Liver Metastases From Colorectal Cancer Research Articles

Active breathing control guided stereotactic body ablative radiotherapy for management of liver metastases from colorectal cancer.

Liver metastases may occur during the course of several cancer types and may be associated with significant morbidity and mortality. There is paucity of data regarding the utility of Active Breathing Control (ABC) guided Stereotactic Ablative Body Radiotherapy (SABR) for management of Liver Metastases from Colorectal Cancer (LMCC). Our aim is to investigate the role of ABC guided SABR for management of liver metastases. 42 liver metastases of 29 patients treated with ABC guided SABR between February 2015 and October 2018 were retrospectively assessed for local control (LC), overall survival (OS), and toxicity outcomes. Primary endpoint was LC. Secondary endpoints were OS and treatment toxicity. At a median follow up duration of 16 months (range: 9-74 months), median OS was 20 months and 3 patients were still alive at last follow up. 1-year OS was 83% and 2-year OS was 28%. LC rates were 92% and 61% at 1 and 2 years, respectively. Comparative analysis of Biological Effective Dose (BED) values revealed that higher BED10 values were associated with higher LC rates (p=0.007). While LC rates for BED10 ≥ 100 Gray (Gy) were 94% and 86% at 1 and 2 years, corresponding LC rates for BED10 < 100 Gy were 89% and 36%, respectively with statistical significance (p=0.007). Assessment of acute and late toxicity outcomes revealed that most common toxicity was fatigue, however, no patients had ≥ grade 3 toxicity. ABC guided SABR is an effective and safe treatment modality for LMCC management.

Tumors located in the central column of the liver are associated with increased surgical difficulty and postoperative complications following open liver resection for colorectal metastases.

To assess the impact of difficult location (based on preoperative computed tomography) of liver metastases from colorectal cancer (LMCRC) on surgical difficulty, and occurrence of severe postoperative complications (POCs). A retrospective single-centre study of 911 consecutive patients with LMCRC who underwent hepatectomy by the open approach between 1998 and 2011, before implementation of laparoscopic surgery to obviate approach selection bias.LMCRC with at least one of the following four features on preoperative imaging: tumor invading the hepatocaval confluence or retro-hepatic inferior vena cava, centrally located (Segments 4,5,8) and >10 cm in diameter, abutting the supra-hilar area, or involving the paracaval portion or caudate process of Segment 1; were considered as topographically difficult (top-diff). Independent predictors of surgical difficulty assessed by number of blood units transfused, duration of ischemia, and number of sessions of pedicle clamping during surgery and of severe POCs were identified by multivariate analysis before, and after propensity score matching. Top-diff tumor location independently predicted surgical difficulty. Severe POCs were associated with the tumor location [top-diff vs. topographically non difficult (non top-diff)], preoperative portal vein embolization, and variables related to surgical difficulty. LMCRC in difficult location independently predicts surgical difficulty and severe POCs.

Hepatic Arterial Infusion Chemotherapy With Folfirinox or Oxaliplatin Alone in Metastatic Colorectal Cancer.

BackgroundHepatic arterial infusion (HAI) of chemotherapy is an option for the treatment of patients with liver metastases from colorectal cancer (LMCRC). Though HAI with oxaliplatin (HAI-Ox) is generally used, intravenous (IV) 5-fluoro-uracil (5FU)-oxaliplatin-irinotecan HAI (HAI-Folfirinox) is feasible and leads to curative-intent surgery in 30% of pretreated patients. We compared the efficacy and safety of HAI-Ox and HAI-Folfirinox.MethodsPatients who underwent HAI chemotherapy for LMCRC were retrospectively included from 2008 to 2019 from six French expert centers.ResultsData were collected from 273 previously treated patients with LMCRC. Patients received HAI-Folfirinox (n = 52) or HAI-Ox (n = 221) combined with IV chemotherapy. The objective response rate (ORR) was 43.2% in patients with HAI-Folfirinox and 45.9% (ns) in patients with HAI-Ox. Median overall survival (OS) was 17 months (95% CI: 15–32.3) with HAI-Folfirinox and 26.2 months (95% CI: 19.4–34.4; p = 0.1) with HAI-Ox. Median progression-free survival (PFS) was 7.9 months (95% CI: 4.9–10.3) with HAI-Folfirinox and 6.4 months (95% CI: 6.0–7.7; p = 0.6) with HAI-Ox. The secondary liver resection rate was 35.6% with HAI-Folfirinox and 16.7% with HAI-Ox (p = 0.007). Grade 2 and above toxicities were significantly more frequent with HAI-Folfirinox. In the global population, only 2 factors were prognostic for OS in multivariable analyses: liver-only disease [hazard ratio (HR): 0.4; 95% CI 0.20–0.83; p = 0.013] and local complications of the catheter (HR: 3.8; 95% CI 1.6–9.0; p = 0.002).ConclusionHepatic arterial infusion results in high response rates, secondary resections, and long survival in pretreated patients with LMCRC.

Added Value of Preoperative Tumor Topology Assessment on Prediction of Complications Following Open Liver Resection for Colorectal Metastases

Introduction: To assess the impact of difficult location (based on preoperative computed tomography) of liver metastases from colorectal cancer (LMCRC) on surgical difficulty, and occurrence of severe postoperative complications (POCs).

P-11 GAME score in patients with liver metastases from colorectal cancer

The Genetic And Morphological Evaluation (GAME) score is a prognostic tool that defines three risk groups (low, moderate, and high risk) of patients with liver metastases from colorectal cancer (LMCRC). This study aimed to evaluate this score in Tunisian patients.

Early tumour response as a survival predictor in previously- treated patients receiving triplet hepatic artery infusion and intravenous cetuximab for unresectable liver metastases from wild-type KRAS colorectal cancer

BackgroundEarly tumour shrinkage has been associated with improved survival in patients receiving cetuximab-based systemic chemotherapy for liver metastases from colorectal cancer (LM-CRC). We tested this hypothesis for previously treated LM-CRC patients receiving cetuximab (500 mg/m2) and triplet hepatic artery infusion (HAI) within European trial OPTILIV. MethodsIrinotecan (180 mg/m2), 5-fluorouracil (2800 mg/m2) and oxaliplatin (85 mg/m2) were given as chronomodulated or conventional delivery. Patients were retrospectively categorised as early responders (complete or partial RECIST response after three courses) or non-early responders (late or no response). Prognostic factors were determined using multivariate logistic or Cox regression models. ResultsResponse was assessed in 57 of 64 registered patients (89%), who had previously received one to three prior systemic chemotherapy protocols. An early response occurred at 6 weeks in 16 patients (28%; 9 men, 7 women), aged 33–76 years, with a median of 12 liver metastases (LMs) (2–50), involving five segments (1–8). Ten patients had a late response, and 31 patients had no response. Grade 3–4 fatigue selectively occurred in the non-early responders (0% versus 26%; p = 0.024). Early tumour response was jointly predicted by chronomodulation—odds ratio (OR): 6.0 (1.2–29.8; p = 0.029)—and LM diameter ≤57 mm—OR: 5.3 (1.1–25.0; p = 0.033). Early tumour response predicted for both R0-R1 liver resection—OR: 11.8 (1.4–100.2; p = 0.024) and overall survival—hazard ratio: 0.39 (0.17–0.88; p = 0.023) in multivariate analyses. ConclusionsEarly tumour response on triplet HAI and systemic cetuximab predicted for complete macroscopic liver resection and prolonged survival for LM-CRC patients within a multicenter conversion-to-resection medicosurgical strategy. Confirmation is warranted for early response on HAI to guide decision making.Protocol numbers: EUDRACT 2007-004632-24NCT00852228.

Combining FoxP3 and Helios with GARP/LAP markers can identify expanded Treg subsets in cancer patients.

Regulatory T cells (Tregs) comprise numerous heterogeneous subsets with distinct phenotypic and functional features. Identifying Treg markers is critical to investigate the role and clinical impact of various Treg subsets in pathological settings, and also for developing more effective immunotherapies. We have recently shown that non-activated FoxP3−Helios+ and activated FoxP3+/–Helios+ CD4+ T cells express GARP/LAP immunosuppressive markers in healthy donors. In this study we report similar observations in the peripheral blood of patients with pancreatic cancer (PC) and liver metastases from colorectal cancer (LICRC). Comparing levels of different Treg subpopulations in cancer patients and controls, we report that in PC patients, and unlike LICRC patients, there was no increase in Treg levels as defined by FoxP3 and Helios. However, defining Tregs based on GARP/LAP expression showed that FoxP3−LAP+ Tregs in non-activated and activated settings, and FoxP3+Helios+GARP+LAP+ activated Tregs were significantly increased in both groups of patients, compared with controls. This work implies that a combination of Treg-specific markers could be used to more accurately determine expanded Treg subsets and to understand their contribution in cancer settings. Additionally, GARP−/+LAP+ CD4+ T cells made IL-10, and not IFN-γ, and levels of IL-10-secreting CD4+ T cells were elevated in LICRC patients, especially with higher tumor staging. Taken together, our results indicate that investigations of Treg levels in different cancers should consider diverse Treg-related markers such as GARP, LAP, Helios, and others and not only FoxP3 as a sole Treg-specific marker.

Microinvasion of liver metastases from colorectal cancer: predictive factors and application for determining clinical target volume.

ObjectivesThis study evaluates the microscopic characteristics of liver metastases from colorectal cancer (LMCRC) invasion and provides a reference for expansion from gross tumor volume (GTV) to clinical targeting volume (CTV).MethodsData from 129 LMCRC patients treated by surgical resection at our hospital between January 2008 and September 2009 were collected for study. Tissue sections used for pathology and clinical data were reviewed. Patient information used for the study included gender, age, original tumor site, number of tumors, tumor size, levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199), synchronous or metachronous liver metastases, and whether patients received chemotherapy. The distance of liver microinvasion from the tumor boundary was measured microscopically by two senior pathologists.ResultsOf 129 patients evaluated, 81 (62.8 %) presented microinvasion distances from the tumor boundary ranging between 1.0 − 7.0 mm. A GTV-to-CTV expansion of 5, 6.7, or 7.0 mm was required to provide a 95, 99, or 100 % probability, respectively, of obtaining clear resection margins by microscopic observation. The extent of invasion was not related to gender, age, synchronous or metachronous liver metastases, tumor size, CA199 level, or chemotherapy. The extent of invasion was related to original tumor site, CEA level, and number of tumors. A scoring system was established based on the latter three positive predictors. Using this system, an invasion distance less than 3 mm was measured in 93.4 % of patients with a score of ≤1 point, but in only 85.7 % of patients with a score of ≤2 points.ConclusionsThe extent of tumor invasion in our LMCRC patient cohort correlated with original tumor site, CEA level, and number of tumors. These positive predictors may potentially be used as a scoring system for determining GTV-to-CTV expansion.

GITR engagement in combination with CTLA-4 blockade completely abrogates immunosuppression mediated by human liver tumor-derived regulatory T cells ex vivo

In liver cancer tumor-infiltrating regulatory T cells (Ti-Treg) are potent suppressors of tumor-specific T-cell responses and express high levels of the Treg-associated molecules cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor (GITR). In this study, we have evaluated the capacity of GITR-ligation, CTLA-4-blockade and a combination of both treatments to alleviate immunosuppression mediated by Ti-Treg. Using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM-CRC) we show that treatment with a soluble form of the natural ligand of GITR (GITRL), or with blocking antibodies to CTLA-4, reduces the suppression mediated by human liver tumor-infiltrating CD4+Foxp3+ Treg, thereby restoring proliferation and cytokine production by effector T cells. Importantly, combined treatment with low doses of both molecules exhibited stronger recovery of T cell function compared with either treatment alone. Our data suggest that in patients with primary and secondary liver cancer both GITR-ligation and anti-CTLA-4 mAb can improve the antitumor immunity by abrogating Ti-Treg mediated suppression.

Selective internal radiation therapy (SIRT) using Y90 resin microspheres as consolidation treatment for liver metastases from colorectal cancer (LCRC).

e14662 Background: SIRT has proved valuable for the treatment of LCRC in combination with chemotherapy (CT) or as a rescue treatment but it has not been explored as a consolidation treatment. Metho...

Real-Life Report on Chemoembolization Using DEBIRI for Liver Metastases from Colorectal Cancer.

Background. Transarterial chemoembolization (TACE) has been investigated in patients with liver metastases from colorectal cancer (LMCRC). Limited experience and available data suggest that TACE can achieve disease stabilization or improvement, even in heavily pretreated patients. Methods. Patients with LMCRC, ECOG 0–2, who failed at least 1 line of systemic chemotherapy, received embolizations with 2 mL of microspheres preloaded with 100 mg of irinotecan. Beads were delivered selectively into hepatic arteries. Primary endpoint was overall survival (OS), analyzed using the Kaplan-Meier method. Secondary endpoint was safety, assessed using CTCAE version 4.0. Results. 27 patients were treated using DEBIRI. Patient median age was 57 years (range was 45–82 years). The median number of total embolizations was 1.3 (range 1–3). The median OS was 5.4 months (95% CI; 1.1–22.7 months). The most reported postembolization events were nausea (8/27), vomiting (6/27), right upper quadrant pain (16/27), fatigue (9/27), and the development of ascites (6/27). 5/26 patients required hospitalization after TACE for severe pain. Hospitalization was also required for 1 case of allergic reaction and 1 case of infection. Conclusion. Our data suggest that TACE with DEBIRI could be efficacious in a palliative setting for patients with LMCRC, but they do not necessarily support routine use in clinical practice.

Constitutive single nucleotide polymorphisms (SNP) assessment for predicting tolerability and efficacy of triplet hepatic artery infusion (HAI) and intravenous cetuximab (IV-CET) in patients (pts) with liver metastases from colorectal cancer (LM-CRC) (European trial OPTILIV, NCT00852228).

3593 Background: The combination of IV-CET and HAI of irinotecan , oxaliplatin and 5-fluorouracil displayed high activity as 2-4thchemotherapy line for initially unresectable wt KRAS LM-CRC, yieldi...

Gene Expression Profiles Accurately Predict Outcome Following Liver Resection in Patients with Metastatic Colorectal Cancer

PurposeThe aim of this study was to build a molecular prognostic model based on gene signatures for patients with completely resected hepatic metastases from colorectal cancer (MCRC).MethodsUsing the Illumina HumanHT-12 gene chip, RNA samples from the liver metastases of 96 patients who underwent R0 liver resection were analyzed. Patients were randomly assigned to a training (n = 60) and test (n = 36) set. The genes associated with disease-specific survival (DSS) and liver-recurrence-free survival (LRFS) were identified by Cox-regression and selected to construct a molecular risk score (MRS) using the supervised principle component method on the training set. The MRS was then evaluated in the independent test set.ResultsNineteen and 115 genes were selected to construct the MRS for DSS and LRFS, respectively. Each MRS was validated in the test set; 3-year DSS/LRFS rates were 42/32% and 79/80% for patients with high and low MRS, respectively (p = 0.007 for DSS and p = 0.046 for LRFS). In a multivariate model controlling for a previously validated clinical risk score (CRS), the MRS remained a significant predictor of DSS (p = 0.001) and LRFS (p = 0.03). When CRS and MRS were combined, the patients were discriminated better with 3-year DSS/LRFS rates of 90/89% in the low risk group (both risk scores low) vs 42/26% in the high risk group (both risk scores high), respectively (p = 0.002/0.004 for DSS/LRFS).ConclusionMRS based on gene expression profiling has high prognostic value and is independent of CRS. This finding provides a potential strategy for better risk-stratification of patients with liver MCRC.

Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer

The mechanisms that enable liver cancer to escape elimination by the immune system remain unclear, but their elucidation may provide novel therapeutic interventions. We investigated the influence of tumor-infiltrating regulatory T cells on tumor-specific T cell responses in patients with liver cancer, using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM-CRC). Here we report that in both HCC and LM-CRC, CD4+CD25+Foxp3+ regulatory T cells (Tregs) accumulate in the tumor milieu and are potent suppressors of autologous tumor-specific T cell responses. Especially in LM-CRC, where Treg accumulation is more prominent, there is good evidence for local proliferation of Tregs at the cancer site. We show that tumor Tregs up-regulate the expression of glucocorticoid-induced tumor necrosis factor receptor (GITR) compared with Tregs in tumor-free liver tissue and blood. Importantly, treatment with soluble GITR ligand (GITRL) induces a decrease in the suppression mediated by the activated tumor-infiltrating Tregs and restores the proliferative capacity and cytokine production of CD4+CD25- T cells. Our results show that tumor-associated Tregs are critical for immune evasion in liver cancer, and we propose that GITRL constitutes a rational treatment for this disease.

Regulatory T Cells Favor Human Cancer Development by Suppressing Anti-Tumor Immunity in Primary and Metastatic Liver Malignancies

The mechanisms that enable liver cancer to escape elimination by the immune system remain unclear, but their elucidation may provide novel therapeutic interventions. Here we report that in both hepatocellular carcinoma (HCC) and in liver metastases from colorectal cancer (LMCRC) CD4+CD25+Foxp3+ regulatory T cells (Treg) accumulate in the tumor milieu. These tumor-associated Treg are activated, express high levels of GITR and ICOS, and are more potent suppressors of tumorspecific CD4+ T cell responses compared to circulating Treg. Especially in LM-CRC, there is good evidence for local proliferation of Treg at the cancer site. Soluble GITR ligand (GITRL) induces a decrease in the suppression mediated by the activated tumor-infiltrating Treg and restores the proliferative capacity and cytokine production by CD4+ T cells. Our results thus show that tumor-associated Tregs are critical for immune evasion in liver cancer and we propose that GITRL constitutes rational treatment for this disease.

FOLFIRINOX for the treatment of colorectal cancer: latest evidence from clinical trials

FOLFIRINOX for the treatment of colorectal cancer: latest evidence from clinical trials

Impact of Grading of Liver Metastasis on Postoperative Outcome in Patients with Liver Metastases from Colorectal Cancer

Few studies have investigated grading of liver metastasis (GLM) in patients with liver metastases from colorectal cancer (LM-CRC). To screen for the most useful predictive factors in patients undergoing hepatic resection for LM-CRC, clinico-pathological factors were subjected to uni- and multivariate analyses. One hundred and twenty-five patients were evaluated retrospectively. Univariate analyses using clinico-laboratory factors demonstrated that nomogram, gender, CRP, albumin, number of hepatic resections, liver metastasis (H) and GLM were related to postoperative death. Multivariate analysis using these seven factors disclosed that albumin (OR, 6.949; 95% CI, 1.994-24.22; p=0.002), CRP (OR, 6.977; 95% CI, 1.937-25.14; p=0.003) and GLM (OR, 2.819; 95% CI, 1.082-7.346; p=0.034) were associated with postoperative death. Kaplan-Meier analysis and log rank test revealed that higher GLM (p<0.001) and CRP (p<0.001) were associated with a higher rate of postoperative death. GLM was able to divide the patients into three independent groups with significantly different total nomogram counts (p<0.001, Kruskal-Wallis test). GLM is able to classify patients with LM-CRC into three independent groups and offers reliable information for predicting postoperative death in such patients.

Métastases hépatiques colorectales La réponse tumorale: pourquoi et comment l’évaluer ?

During chemotherapy, obtaining a tumor response or at least stability, is a major goal for the oncologist. Therefore, evaluation of tumor response of LMCRC (Liver Metastases from Colorectal Cancer) is important; it allows to judge the effectiveness of the treatment and to modify it in case of progression. The criteria currently used are RECIST criteria that apply only to solid tumors and are based on the unidimensional measure of target tumor viewed on imaging.The tumor response rate has steadily increased with the progress of chemotherapy and then with the advent of targeted therapies in 2004. The anti-angiogenic bevacizumab induces decrease in tumors neovascularization, resulting in devascularization on imaging without changing the size. Therefore, new criteria to evaluate tumor response have been described: Chun criteria, based on morphological changes of the target lesions. Finally, another method to asses the response to these anti-angiogenic treatments was developed using ultrasound after injection of a contrast agent (SonoVue®), the main purpose of this review is to assess the effectiveness of an anti-angiogenic treatment shortly after its administration morder to stop very quickly any ineffective treatmend.Tumour response is also analyzed histologically after resection of LMCRC. The major prognostic impact of histological response was recently demonstrated. Two classifications are currently used: on developed by the Geneva team (TRG) and the other by the MD Anderson team.Nowadays, tumor response is assessed on imaging studies, primarily, CT, and histological analysis. New criteria have been gradually developed as a result of to the progress in imaging and a better knowledge of the mechanism of action of targeted therapies. The integration of these new data in the therapeutic strategy of colorectal liver metastases remains to be defined.

Systemic inflammatory response predicts postoperative outcome in patients with liver metastases from colorectal cancer

Few studies have investigated the Glasgow Prognostic Score (GPS) in patients with liver metastases from colorectal cancer (LM-CRC). The GPS was calculated as follows: patients with both an elevated level of CRP (>10 mg/L) and hypoalbuminemia (Alb <35 g/L) were allocated a score of 2, and patients showing one or neither of these blood chemistry abnormalities were allocated a score of 1 or 0, respectively. Ninety-three patients were evaluated retrospectively. Kaplan-Meier analysis and log rank test revealed that a higher GPS predicted a higher postoperative death (P < 0.0001). Univariate analysis revealed that sex, number of hepatectomy, number of tumors, synchronous lung metastasis and CRP were associated with postoperative death. Multivariate analysis revealed that number of hepatectomy (odds ratio, 3.193; 95% CI, 1.093-9.330; P = 0.0338), number of tumors (odds ratio, 2.946; 95% CI, 1.094-7.931; P = 0.0325), synchronous lung metastasis (odds ratio, 3.424; 95% CI, 1.055-11.11; P = 0.0404) and CRP (odds ratio, 4.509; 95% CI, 1.313-15.49; P = 0.0167) were associated with postoperative death. GPS is able to classify patients with LM-CRC into three independent groups. Among the selected factors, CRP is considered an important and high sensitive predictor of postoperative death in such patients.

Preliminary results of a randomized phase II trial comparing standard bi-therapy versus three intensified chemotherapy regimens as treatment for patients with non resectable liver metastases from colorectal cancer (LMCRC). (METHEP)

4075 Background: LVFU combinations with irinotecan (FOLFIRI) or oxaliplatin (FOLFOX) have shown to improve outcome of advanced colorectal cancer. However, the standard doses of these regimens applied to patients with initially unresectable LMCRC have shown poor rates of resectability. The aim of this randomized trial was to select the most efficacious experimental intensified chemotherapy arm among high dose (HD) FOLFIRI (Iri 260mg/m²), FOLFOX-7 (Ox 130mg/m²) and FOLFIRINOX (Iri 180mg/m² + Ox 85mg/m²) in patients (pts) with initially unresectable or potentially resectable LMCRC. Methods: Main inclusion criteria: non pretreated potentially resectable LM (class II) or unresectable LM without extra-hepatic metastases except 1 to 3 resectable lung metastases. Pts were randomized to either standard (A/B) or intensified chemotherapy (C/D/E): FOLFIRI (A), FOLFOX-4 (B), FOLFIRI-HD (C), FOLFOX-7 (D), or FOLFIRINOX (E). In arms C/D/E, prophylactic G-CSF was given. Primary endpoint was objective response rate (RR) (...