detect all somatic mutations present in tissue. Digital PCR and mutant allele enrichment before NGS appeared to be more sensitive to detect somatic mutations.

Large variation in the utilization of liver resections in stage IV colorectal cancer patients with metastases confined to the liver

BackgroundSurgical resection of both the primary tumor and all metastases is considered the only chance of cure for patients with stage IV colorectal cancer. The aim of this study was to investigate change over time in the utilization of liver resections, as well as possible institutional variations. Patients and methodsAll patients diagnosed with stage IV colorectal cancer with metastases confined to the liver (n = 1617) between 2004 and 2012 were selected from the population-based Eindhoven Cancer Registry. The proportion of patients undergoing liver resection was investigated. Institutional variation in the period 2010–2012 was analyzed using logistic regression. Kaplan–Meier and Cox regression analyses were used to analyze overall survival. ResultsThe proportion of patients undergoing liver metastasectomy increased over time from 8% in 2004 to approximately 24% in 2012. There was a wide inter-hospital variation in the proportion of patients that underwent a liver resection (range: 14–34%) in the period 2010–2012. Liver resection was more often performed in younger patients and in rectal cancer patients. Median overall survival in patients undergoing liver resection was 55 months. Adjusted for potential confounders, resection of liver metastases was strongly associated with improved overall survival (HR 0.32, 95%CI 0.25–0.40). DiscussionThis study shows that despite the excellent long-term prognosis for patients with stage IV colorectal cancer after liver resection, there is still a large institutional variation in the utilization of this potentially curative therapy.