Treatment Of Colorectal Liver Metastases Research Articles

Non-Alcoholic Fatty Liver Disease May Be a Risk Factor for Liver Metastasis After Radical Surgery for Colorectal Cancer: A Retrospective Study.

Distant metastasis develops in approximately one-third of patients with colorectal cancer (CRC) who undergo radical surgery, and colorectal liver metastasis (CRLM) is the most common form of distant metastasis in CRC. Hepatectomy is the only potentially curative treatment for CRLM, but few patients with metastatic CRC meet the criteria for this radical resection, and the 5-year survival rate is poor. Identifying risk factors for CRLM is critical. Non-alcoholic fatty liver disease (NAFLD) is an independent risk factor for CRC. However, the effect of NAFLD on CRC liver metastasis after radical surgery remains unclear. Therefore, we examined the impact of NAFLD-associated hepatic fibrosis on liver metastasis after radical surgery for CRC. We retrospectively analyzed data from 388 patients who underwent curative surgery for CRC at our hospital between April 2008 and March 2015. The patients' clinical results, surgical procedures, postoperative course, and pathological and survival data were collected from the hospital records. The NAFLD fibrosis score was calculated and used to divide the patients into two groups (NAFLD and non-NAFLD). Recurrence was observed in 83/388 (21.4%) patients after a mean follow-up of 65.6 ± 15.1months. Twenty-five patients had liver metastasis: 8 in the NAFLD group (8/45; 17.8%) and 17 in the non-NALFD group (17/343; 5.0%) (p = 0.004). Liver metastasis-free survival was significantly worse in the NAFLD than non-NAFLD group (p < 0.001). NAFLD and cancer stage were independent risk factors for liver metastasis recurrence. NAFLD may be a risk factor for liver metastasis in patients with CRC who undergo curative surgery.

Local Treatment of Colorectal Liver Metastases in the Presence of Extrahepatic Disease: Survival Outcomes from the Amsterdam Colorectal Liver Met Registry (AmCORE).

The simultaneous presence of colorectal liver metastases (CRLMs) and extrahepatic metastases in patients with colorectal cancer (CRC) can be considered a relative contraindication for local treatment with curative intent. This study aims to assess the survival outcomes of patients with CRLMs and extrahepatic metastases after comprehensive local treatment of all metastatic sites. Patients with CRLMs who received local treatment of all metastatic sites were extracted from the prospective AmCORE registry database and subdivided into two groups: CRLM only vs. CRLM and extrahepatic metastasis. To address potential confounders, multivariate analysis was performed. The primary endpoint was overall survival (OS). In total, 881 patients with CRLM only and 60 with CRLM and extrahepatic disease were included, and the median OS was 55.7 months vs. 42.7 months, respectively. Though OS was significantly lower in patients with concomitant extrahepatic metastases (HR 1.477; 95% CI 1.029-2.121; p = 0.033), the survival curve plateaued after 6.2 years. Extrahepatic manifestations were pulmonary (43.3%), peritoneal (16.7%) and non-regional lymph node metastases (10.0%). In patients with pulmonary and non-regional lymph node metastases, OS did not significantly differ from patients with CRLM-only disease; concomitant peritoneal metastases showed an inferior OS (HR 1.976; 95% CI 1.017-3.841, p = 0.041). In this comparative series, OS was inferior for patients with multi-organ metastatic CRC versus patients with CRLMs alone. Nonetheless, the long-term survival curve plateau seemed to justify local treatment in a subset of patients with multi-organ metastatic CRC, especially for patients with CRLMs and pulmonary or lymph node metastases.

Contemporary Surgical Management of Colorectal Liver Metastases.

Colorectal cancer is the third most common cancer in the United States and the second most common cause of cancer-related death. Approximately 20-30% of patients will develop hepatic metastasis in the form of synchronous or metachronous disease. The treatment of colorectal liver metastasis (CRLM) has evolved into a multidisciplinary approach, with chemotherapy and a variety of locoregional treatments, such as ablation and portal vein embolization, playing a crucial role. However, resection remains a core tenet of management, serving as the gold standard for a curative-intent therapy. As such, the input of a dedicated hepatobiliary surgeon is paramount for appropriate patient selection and choice of surgical approach, as significant advances in the field have made management decisions extremely nuanced and complex. We herein aim to review the contemporary surgical management of colorectal liver metastasis with respect to both perioperative and operative considerations.

Radiofrequency Combined with Intratumoral Immunotherapy: Preclinical Results and Safety in Metastatic Colorectal Carcinoma.

Radiofrequency ablation (RFA) of cancer induces an anti-tumor immunity, which is insufficient to prevent recurrences. In mice, RFA-intratumoral immunotherapy by granulocyte-macrophage colony-stimulating factor (GM-CSF) and Bacillus Calmette-Guerin resulted in complete metastases regression. Infectious risk in human needs replacement of live vaccines. Intratumoral purified protein derivatives (PPD) have never been tested in digestive cancers, and the safety of intratumoral immunotherapy after RFA has not yet been validated in human models. We investigated the therapeutic efficacy of combined radiofrequency ablation (RFA) and intratumoral immunotherapy (ITI) using an immune-muco-adherent thermogel (IMT) in a mouse model of metastatic colorectal cancer (CRC) and the safety of this approach in a pig model. Intratumoral stability of the immunogel was assessed using magnetic resonance imaging (MRI) and bioluminescent imaging. Seventy-four CT26 tumor-bearing female BALB/c mice were treated with RFA either alone or in combination with intratumoral IMT. Regression of distant metastasis and survival were monitored for 60 days. Six pigs that received liver radiofrequency and intralesional IMT injections were followed for 15 days. Experimental gel embolisms were treated using an intravascular approach. Pertinent rheology of IMT was confirmed in tumors, by the signal stability during 3 days in MRI and 7 days in bioluminescence imaging. In mice, the abscopal effect of RFA-intratumoral immunotherapy resulted in regression of distant lesions completed at day 16 vs. a volume of 350 ± 99.3 mm3 in the RFA group at day 25 and a 10-fold survival rate at 60 days. In pigs, injection of immunogel in the liver RFA area was safe after volume adjustment without clinical, hematological, and liver biology disorder. Flow cytometry showed an early increase in CD3 TCRγδ+T cells at D7 (p < 0.05) and a late decrease in CD29+-CD8 T cells at D15 (p < 0.05), reflecting the inflammation status changes. Systemic GM-CSF release was not detectable. Experimental caval and pulmonary thermogel embolisms were treated by percutaneous catheterism and cold serum infusion. RFA-intratumoral immunotherapy as efficient and safe mini-invasive interventional oncology is able to improve ablative treatment of colorectal liver metastases.

Quantitative peritumoral magnetic resonance imaging fingerprinting improves machine learning-based prediction of overall survival in colorectal cancer.

To investigate magnetic resonance imaging (MRI)-based peritumoral texture features as prognostic indicators of survival in patients with colorectal liver metastasis (CRLM). From 2007-2015, forty-eight patients who underwent MRI within 3 months prior to initiating treatment for CRLM were identified. Clinicobiological prognostic variables were obtained from electronic medical records. Ninety-four metastatic hepatic lesions were identified on T1-weighted post-contrast images and volumetrically segmented. A total of 112 radiomic features (shape, first-order, texture) were derived from a 10 mm region surrounding each segmented tumor. A random forest model was applied, and performance was tested by receiver operating characteristic (ROC). Kaplan-Meier analysis was utilized to generate the survival curves. Forty-eight patients (male:female = 23:25, age 55.3 years ± 18 years) were included in the study. The median lesion size was 25.73 mm (range 8.5-103.8 mm). Microsatellite instability was low in 40.4% (38/94) of tumors, with Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation detected in 68 out of 94 (72%) tumors. The mean survival was 35 months ± 21 months, and local disease progression was observed in 35.5% of patients. Univariate regression analysis identified 42 texture features [8 first order, 5 gray level dependence matrix (GLDM), 5 gray level run time length matrix (GLRLM), 5 gray level size zone matrix (GLSZM), 2 neighboring gray tone difference matrix (NGTDM), and 17 gray level co-occurrence matrix (GLCM)] independently associated with metastatic disease progression (P < 0.03). The random forest model achieved an area under the curve (AUC) of 0.88. MRI-based peritumoral heterogeneity features may serve as predictive biomarkers for metastatic disease progression and patient survival in CRLM.

Preoperative CT and survival data for patients undergoing resection of colorectal liver metastases

The liver is a common site for the development of metastases in colorectal cancer. Treatment selection for patients with colorectal liver metastases (CRLM) is difficult; although hepatic resection will cure a minority of CRLM patients, recurrence is common. Reliable preoperative prediction of recurrence could therefore be a valuable tool for physicians in selecting the best candidates for hepatic resection in the treatment of CRLM. It has been hypothesized that evidence for recurrence could be found via quantitative image analysis on preoperative CT imaging of the future liver remnant before resection. To investigate this hypothesis, we have collected preoperative hepatic CT scans, clinicopathologic data, and recurrence/survival data, from a large, single-institution series of patients (n = 197) who underwent hepatic resection of CRLM. For each patient, we also created segmentations of the liver, vessels, tumors, and future liver remnant. The largest of its kind, this dataset is a resource that may aid in the development of quantitative imaging biomarkers and machine learning models for the prediction of post-resection hepatic recurrence of CRLM.

Association of modified textbook outcome and overall survival after surgery for colorectal liver metastases: A nationwide analysis

BackgroundTextbook outcome (TO) represents a multidimensional quality measurement, encompassing the desirable short-term outcomes following surgery. This study aimed to investigate whether achieving TO after resection of colorectal liver metastases (CRLM) surgery is related to better overall survival (OS) in a national cohort. MethodData was retrieved from the Dutch Hepato Biliary Audit. A modified definition of TO (mTO) was used because readmissions were only recorded from 2019. mTO was achieved when no severe postoperative complications, mortality, prolonged length of hospital stay, occurred and when adequate surgical resection margins were obtained. To compare outcomes of patients with and without mTO and reduce baseline differences between both groups propensity score matching (PSM) was used for patients operated on between 2014 and 2018. ResultsOut of 6525 eligible patients, 81 % achieved mTO. For the cohort between 2014 and 2018, those achieving mTO had a 5-year OS of 46.7 % (CI 44.8–48.6) while non-mTO patients had a 5-year OS of 33.7 % (CI 29.8–38.2), p < 0.001. Not achieving mTO was associated with a worse OS (aHR 1.34 (95 % CI 1.17–1.53), p < 0.001. Median follow-up was 76 months., PSM assigned 519 patients to each group. In the PSM cohort patients achieving mTO, 5-year OS was 43.6 % (95 % CI 39.2–48.5) compared to 36.4 % (95 % CI 31.9–41.2) in patients who did not achieve mTO, p = 0.006. ConclusionAchieving mTO is associated with improved long-term survival. This emphasizes the importance of optimising perioperative care and reducing postoperative complications in surgical treatment of CRLM.

Differential cytokine and chemokine expression after ablation vs. resection in colorectal cancer liver metastasis

BackgroundSurgical resection remains the main curative treatment for colorectal liver metastases (CRLM). Radiofrequency ablation (RFA) is increasingly employed for small, deep lying or otherwise inoperable lesions. However, RFA can induce pro-tumorigenic effects on residual tumor cells, hereby possibly promoting tumor recurrence. Contrastingly, post-RFA tumor debris as an antigen source can also generate anti-cancer immune responses. Utilizing this, current studies on combining RFA with immune therapy appear promising. Here, in an attempt to shed light on this controversy, cytokines involved in inflammation, (lymph)angiogenesis, immune cell recruitment and tumor cell invasion were investigated post-RFA versus post-resection in CRLM patients. MethodsCytokine and chemokine serum levels pre-operation, 4 h and 24 h post-operation were analyzed in CRLM patients undergoing RFA (n = 8) or partial hepatectomy (n = 9) using Multiplex immunoassays. Statistical analyses were performed between as well as within individual intervention groups. ResultsPost-RFA, significantly increased levels of acute phase proteins SAA1 and S100A8, IL-6, IL-1Ra, MIP3b (CCL19) and MMP9 were observed along with decreases in Fibronectin, MCP-1 (CCL2), and Tie-2. Post-resection, increased levels of PDGFbb, I309 (CCL1), Apelin, MIF, IL-1b and TNFα were seen. All p-values <0.05. ConclusionPro-inflammatory responses mediated by different cytokines were seen after both RFA and resection, possibly influencing residual tumor cells and tumor recurrence. As both ablation and resection trigger inflammation and immune cell recruitment (albeit via distinct mechanisms), these data suggest that further research may explore combining immune therapy with not only RFA but also resection. Key messageAnalysis of patients' serum after radiofrequency ablation versus resection of colorectal liver metastases (CRLM) showed that these interventions trigger inflammation and immune cell recruitment, via different cyto- and chemokine pathways. This suggests a possible future strategy of combining immune therapy with not only ablative techniques but also with resection of CRLM.

Changing perspectives in the treatment of colorectal liver metastases.

Changing perspectives in the treatment of colorectal liver metastases.

Comparison of post-hepatectomy long-term survival outcome between non-colorectal non-neuroendocrine and colorectal liver metastases: A population-based propensity-score matching analysis

BackgroundHepatectomy is an established treatment for colorectal liver metastasis (CLM) or neuroendocrine liver metastasis. However, its role in non-colorectal non-neuroendocrine liver metastasis (NCNNLM) is controversial. This study aims to compare long-term survival outcomes after hepatectomy between NCNNLM and CLM in a population-based cohort. MethodsFrom 2009 to 2018, curative hepatectomy were performed in 964 patients with NCNNLM (n ​= ​133) or CLM (n ​= ​831). Propensity score (PS) matching was performed. Short-term and long-term outcomes were compared between PS-matched groups. Univariate and multivariate analyses were performed to identify prognostic factors affecting survival. ResultsThere were 133 patients in the NCNNLM group and 266 patients in the CLM group. The mortality (1.5 ​% vs 1.5 ​%) and morbidity (19.5 ​% vs 20.3 ​%) rates were comparable between the two groups. There was no statistically significant difference in 5-year overall (48.9 ​% vs 39.8 ​%) and recurrence-free (25.1 ​% vs 23.4 ​%) survival rates between NCNNLM and CLM groups. A high pre-operative serum bilirubin level, severe postoperative complications and multiple tumors were independent prognostic factors for poor survival. ConclusionHepatectomy for selected patients with NCNNLM can achieve similar long-term oncological outcomes as those with CLM. High serum bilirubin, severe postoperative complication and multiple tumors are poor prognostic factors for survival.

MRI in addition to CT in patients scheduled for local therapy of colorectal liver metastases (CAMINO): an international, multicentre, prospective, diagnostic accuracy trial

Guidelines are inconclusive on whether contrast-enhanced MRI using gadoxetic acid and diffusion-weighted imaging should be added routinely to CT in the investigation of patients with colorectal liver metastases who are scheduled for curative liver resection or thermal ablation, or both. Although contrast-enhanced MRI is reportedly superior than contrast-enhanced CT in the detection and characterisation of colorectal liver metastases, its effect on clinical patient management is unknown. We aimed to assess the clinical effect of an additional liver contrast-enhanced MRI on local treatment plan in patients with colorectal liver metastases amenable to local treatment, based on contrast-enhanced CT. We did an international, multicentre, prospective, incremental diagnostic accuracy trial in 14 liver surgery centres in the Netherlands, Belgium, Norway, and Italy. Participants were aged 18 years or older with histological proof of colorectal cancer, a WHO performance status score of 0-4, and primary or recurrent colorectal liver metastases, who were scheduled for local therapy based on contrast-enhanced CT. All patients had contrast-enhanced CT and liver contrast-enhanced MRI including diffusion-weighted imaging and gadoxetic acid as a contrast agent before undergoing local therapy. The primary outcome was change in the local clinical treatment plan (decided by the individual clinics) on the basis of liver contrast-enhanced MRI findings, analysed in the intention-to-image population. The minimal clinically important difference in the proportion of patients who would have change in their local treatment plan due to an additional liver contrast-enhanced MRI was 10%. This study is closed and registered in the Netherlands Trial Register, NL8039. Between Dec 17, 2019, and July 31, 2021, 325 patients with colorectal liver metastases were assessed for eligibility. 298 patients were enrolled and included in the intention-to-treat population, including 177 males (59%) and 121 females (41%) with planned local therapy based on contrast-enhanced CT. A change in the local treatment plan based on liver contrast-enhanced MRI findings was observed in 92 (31%; 95% CI 26-36) of 298 patients. Changes were made for 40 patients (13%) requiring more extensive local therapy, 11 patients (4%) requiring less extensive local therapy, and 34 patients (11%) in whom the indication for curative-intent local therapy was revoked, including 26 patients (9%) with too extensive disease and eight patients (3%) with benign lesions on liver contrast-enhanced MRI (confirmed by a median follow-up of 21·0 months [IQR 17·5-24·0]). Liver contrast-enhanced MRI should be considered in all patients scheduled for local treatment for colorectal liver metastases on the basis of contrast-enhanced CT imaging. The Dutch Cancer Society and Bayer AG - Pharmaceuticals.

Drug-eluting bead transarterial chemoembolization (DEB-TACE) versus conventional transarterial chemoembolization (cTACE) in colorectal liver metastasis: Efficacy, safety, and prognostic factors.

To comparatively evaluate drug-eluting bead transarterial chemoembolization (DEB-TACE) and conventional transarterial chemoembolization (cTACE) for efficacy, safety, and related prognostic factors in the treatment of colorectal liver metastasis (CRLM). This study retrospectively analyzed 75 patients with CRLM-administered DEB-TACE (n = 36) or cTACE (n = 39) between January 2016 and December 2017. Local control, survival outcome, and complications were compared between the two groups. Univariate and multivariate analyses of prognostic factors affecting progression-free survival (PFS) and overall survival (OS) were performed. The median follow-up in the two groups was 10.5 months (range, 0.5-22). Median PFS and OS in the DEB-TACE group were 10.0 and 13.0 months, respectively, and 6.0 and 8.5 months in the cTACE group, respectively (P = 0.009 and P = 0.008). The 3-, 6-, and 12-month OS rates in the DEB-TACE group were 100.0%, 94.4%, and 55.6%, respectively, and 92.3%, 71.8%, and 35.9% in the cTACE group, respectively. The 3-month OS rate (P = 0.083) showed no significant difference between the two groups, but significant differences were found in the 6- and 12-month OS rates (P = 0.008 and P = 0.030). Univariate and multivariate survival analyses showed that treatment method, tumor size, and tumor number were independent prognostic factors affecting PFS and OS. DEB-TACE has advantages over cTACE in prolonging PFS and OS in patients with CRLM. Treatment method, tumor number, and tumor size are important prognostic factors affecting PFS and OS. However, further multicenter and prospective trials are needed to confirm a deeper comparison between DEB-TACE and cTACE in patients with CRLM.

Minimal Invasive Versus Open Surgery for Colorectal Liver Metastases: A Multicenter German StuDoQ|Liver Registry-Based Cohort Analysis in Germany.

To compare the outcome of minimally invasive liver surgery (MILS) to open liver surgery (OLS) for resection of colorectal liver metastases (CRLM) on a nationwide level. Colorectal cancer is the third most common malignancy worldwide. Up to 50% of all patients with colorectal cancer develop CRLM. MILS represents an attractive alternative to OLS for treatment of CRLM. Retrospective cohort study using the prospectively recorded German Quality management registry for liver surgery. Propensity-score matching was performed to account for variance in the extent of resection and patient demographics. In total, 1037 patients underwent liver resection for CRLM from 2019 to 2021. MILS was performed in 31%. Operative time was significantly longer in MILS (234 vs 222 minutes, P = 0.02) compared with OLS. After MILS, median length of hospital stay (LOS) was significantly shorter (7 vs 10 days; P < 0.001). Despite 76% of major resections being OLS, postoperative complications and 90-day morbidity and mortality did not differ. The Pringle maneuver was more frequently used in MILS (48% vs 40%, P = 0.048). After propensity-score matching for age, body mass index, Eastern Cooperative Oncology Group, and extent of resection, LOS remained shorter in the MILS cohort (6 vs 10 days, P < 0.001) and operative time did not differ significantly (P = 0.2). MILS is not the standard for resection of CRLM in Germany. Drawbacks, such as a longer operative time remain. However, if technically possible, MILS is a reasonable alternative to OLS for resection of CRLM, with comparable postoperative complications, reduced LOS, and equal oncological radicality.

HPB P32 Ablative techniques in Colorectal Liver Metastases: A Systematic Review and Descriptive Summary of Practice

Abstract Background In the UK, over 40,000 patients are diagnosed with colorectal cancer annually. Many of these patients develop liver metastases. Although surgical resection is the gold-standard treatment for colorectal liver metastasis (CRLM), some patients are unsuitable for resection. Radiofrequency Ablation (RFA) and Microwave Ablation (MWA) are alternative treatments for CRLM. However, consensus is lacking regarding selection criteria, tumour characteristics, ablation technique delivery, and device settings. This systematic review summarises current evidence regarding selection criteria, treatment indications, and ablation delivery to inform future prospective studies. Methods A systematic review was conducted following PRISMA guidelines. Studies assessing RFA and MWA treatment of CRLM were identified in Medline, Embase, Web of Science and the Cochrane database of systematic reviews, from inception until 1st June 2021. Eligible studies included those reporting patient selection, tumour characteristics, treatment delivery, ablation device settings, and ablation outcomes for CRLM. Data extraction and analysis were performed. Results Forty-six studies were included (retrospective cohort n=40, prospective cohort n=4, non-randomized comparative studies n=2). Fifty-four inclusion criteria were used across 39 studies and were not stated in 7 studies. Tumours varied in mean number (1-8) and diameter (1.54-4.35cm). Neoadjuvant chemotherapy use (10-100% of patients), ablation delivery approach (Open n=4, laparoscopic n=11, percutaneous n=23, mixed n=2), anaesthetic mode (GA n=17, LA n=9, mixed n=2) and delivering clinician (radiologist n=8, surgeon n=15) all varied. Thirty studies lacked complete ablation device settings. Six studies followed a standardised ablation algorithm and 10 studies had specific settings. Five-year survival ranged from 0-69.7% for ablation. Conclusions There is significant heterogeneity in study design, patient selection, and ablation techniques for CRLM. The lack of standardized approaches and inconsistent reporting of methodology and outcomes make it challenging to determine the optimal ablative treatment for CRLM. Future research should focus on clearly defining selection and treatment criteria, as well as treatment delivery to facilitate generalisability. An RCT investigating ablation techniques may be difficult to implement due to a lack of clinician and patient equipoise, however, a high-quality, multi-centre nationwide prospective cohort study to investigate ablation as an alternative to surgery is required for high-risk patients with CRLM.

Whole tumor based texture analysis of magnetic resonance diffusion imaging for colorectal liver metastases: A prospective study for diffusion model comparison and early response biomarker

PurposeTo evaluate and compare the diagnostic value of diffusion-related texture analysis parameters obtained from various magnetic resonance diffusion models as early predictors of the clinical response to chemotherapy in patients with colorectal liver metastases (CRLM). MethodsPatients (n = 145) with CRLM were prospectively and consecutively enrolled and scanned using diffusion-weighted imaging (DWI)-magnetic resonance imaging (MRI)/intravoxel incoherent motion (IVIM)/diffusion kurtosis imaging (DKI) before (baseline) and two–three weeks after (follow-up) commencing chemotherapy. Therapy response was evaluated based on the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). The histogram and texture parameters of each diffusion-related parametric map were analysed between the responding and non-responding groups, screened using LASSO, and fitted with binary logistic regression models. The diagnostic efficacy of each model in the early prediction of CRLM was analysed, and the corresponding receiver operating characteristic (ROC) curve was drawn. The area under the curve (AUC) and 95% confidence intervals (CI) were calculated. ResultsOf the 145 analysed patients, 69 were in the responding group and 76 were in the non-responding group. Among all models, the difference value based on the histogram and texture features of the DKI-derived parameters performed best for the early prediction of CRLM treatment efficacy. The AUC of the DKI model in the validation set reached 0.795 (95% CI 0.652–0.938). Among the IVIM-derived parameters, the difference model based on D and D* performed best, and the AUC in the validation set reached 0.737 (95% CI 0.586–0.889). Finally, in the DWI sequence, the model comprising baseline features performed the best, with an AUC of 0.699 (95% CI 0.537–0.86) in the validation set. ConclusionsBaseline DWI parameters and follow-up changes in IVIM and DKI parameters predicted the chemotherapeutic response in patients with CRLM. In addition, as very early predictors, DKI-derived parameters were more effective than DWI- and IVIM-related parameters, in which changes in D-parameters performed best.

Hepatic arterial oxaliplatin plus intravenous 5-fluorouracil and cetuximab for first-line treatment of colorectal liver metastases: A multicenter phase II trial

BackgroundThe efficacy and tolerability of hepatic arterial infusion (HAI) oxaliplatin plus systemic 5-fluorouracil and cetuximab as frontline treatment in patients with colorectal liver metastases (CRLM) are unknown. MethodsIn this multicenter, single-arm phase II study, patients with CRLM not amenable to curative-intent resection or requiring complex/major liver resection, and no prior chemotherapy for metastatic disease, received HAI oxaliplatin and intravenous 5-fluorouracil, leucovorin and cetuximab, every two weeks until disease progression, limiting toxicity or at least 3 months after complete response or curative-intent resection/ablation. The primary endpoint was overall response rate (ORR). Results35 patients, mostly with bilateral (89%), multiple CRLM (>4, 86%; >10, 46%) were enrolled in eight centers. The ORR was 88% (95% CI, 71%−96%) among evaluable patients (n = 32), and 95% (95% CI 70–100%) among the 22 wild-type RAS/BRAF evaluable patients. After a median follow-up of 8.8 years (95% CI, 8.7-not reached), median progression-free survival was 17.9 months (95% CI, 15–23) and median overall survival (OS) was 46.3 months (95% CI, 40.0-not reached). 23 of the 35 patients (66%), including 22 (79%) of the 25 patients with wild-type RAS tumor, underwent curative-intent surgical resection and/or ablation of CRLM. HAI catheter remained patent in 86% of patients, allowing for a median of eight oxaliplatin infusions (range, 1–19). Treatment toxicity was manageable, without toxic death. ConclusionHAI oxaliplatin plus systemic 5-fluorouracil and cetuximab appears highly effective in the frontline treatment of patients with unresectable CRLM and should be investigated further.

Perioperative Chemotherapy is Associated with Superior Overall Survival in Patients with Synchronous Colorectal Liver Metastases.

The sequence of localized and systemic treatment for colorectal liver metastases (CRLM) remains debated. Our objective is to analyze the effect of treatment sequence on overall survival (OS) in patients with CRLM using a large cancer database. The national cancer database (NCDB) was utilized to identify patients with stage IV colorectal cancer (CRC) diagnosed between 2004 and 2016. OS was analyzed using standard univariate and multivariate methods. We identified 72,376 patients with synchronous CRLM, of whom 43,039 had liver-only metastases. Patients with liver-only CRLM had a median OS of 18.9 months, versus those with CRLM plus extrahepatic sites (11.3 months). In patients with liver-only CRLM, resection of both the primary and metastatic site was associated with median OS 38.9 months versus 30.2 months after resection of the metastatic site alone, and resection of the primary tumor alone (22.3 months, all p < 0.001). Receipt of perioperative chemotherapy correlated with a median OS of 44.7 months versus preoperative chemotherapy only (38.4 months) or postoperative chemotherapy only (27.9 months, all p < 0.001). Patients who received chemotherapy alone had a median OS of 16.4 months versus those who underwent resection without chemotherapy (9.5 months, p < 0.001). This study reveals a correlation between perioperative chemotherapy and superior OS in patients with liver-only CRLM, and shows that resection of the metastatic site was linked to better OS. Despite obvious cohort heterogeneity, the data can support a resection approach with additional, preferably peri- or preoperative systemic therapy for patients with CRLM.

Integrated Clinical-Molecular Classification of Colorectal Liver Metastases

Personalized treatment approaches for patients with oligometastatic colorectal liver metastases are critically needed. We previously defined 3 biologically distinct molecular subtypes of colorectal liver metastases: (1) canonical, (2) immune, and (3) stromal. To independently validate these molecular subtypes in the phase 3 New EPOC randomized clinical trial. This retrospective secondary analysis of the phase 3 New EPOC randomized clinical trial included a bi-institutional discovery cohort and multi-institutional validation cohort. The discovery cohort comprised patients who underwent hepatic resection for limited colorectal liver metastases (98% received perioperative chemotherapy) from May 31, 1994, to August 14, 2012. The validation cohort comprised patients who underwent hepatic resection for liver metastases with perioperative chemotherapy (fluorouracil, oxaliplatin, and irinotecan based) with or without cetuximab from February 26, 2007, to November 1, 2012. Data were analyzed from January 18 to December 10, 2021. Resected metastases underwent RNA sequencing and microRNA (miRNA) profiling in the discovery cohort and messenger RNA and miRNA profiling with microarray in the validation cohort. A 31-feature (24 messenger RNAs and 7 miRNAs) neural network classifier was trained to predict molecular subtypes in the discovery cohort and applied to the validation cohort. Integrated clinical-molecular risk groups were designated based on molecular subtypes and the clinical risk score. The unique biological phenotype of each molecular subtype was validated using gene set enrichment analyses and immune deconvolution. The primary clinical end points were progression-free survival (PFS) and overall survival (OS). A total of 240 patients were included (mean [range] age, 63.0 [56.3-68.0] years; 151 [63%] male), with 93 in the discovery cohort and 147 in the validation cohort. In the validation cohort, 73 (50%), 28 (19%), and 46 (31%) patients were classified as having canonical, immune, and stromal metastases, respectively. The biological phenotype of each subtype was concordant with the discovery cohort. The immune subtype (best prognosis) demonstrated 5-year PFS of 43% (95% CI, 25%-60%; hazard ratio [HR], 0.37; 95% CI, 0.20-0.68) and OS of 63% (95% CI, 40%-79%; HR, 0.38; 95% CI, 0.17-0.86), which was statistically significantly higher than the canonical subtype (worst prognosis) at 14% (95% CI, 7%-23%) and 43% (95% CI, 32%-55%), respectively. Adding molecular subtypes to the clinical risk score improved prediction (the Gönen and Heller K for discrimination) from 0.55 (95% CI, 0.49-0.61) to 0.62 (95% CI, 0.57-0.67) for PFS and 0.59 (95% CI, 0.52-0.66) to 0.63 (95% CI, 0.56-0.70) for OS. The low-risk integrated group demonstrated 5-year PFS of 44% (95% CI, 20%-66%; HR, 0.38; 95% CI, 0.19-0.76) and OS of 78% (95% CI, 44%-93%; HR, 0.26; 95% CI, 0.08-0.84), superior to the high-risk group at 16% (95% CI, 10%-24%) and 43% (95% CI, 32%-52%), respectively. In this prognostic study, biologically derived colorectal liver metastasis molecular subtypes and integrated clinical-molecular risk groups were highly prognostic. This novel molecular classification warrants further study as a possible predictive biomarker for personalized systemic treatment for colorectal liver metastases. isrctn.org Identifier: ISRCTN22944367.

Rates and Patterns of Recurrence After Microwave Ablation of Colorectal Liver Metastases: A Per Lesion Analysis of 416 Tumors in the Era of 2.45GHz Generators.

For some patients with colorectal liver metastases (CRLMs), surgical resection of all visible disease can lead to long-term survival and even cure. When complete resection is not feasible, microwave ablation (MWA) can help achieve hepatic disease control. As modern 2.45-GHz MWA generators gain popularity, the characteristics of tumors most likely to benefit from this method remain unclear. This study aimed to evaluate local recurrence (LR) rates, patterns of recurrence, and factors contributing to treatment failure after 2.45-GHz MWA of CRLM. Patients with CRLM who underwent operative 2.45-GHz MWA between 2011 and 2019 were identified in a prospectively maintained single-institution database. Recurrence outcomes were ascertained for each lesion by imaging review. Factors associated with LR were analyzed. The study enrolled 184 patients bearing 416 ablated tumors. Most of the patients (65.8%) had high clinical risk scores (3-5), and 165 (90%) underwent concurrent liver resection. The median tumor size was 10 mm. After a median follow-up period of 28.8 months, LR was observed in 45 tumors, and the cumulative incidence of LR at 24 months was 10.9% (95% confidence interval [CI], 8.0-14.3%]. In 7%, LR was the first recurrence site, often combined with recurrence elsewhere. The cumulative incidence of LR at 24 months was 6.8% (95% CI 3.8-11.0%) for tumors 10 mm in size or smaller, 12.4% (95% CI 7.8-18.1%) for tumors 11 to 20 mm in size, and 30.2% (95% CI 14.2-48.0%) for tumors larger than 20 mm. In the multivariable analysis, tumors larger than 20 mm with a subcapsular location were significantly associated with increased LR risk. Treatment of CRLM with 2.45-GHz MWA offers excellent local control at 2 years and is most successful for small tumors deep within the parenchyma.

P-388 Impact of the curative treatment of colorectal liver metastases

P-388 Impact of the curative treatment of colorectal liver metastases