Current landscape of preoperative neoadjuvant therapies for initial resectable colorectal cancer liver metastasis

Colorectal cancer liver metastasis(CRLM)presents a clinical challenge,and optimizing treatment strategies is crucial for improving patient outcomes.Surgical resection,a key element in achieving prolonged survival,is often linked to a heightened risk of recurrence.Acknowledging the potential benefits of preoperative neoadjuvant chemotherapy in managing resectable liver metastases,this approach has gained attention for its role in tumor downsizing,assessing biological behavior,and reducing the risk of postoperative recurrence.However,the use of neoadjuvant chemotherapy in initially resectable CRLM sparks ongoing debates.The balance between tumor reduction and the risk of hepatic injury,coupled with concerns about delaying surgery,necessitates a nuanced approach.This article explores recent research insights and draws upon the practical experiences at our center to address critical issues regarding considerations for initially resectable cases.Examining the criteria for patient selection and the judicious choice of neoadjuvant regimens are pivotal areas of discussion.Striking the right balance between maximizing treatment efficacy and minimizing adverse effects is imperative.The dynamic landscape of precision medicine is also reflected in the evolving role of gene testing,such as RAS/BRAF and PIK3CA,in tailoring neoadjuvant regimens.Furthermore,the review emphasizes the need for a multidisciplinary approach to navigate the comp-lexities of CRLM.Integrating technical expertise and biological insights is crucial in refining neoadjuvant strategies.The management of progression following neoadjuvant chemotherapy requires a tailored approach,acknowledging the diverse biological behaviors that may emerge.In conclusion,this review aims to provide a comprehensive perspective on the considerations,challenges,and advancements in the use of neoadjuvant chemotherapy for initially resectable CRLM.By combining evidencebased insights with practical experiences,we aspire to contribute to the ongoing discourse on refining treatment paradigms for improved outcomes in patients with CRLM.

Prognostic Impact of Surgical Margin Width in Hepatectomy for Colorectal Liver Metastasis

As for resection for colorectal liver metastasis (CRLM), secur-ing an adequate surgical margin is important for achieving a better prognosis. However, it is often difficult to achieve ade-quate margins for the resection of CRLM. So the current sur-vival impact of sub-centi/millimeter surgical margins in he-patectomy for CRLM should be evaluated. In the current era of multidisciplinary treatment options, this review focused on the prognostic impact of a sub-centi/millimeter surgical margin width in hepatectomy for CRLM. We systematically reviewed retrospective studies that clearly described the sur-gical margin width for hepatectomy for CRLM. We selected studies conducted since 2000 that involved patients diag-nosed as having CRLM. We focused on studies that investi-gated not only surgical margins, but also microscopic surgical curability such as R0 (microscopically complete resection) or R1 (microscopically incomplete resection), which clearly de-scribe their definitions. Based on our literature review, 1, 2, or 5 mm was considered the minimum surgical margin width for hepatectomy for CRLM. Although a surgical margin width of 1 mm is acceptable for hepatectomy for CRLM, submil-limeter margins, which are defined as R1 in many reports, are only acceptable for limited patients such as those who have undergone preoperative chemotherapy. Zero-mm mar-gins are also acceptable in limited patients such as those who show a good response to preoperative chemotherapy. New chemotherapy agents have been reported to reduce the prognostic impact of a narrow surgical margin width. The incidence of margin recurrence, which is a major concern regarding R1 resection of CRLM, is about 20-30% according to the majority of earlier reports. As evaluations of the actual prognostic impact of the surgical margin remain difficult, fur-ther study is warranted.

A machine learning model for colorectal liver metastasis post-hepatectomy prognostications

Background:Currently,surgical resection is the mainstay for colorectal liver metastases(CRLM)management and the only potentially curative treatment modality.Prognostication tools can support patient selection for surgical resection to maximize therapeutic benefit.This study aimed to develop a survival prediction model using machine learning based on a multicenter patient sample in Hong Kong.Methods:Patients who underwent hepatectomy for CRLM between 1 January 2009 and 31 December 2018 in four hospitals in Hong Kong were included in the study.Survival analysis was performed using Cox proportional hazards(CPH).A stepwise selection on Cox multivariable models with Least Absolute Shrinkage and Selection Operator(LASSO)regression was applied to a multiply-imputed dataset to build a prediction model.The model was validated in the validation set,and its performance was compared with that of Fong Clinical Risk Score(CRS)using concordance index.Results:A total of 572 patients were included with a median follow-up of 3.6 years.The full models for overall survival(OS)and recurrence-free survival(RFS)consist of the same 8 established and novel variables,namely colorectal cancer nodal stage,CRLM neoadjuvant treatment,Charlson Comorbidity Score,pre-hepatectomy bilirubin and carcinoembryonic antigen(CEA)levels,CRLM largest tumor diameter,extrahepatic metastasis detected on positron emission-tomography(PET)-scan as well as KRAS status.Our CRLM Machine-learning Algorithm Prognostication model(CMAP)demonstrated better ability to predict OS(C-index=0.651),compared with the Fong CRS for 1-year(C-index=0.571)and 5-year OS(C-index=0.574).It also achieved a C-index of 0.651 for RFS.Conclusions:We present a promising machine learning algorithm to individualize prognostications for patients following resection of CRLM with good discriminative ability.

Prognostic role of serum carcinoembryonic antigen in patients receiving liver resection for colorectal cancer liver metastasis:A meta-analysis

BACKGROUND Carcinoembryonic antigen(CEA)is a broad-spectrum tumor marker for differential diagnosis,monitoring,and response assessment of a variety of malignancies.AIM To evaluate whether serum CEA could predict the prognosis in patients with colorectal cancer liver metastasis(CRCLM)before and after liver resection(LR).METHODS PubMed,Embase,Cochrane,and Web of Science were systematically searched to retrieve literature,with a search cut-off date of February 27,2023.Articles were strictly screened for inclusion according to pre-specified inclusion and exclusion criteria.Data were pooled and analyzed using Stata 16.0.RESULTS This meta-analysis included 36 studies involving a total of 11143 CRCLM patients.The results showed that a high pre-LR serum CEA level was correlated with poor overall survival(OS)[hazard ratio(HR)=1.61,95%confidence interval(CI):1.49-1.75,P<0.001]and recurrence-free survival(HR=1.27,95%CI:1.11-1.45,P<0.001)in CRCLM patients.A high post-LR serum CEA level predicted poor OS(HR=2.66,95%CI:2.10-3.38,P<0.001).A comparison by treatment modality,analysis modality,patient source,and cutoff-value showed that overall,high preoperative and postoperative serum CEA levels remained correlated with a poor prognosis.CONCLUSION This study concluded that high pre-LR and post-LR serum CEA levels were significantly correlated with a poor prognosis in CRCLM patients.

Successful multidisciplinary therapy for a patient with liver metastasis from ascending colon adenocarcinoma:A case report and review of literature

BACKGROUND Liver metastasis is the most common form of distant metastasis in colorectal cancer,and the only possible curative treatment for patients with colorectal liver metastases(CRLM)is hepatectomy.However,approximately 25%of patients with CRLM have indications for liver resection at the initial diagnosis.Strategies aimed at downstaging large or multifocal tumors to enable curative resection are appealing.CASE SUMMARY A 42-year-old man was diagnosed with ascending colon cancer and liver metastases.Due to the huge lesion size and compression of the right portal vein,the liver metastases were initially diagnosed as unresectable lesions.The patient was treated with preoperative transcatheter arterial chemoembolization(TACE)consisting of 5-fluorouracil/Leucovorin/oxaliplatin/Endostar®.After four courses,radical right-sided colectomy and ileum transverse colon anastomosis were performed.Postoperatively,the pathological analysis revealed moderately differentiated adenocarcinoma with necrosis and negative margins.Thereafter,S7/S8 partial hepatectomy was performed after two courses of neoadjuvant chemotherapy.Pathological examination of the resected specimen revealed a pathologically complete response(pCR).Intrahepatic recurrence was detected more than two months after the operation,and the patient was then treated with TACE consisting of irinotecan/Leucovorin/fluorouracil therapy plus Endostar®.Subsequently,the patient was treated with aγ-knife to enhance local control.Notably,a pCR was reached,and the patient's overall survival time was>9 years.CONCLUSION Multidisciplinary treatment can promote the conversion of initially unresectable colorectal liver metastasis and facilitate complete pathological remission of liver lesions.

Associating liver partition and portal vein ligation for staged hepatectomy for colorectal liver metastasis:a single-center experience

Background:Associated liver partition and portal vein ligation for staged hepatectomy(ALPPS)is increasingly used for the treatment of primarily unresectable colorectal liver metastases(CRLM)because of the insufficient future liver remnant(FLR).The aim of this study was to share our experience with ALPPS for advanced CRLM and review the role of ALPPS in the management of patients with CRLM.Methods:Consecutive patients(n=10)with CRLM who underwent ALPPS at our center between December 2014 and October 2021 were retrospectively studied.Results:The median age of patients was 58 years(range 49–70 years).Five patients had metachronous CRLM and the other 5 patients had synchronous CRLM.Five patients had unilateral CRLM and the other 5 patients had bilateral CRLM.All patients previously underwent neoadjuvant chemotherapy.The FLR volume increased by 45.3%(35.8%–61.6%)over 14 days(range 7–21 days).The absolute and relative kinetic growth rates were 17.9 mL/day(range 7.5–32.1 mL/day)and 4.6%/day(range 2.3%–8.8%/day),respectively.Overall morbidity rates were 20%(2/10)and 40%(4/10)after ALPPS stage 1 and stage 2,respectively.The 30-day and 90-day mortality rates were 0%and 10%,respectively.R0 resection was achieved for all patients,and the median disease-free survival was 18.7 months.Conclusions:ALPPS is an effective treatment option for advanced CRLM.It enables rapid hypertrophy of the FLR and achieves a high R0 resection rate with an acceptable oncological outcome.However,ALPPS should be reserved for selected patients because of its relatively high morbidity and mortality.

Neutrophil-to-lymphocyte ratio as a prognostic factor for survival in patients with colorectal liver metastases: A systematic review

BACKGROUND The inflammatory response to tumor has been proven to be closely related to the prognosis of colorectal cancer.Neutrophil to lymphocyte ratio(NLR)is a widely available inflammatory biomarker that may have prognostic value for patients with colorectal liver metastasis(CRLM).AIM To assess the role of NLR as a prognostic factor of survival and tumor recurrence in patients with CRLM.METHODS A systematic literature search of PubMed,Cochrane Library and clinicaltrials.gov was conducted by two independent researchers in order to minimize potential errors and bias.Conflicts were discussed and settled between three researchers.Studies including patients undergoing different types of medical interventions for the treatment of CRLM and evaluating the correlation between pretreatment NLR and disease-free survival(DFS)and overall survival(OS)were included in the review.Nineteen studies,involving 3283 patients matched our inclusion criteria.RESULTS In the studies included,NLR was measured before the intervention and the NLR thresholds ranged between 1.9 and 7.26.Most studies used 5 as the cut-off value.Liver metastases were treated with hepatectomy with or without chemotherapy regimens in 13 studies and with radiofrequency ablation,radioembolization,chemoembolization or solely with chemotherapy in 6 studies.High NLR was associated with decreased OS and DFS after liver resection or other medical intervention.Moreover,high NLR was associated with poor chemosensitivity.On the contrary,CRLM patients with low pretreatment NLR demonstrated improved OS and DFS.NLR could potentially be used as a predictive factor of survival and tumor recurrence in patients with CRLM treated with interventions of any modality,including surgery,chemotherapy and ablative techniques.CONCLUSION NLR is an inflammatory biomarker that demonstrates considerable prognostic value.Elevated pretreatment NLR is associated with poor OS and DFS in patients with CRLM who are submitted to different treatments.

Oncological outcomes and predictors of radiofrequency ablation of colorectal cancer liver metastases

BACKGROUND Surgical resection is considered the standard treatment option for long-term survival in colorectal cancer liver metastasis(CRLM)patients,but only a small number of patients are suitable for resection following diagnosis.Radiofrequency ablation(RFA)is an accepted alternative therapy for CRLM patients who are not suitable for resection.However,the relatively high rate of local tumor progression(LTP)is an obstacle to the more widespread use of RFA.AIM To determine the oncological outcomes and predictors of RFA in CRLM patients.METHODS A retrospective analyze was performed on the clinical data of 85 consecutive CRLM patients with a combined total of 138 liver metastases,who had received percutaneous RFA treatment at our institution from January 2013 to December 2018.Contrast-enhanced computed tomography was performed the first month after RFA to assess the technique effectiveness of the RFA and to serve as a baseline for subsequent evaluations.The Kaplan-Meier method was used to calculate overall survival(OS)and LTP-free survival(LTPFS).The log-rank test and Cox regression model were used for univariate and multivariate analyses to determine the predictors of the oncological outcomes.RESULTS There were no RFA procedure-related deaths,and the technique effectiveness of the treatment was 89.1%(123/138).The median follow-up time was 30 mo.The LTP rate was 32.6%(45/138),and the median OS was 36 mo.The 1-,3-,and 5-year OS rates were 90.6%,45.6%,and 22.9%,respectively.Univariate analysis revealed that tumor size and ablative margin were the factors influencing LTPFS,while extrahepatic disease(EHD),tumor number,and tumor size were the factors influencing OS.Multivariate analysis showed that tumor size larger than 3 cm and ablative margin of 5 mm or smaller were the independent predictors of shorter LTPFS,while tumor number greater than 1,size larger than 3 cm,and presence of EHD were the independent predictors of shorter OS.CONCLUSION RFA is a safe and effective treatment method for CRLM.Tumor size and ablative margin are the important factors affecting LTPFS.Tumor number,tumor size,and EHD are also critical factors for OS.

Advances in liver transplantation for unresectable colon cancer liver metastasis

It is estimated that 50%of patients with colorectal cancer will develop liver metastasis.Surgical resection significantly improves survival and provides a chance of cure for patients with colorectal cancer liver metastasis(CRLM).Increasing the resectability of primary unresectable liver metastasis provides more survival benefit for those patients.Considerable surgical innovations have been made to increase the resection rate and decrease the potential risk of hepatic failure postoperation.Liver transplantation(LT)has been explored as a potential curative treatment for unresectable CRLM.However,candidate selection criteria,chemotherapy strategies,refined immunity regimens and resolution for the shortage of grafts are lacking.This manuscript discusses views on surgical indication,peritransplantation anti-tumor and anti-immunity therapy and updated advances in LT for unresectable CRLM.A literature review of published articles and registered clinical trials in PubMed,Google Scholar,and Clinicaltrials.gov was performed to identify studies related to LT for CRLM.Some research topics were identified,including indications for LT for CRLM,oncological risk,antitumor regimens,graft loss,administration of anti-immunity drugs and solutions for graft deficiency.The main candidate selection criteria are good patient performance,good tumor biological behavior and chemosensitivity.Chemotherapy should be administered before transplantation but is not commonly administered posttransplantation for preventive purposes.Mammalian target of rapamycin regimens are recommended for their potential oncological benefit,although there are limited cases.In addition to extended criterion grafts,living donor grafts and small grafts combined with two-stage hepatectomy are efficient means to resolve organ deficiency.LT has been proven to be an effective treatment for selected patients with liver-only CRLM.Due to limited donor grafts,high cost and poorly clarified oncological risks,LT for unresectable CRLM should be strictly performed under a well-organized study plan in selected patients.Some vital factors,like LT indication and anti-tumor and anti-immune treatment,remain to be confirmed.Ongoing clinical trials are expected to delineate these topics.

Is CA19-9 effective in predicting chemotherapeutic response in patients with synchronous liver metastases with colorectal cancer?

Evaluation of response to chemotherapy in colorectal cancer patients with synchronous liver metastases is important in terms of treatment management.In this Letter to the Editor,several issues in the article are discussed.For the comparison of carbohydrate antigen 19-9(CA19-9)values referenced in the study,the patient group was not matched for cancer stage.Therefore,it may be more appropriate to select and compare CA19-9 values in patients with same-stage cancer.

Enhanced recovery nursing and mental health education on postoperative recovery and mental health of laparoscopic liver resection

BACKGROUND Patients undergoing laparoscopic resection of liver metastases of colorectal cancer are prone to negative emotions and decrease of digestive function.Early nursing and psychological intervention are necessary.AIM To observe the effect of enhanced recovery nursing combined with mental health education on postoperative recovery and mental health of patients undergoing laparoscopic resection of liver metastases of colorectal cancer.METHODS One hundred and twenty patients who underwent laparoscopic resection of liver metastases of colorectal cancer at our hospital between March 2021 and March 2023,were selected as participants.The patients admitted from March 1,2021 to February 28,2022 were set as the control group,and they were given routine nursing combined with mental health education intervention.While the patients admitted from March 1,2022 to March 31,2023 were set as the observation group,they were given accelerated rehabilitation surgical nursing combined with mental health education intervention.The differences in postoperative recovery-related indices,complications and pain degrees,and mental health-related scores were compared between groups.The T lymphocyte subset levels of the two groups were also compared.RESULTS The postoperative exhaust,defecation,eating and drainage time of the observation group were shorter than those of the control group.The pain scores of the observation group were lower than those of the control group at 6,12,24,48,and 72 h after surgery.The cumulative complication rate of the observation group was lower than that of the control group(P<0.05).The CD4+/CD8+in the observation group was higher than that in the control group 3 d after surgery(P<0.05).After intervention,the self-rating depression scale,self-rating anxiety scale,avoidance dimension,and yielding dimension in Medical coping style(MCMQ)scores of the two groups were lower than those prior to intervention,and the scores in the observation group were lower than those in the control group(P<0.05).The face dimension score in the MCMQ score was higher than that before intervention,and that of the observation group was higher than that of the control group(P<0.05).After intervention,the total scores of the life function index scale(FLIC)and psychological well-being scores of cancer patients in the two groups,and the physical and social well-being scores in the observation group,were higher than those before intervention.The nursing satisfaction of the observation group was higher than that of the control group(P<0.05).The physical,psychological,and social well-being,and the total FLIC scores of the observation group were higher than those in the control group after surgery(P<0.05).CONCLUSION Enhanced recovery nursing combined with mental health education can promote the recovery of gastrointestinal function,improve the mental health and quality of life of patients after laparoscopic resection of colorectal cancer liver metastases,and reduce the incidence of complications.

Gut microbiota and immune system in liver cancer:Promising therapeutic implication from development to treatment

Liver cancer is a leading cause of death worldwide,and hepatocellular carcinoma(HCC)is the most frequent primary liver tumour,followed by cholangiocarcinoma.Notably,secondary tumours represent up to 90% of liver tumours.Chronic liver disease is a recognised risk factor for liver cancer development.Up to 90% of the patients with HCC and about 20% of those with cholangiocarcinoma have an underlying liver alteration.The gut microbiota-liver axis represents the bidirectional relationship between gut microbiota,its metabolites and the liver through the portal flow.The interplay between the immune system and gut microbiota is also well-known.Although primarily resulting from experiments in animal models and on HCC,growing evidence suggests a causal role for the gut microbiota in the development and progression of chronic liver pathologies and liver tumours.Despite the curative intent of“traditional”treatments,tumour recurrence remains high.Therefore,microbiota modulation is an appealing therapeutic target for liver cancer prevention and treatment.Furthermore,microbiota could represent a non-invasive biomarker for early liver cancer diagnosis.This review summarises the potential role of the microbiota and immune system in primary and secondary liver cancer development,focusing on the potential therapeutic implications.

Liver transplantation for non-resectable colorectal metastases-an evolving paradigm in transplant oncology

A better understanding of colorectal liver metastasis(CRLM)onco-genomics and the improvement of systemic treatments,including targeted and immune therapies,have shifted the paradigm of CRLM prognosis over the past two decades.While 40%of the patients with colorectal cancers are likely to develop CRLM[and 50%of them to be non-resectable(nCRLM)],current oncologic management allows for the identification of a subset of CRLM patients with controlled diseases likely to highly benefit from curative resections and,perhaps,liver transplantation(LT).Indeed,the Norwegian SECA I trial in 2013(1)triggered a growing interest in LT as a curative treatment for non-resectable colorectal liver metastasis(nCRLM).This strategy is supported by several pilot studies reporting up to 80%of 5-year estimated overall survival(OS)after LT for CRLM,in contrast to the poor results obtained in the early 80’s series.