Selection for hepatic resection of colorectal liver metastases: expert consensus statement

Hepatic resection offers a chance of a cure in selected patients with colorectal liver metastases (CLM). To achieve adequate patient selection and curative surgery, (i) precise assessment of the extent of disease, (ii) sensitive criteria for chemotherapy effect, (iii) adequate decision making in surgical indication and (iv) an optimal surgical approach for pre-treated tumours are required. For assessment of the extent of the disease, contrast-enhanced computed tomography (CT) and/or magnetic resonance imaging (MRI) with gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) is recommended depending on the local expertise and availability. Positron emission tomography (PET) and PET/CT may offer additive information in detecting extrahepatic disease. The RECIST criteria are a reasonable method to evaluate the effect of chemotherapy. However, they are imperfect in predicting a pathological response in the era of modern systemic therapy with biological agents. The assessment of radiographical morphological changes is a better surrogate of the pathological response and survival especially in the patients treated with bevacizumab. Resectability of CLM is dependent on both anatomic and oncological factors. To decrease the surgical risk, a sufficient volume of liver remnant with adequate blood perfusion and biliary drainage is required according to the degree of histopathological injury of the underlying liver. Portal vein embolization is sometimes required to decrease the surgical risk in a patient with small future liver remnant volume. As a complete radiological response does not signify a complete pathological response, liver resection should include all the site of a tumour detected prior to systemic treatment.     

Multi-modality treatment of colorectal liver metastases

Liver metastases synchronously or metachronously occur in approximately 50% of colorectal cancer patients. Multimodality comprehensive treatment is the best therapeutic strategy for these patients. However, the optimal pattern of multimodality therapy is still controversial, and it raises several significant concerns. Liver resection is the most important treatment for colorectal liver metastases. The definition of resectability has shifted to focus on the completion of R0 resection and normal liver function maintenance. The role of neoadjuvant and adjuvant chemotherapy still needs to be clarified. The management of either progression or complete remission during neoadjuvant chemotherapy is challenging. The optimal sequencing of surgery and chemotherapy in synchronous colorectal liver metastases patients is still unclear. Conversional chemotherapy, portal vein embolization, two-stage resection, and tumor ablation are effective approaches to improve resectability for initially unresectable patients. Several technical issues and concerns related to these methods need to be further explored. For patients with definitely unresectable liver disease, the necessity of resecting the primary tumor is still debatable, and evaluating and predicting the efficacy of targeted therapy deserve further investigation. This review discusses different patterns and important concerns of multidisciplinary treatment of colorectal liver metastases.     

Simultaneous surgery for primary colorectal cancer and metastatic lesions?

Approximately 20-25% of patients with colorectal cancer present with liver metastases at the time of diagnosis. Traditionally, resection of the primary tumor has been advocated in order to prevent complications of the primary tumor colorectal cancer in patients with synchronous liver metastases. The published data concerning long-term prognosis in this group of patients are discordant. Although some of the reports show survival benefits from resection of the primary tumor, these studies are retrospective with small number of patients and using single drug chemotherapy. For patients with resectable liver metastases, new studies indicate that progression-free survival is best in patients receiving perioperative chemotherapy. In patients with synchronous nonresectable liver metastases and colorectal cancer, there is no published prospective randomized study comparing initial surgery of the primary tumor with neoadjuvant chemotherapy. However, recent publications show that in patients receiving chemotherapy based on oxaliplatin or irinotecan combined with targeted treatments, the complications associated with the primary tumor are less than 10%. The conclusion should be that today prophylactic surgery of asymptomatic primary colorectal cancer in patients with liver metastases cannot be recommended.     

Refining pathological evaluation of neoadjuvant therapy for adenocarcinoma of the esophagus

AIM:To assess tumour regression grade(TRG)and lymph node downstaging to help define patients who benefit from neoadjuvant chemotherapy.METHODS:Two hundred and eighteen consecutive patients with adenocarcinoma of the esophagus or gastro-esophageal junction treated with surgery alone or neoadjuvant chemotherapy and surgery between 2005and 2011 at a single institution were reviewed.Triplet neoadjuvant chemotherapy consisting of platinum,fluoropyrimidine and anthracycline was considered for operable patients(World Health Organization performance status≤2)with clinical stage T2-4 N0-1.Response to neoadjuvant chemotherapy(NAC)was assessed using TRG,as described by Mandard et al.In addition lymph node downstaging was also assessed.Lymph node downstaging was defined by cN1 at diagnosis:assessed radiologically(computed tomography,positron emission tomography,endoscopic ultrasonography),then pathologically recorded as N0 after surgery;ypN0 if NAC given prior to surgery,or pN0if surgery alone.Patients were followed up for 5 years post surgery.Recurrence was defined radiologically,with or without pathological confirmation.An association was examined between t TRG and lymph node downstaging with disease free survival(DFS)and a comprehensive range of clinicopathological characteristics.RESULTS:Two hundred and eighteen patients underwent esophageal resection during the study interval with a mean follow up of 3 years(median follow up:2.552,95%CI:2.022-3.081).There was a 1.8%(n=4)inpatient mortality rate.One hundred and thirty-six(62.4%)patients received NAC,with 74.3%(n=101)of patients demonstrating some signs of pathological tumour regression(TRG 1-4)and 5.9%(n=8)having a complete pathological response.Forty four point one percent(n=60)had downstaging of their nodal disease(cN1 to ypN0),compared to only 15.9%(n=13)that underwent surgery alone(pre-operatively overstaged:cN1 to pN0),(P<0.0001).Response to NAC was associated with significantly increased DFS(mean DFS;TRG 1-2:5.1years,95%CI:4.6-5.6 vs TRG 3-5:2.8 years,95%CI:2     

Therapeutic strategies for hepatic metastasis of colorectal cancer: overview

To determine the treatment strategy for hepatic metastases of colorectal cancer, it is important to take into account whether metastases are still localized in the liver, or whether the tumor has metastasized throughout the body. For liver-limited metastasis, hepatectomy is the therapeutic strategy that offers the best prospect of improving a patient's prognosis if the case is deemed resectable. In cases when surgery is not indicated for hepatic metastases of colorectal cancer, chemotherapy is the first-choice treatment. Chemotherapy for colorectal cancer has made vast strides in recent years through advances such as the development of molecular targeted drugs. In cases where chemotherapy is effective and surgical resection becomes possible (conversion chemotherapy), the long-term prognosis may be good. The value of preoperative chemotherapy in resectable cases (neoadjuvant chemotherapy) has also been reported. The improvement in prognosis achieved by eradicating tiny latent metastases is important in conversion therapy, as well as in neoadjuvant chemotherapy. It will be important to achieve further improvements in the prognoses of patients with hepatic metastases of colorectal cancer through a combination of advances in diagnostic imaging, improvements in surgical techniques, and more effective chemotherapy treatments.     

Complete resection of unresectable liver metastases from colorectal cancer without deterioration of liver function after cetuximab and irinotecan: two case reports

Complete resection for colorectal metastases is the only treatment that can provide long-term survival and may lead to cure. Recent reports have shown that liver resection following systemic chemotherapy in patients with initially unresectable metastases from colorectal cancer may also result in a good long-term survival, and rescue surgery after chemotherapy has become a strategy of choice. A 29-year-old male and a 35-year-old female with unresectable liver metastases from colorectal cancer underwent complete resection after administration of third-line combination therapy of cetuximab and irinotecan. Although systemic chemotherapy may decrease liver function, which may make liver resection unfeasible, in the two cases reported, liver function did not deteriorate after cetuximab plus irinotecan. The indocyanine green retention rate at 15 minutes, which is useful in deciding the safe limit of hepatectomy, was optimal after the administration of cetuximab plus irinotecan in both patients. Cetuximab plus irinotecan may be beneficial as neoadjuvant chemotherapy for metastatic colorectal cancer, not only because of its oncological efficacy but also for preservation of liver function.     

How reliable is current imaging in restaging rectal cancer after neoadjuvant therapy?

In patients with advanced rectal cancer,neoadjuvant chemo radiotherapy provides tumor downstaging and downsizing and complete pathological response in up to 30%of cases.After proctectomy complete pathological response is associated with low rates of local recurrence and excellent long term survival.Several authors claim a less invasive surgery or a non operative policy in patients with partial or clinical complete response respectively,however to identify patients with true complete pathological response before surgical resection remains a challenge.Current imaging techniques have been reported to be highly accurate in the primary staging of rectal cancer,however neoadjuvant therapy course produces deep modifications on cancer tissue and on surrounding structures such as overgrowth fibrosis,deep stroma alteration,wall thickness,muscle disarrangement,tumor necrosis,calcification,and inflammatory infiltration.As a result,the same imaging techniques,when used for restaging,are far less accurate.Local tumor extent may be overestimated or underestimated.The diagnostic accuracy of clinical examination,rectal ultrasound,computed tomography,magnetic resonance imaging,and positron emission tomography using 18F-fluoro-2’-deoxy-Dglucose ranges between 25%and 75%being less than 60%in most studies,both for rectal wall invasion and for lymph nodes involvement.In particular the ability to predict complete pathological response,in order to tailor the surgical approach,remains low.Due to the radio-induced tissue modifications,combined with imaging technical aspects,low rate accuracy is achieved,making modern imaging techniques still unreliable in restaging rectal cancer after chemo-radiotherapy.     

Neoadjuvant and adjuvant therapy in relation to surgery for colorectal liver metastases

Liver resection is associated with prolonged survival in patients with colorectal liver metastases. At diagnosis, 15-20% of patients have resectable colorectal liver metastases whereas other patients have too advanced disease to enable surgical treatment and receive chemotherapy. In patients undergoing resection of colorectal liver metastases, disease relapse occurs in up to 70%. Therefore, a combined approach including preoperative or postoperative chemotherapy or both has been tested to improve outcome after surgery. In patients with unresectable colorectal liver metastases, chemotherapy is initially the sole treatment option. The considerable improvement of the efficacy of anticancer agents has contributed to increase the response rate in patients with advanced colorectal cancer. In case of major response to chemotherapy, surgery with curative intent can be offered to patients with initially unresectable liver metastases.     

The Role of Positron Emission Tomography in the Management of Recurrent Colorectal Cancer: A Review

Purpose Surgery remains the only option for potential cure in patients with recurrent colorectal cancer. Accurate staging modalities aid in the avoidance of futile surgery, which may result in considerable morbidity in patients with incurable disease. Current imaging techniques used in disease staging often are not sensitive enough to identify low-volume metastatic disease. This study reviews the role of positron emission tomography in the assessment of patients with suspected recurrent colorectal cancer. Methods A literature search using the PubMed, MEDLINE, and Embase database was performed, locating English language articles on positron emission tomography, positron emission tomography, recurrent colon, and/or rectal cancer. The references of these papers were searched manually for further references. Results Positron emission tomography is more sensitive and more specific than conventional diagnostic imaging for metastatic disease and local recurrence respectively. Studies confirm the superior ability of positron emission tomography scans compared with conventional diagnostic imaging in differentiating between scar tissue and invasive tumor. Positron emission tomography scanning is more sensitive and specific for the assessment of liver metastases (and probably in patients with lung metastasis) than conventional diagnostic imaging. Positron emission tomography is superior to conventional diagnostic imaging in the investigation of raised carcinoembryonic antigen in the postoperative patient and alters management in approximately 37 percent of patients with recurrent colorectal cancer. The limitations and cost effectiveness of positron emission tomography are discussed. Conclusions Positron emission tomography scanning is emerging as the imaging modality of choice for patients being considered for surgery for locally recurrent colorectal cancer. Positron emission tomography has the greatest impact by detecting unresectable disease and thereby averting inappropriate surgery. Despite the high set-up costs, its use seems to be cost effective. Reprints are not available.     

Accuracy of Investigations for Asymptomatic Colorectal Liver Metastases

PURPOSE: The aim of this study was to prospectively assess the accuracy of the most promising imaging and tumor marker tests in liver metastasis diagnosis on follow-up of asymptomatic colorectal cancer patients during a median of 57 months after primary tumor resection. METHODS: One hundred patients, who were considered free of liver metastases after primary colorectal cancer resection and conventional follow-up, were screened for liver metastases by computerized tomography, magnetic resonance and ultrasound scans, ultrasound Doppler and isotope assessment of changes in hepatic arterial and portal venous flow, and serum estimation of carcinoembryonic antigen. Patients were followed up during a median of 41 months to identify those who developed liver metastases. RESULTS: The most sensitive technique was computerized tomography (sensitivity 0.67, specificity 0.91). Computerized tomography and magnetic resonance but not ultrasound were 100 percent accurate in differentiating liver metastases from other hepatic lesions. Techniques based on changes in hepatic arterial and portal venous flow had lower diagnostic accuracies (Doppler perfusion index, sensitivity 0.58, specificity 0.57; hepatic perfusion index, sensitivity 0.50, specificity 0.55), whereas ultrasound scanning identified only 43 percent (sensitivity 0.43, specificity 0.96) and serum carcinoembryonic antigen 33 percent (sensitivity 0.33, specificity 0.81) of patients with asymptomatic liver metastasis. Sensitivity could be improved by using tests in combination but this reduced specificity. CONCLUSIONS: Computerized tomography was the most sensitive test for asymptomatic colorectal liver metastases, but only 67 percent of affected patients were identified.     

Hepatic resection for liver metastasis of sigmoid colon cancer after incomplete percutaneous microwave coagulation therapy

We report a case of colon cancer with liver metastasis that had been treated previously by sigmoidectomy and partial hepatic segmentectomy. A 55-year-old woman presented with two asynchronous liver metastases, which were treated with percutaneous microwave coagulation therapy. However, evaluation by dynamic computed tomography one week later showed incomplete necrosis in at least one tumor. Surgical resection was subsequently performed and histopathological examination showed the presence of viable cancer cells in both tumors. We conclude that surgical resection is perhaps the best curative method of treatment of metastatic liver tumors of colorectal carcinomas and that dynamic computed tomography is not always accurate for evaluating the effect of microwave coagulation therapy.     

Long-term complete response of unresectable liver metastases from colorectal cancer

Recent advances in chemotherapy for metastatic colorectal cancer, such as fluorouracil -leucovorin, irinotecan, oxliplatin, and bevacizumab, have been demonstrated to achieve a high response rate. For most patients with unresectable liver metastases, however, chemotherapy is still not considered to provide a sufficient long-term disease-free survival without a surgical resection. We herein report two cases of a complete response for more than 8 years after having received treatment consisting of hepatic arterial infusion of fluorouracil and oral chemotherapy for unresectable liver metastases. The clinicopathological characteristics of these two cases were as follows: the number of liver metastases, 20, 11; the maximum size, 1.2 cm, 2.8 cm; the serum carcinoembryonic antigen level, 1.2 ng/ ml, 2.4 ng/ml. The following computed tomography scan revealed the liver metastases to have completely disappeared 7 months and 22 months after the treatment, respectively. It is speculated that a small size and a low level carcinoembryonic antigen may predict a good response to chemotherapy for unresectable liver metastases from colorectal cancer.     

Good embolization response for colorectal liver metastases with hypervascularity

BACKGROUND/AIMS: We investigated whether tumor hypervascularity in diagnostic images predicts response to transcatheter arterial embolization in colorectal liver metastases. METHODOLOGY: Forty-five patients undergoing transcatheter arterial embolization for liver metastases were grouped by tumor vascularity on contrast-enhanced computed tomography and angiography. Group IA (n = 10) included patients with hypervascular tumors by both contrast-enhanced computed tomography and early-phase angiography; group IB (n = 15), hypervascularity by contrast-enhanced computed tomography and only late-phase angiography; group IIB (n = 2), hypovascularity by contrast-enhanced computed tomography and only early-phase angiography; group IIC (n = 18), hypovascularity by contrast-enhanced computed tomography and both angiography phases (unmentioned groups included no patients). Tumor response assessed by computed tomography and changes in serum carcinoembryonic antigen concentration at 1 month, as well as survival rates, were compared between groups. RESULTS: Patients with a partial response numbered only 5, all in group IA. Patients with no change included 26 (group IA, 4; group IB, 10; group IIB, 1; group IIC, 11), while patients with progressive disease numbered 14 (group IA, 1; group IB, 5; group IIB, 1; group IIC, 7). Serum carcinoembryonic antigen concentrations were 0.62, 1.03, 1.31, and 2.01% of pretreatment rates in groups IA, IB, IIB, and IIC, respectively. Carcinoembryonic antigen increases in group IA plus IB were significantly lower (P = 0.04) than in group IIB plus IIC. The decreases in group IA differed significantly from changes in group IB plus IIB (P = 0.05), or group IIC (P = 0.02). Survival rates were somewhat higher group IA than in other, but not significantly. CONCLUSIONS: Transcatheter arterial embolization is effective against colorectal liver metastases only when hypervascularity is evident.     

Neoadjuvant chemotherapy affects staging of colorectal liver metastasis��a comparison of PET, CT and intraoperative ultrasound

Purpose  

Surgery for colorectal liver metastasis facilitates long-term survival, and neoadjuvant chemotherapy improves resectability but may also alter staging accuracy. The aim of this study was to evaluate the effects of neoadjuvant chemotherapy on the efficacy of positron emission tomography (PET), PET–computed tomography (CT), CT and intraoperative ultrasound (IUS) in the detection of liver metastasis.     

Xelox (capecitabine plus oxaliplatin) as neoadjuvant chemotherapy of unresectable liver metastases in colorectal cancer patients

Complete resection of liver metastasis may provide long term survival in patients with colorectal cancer. Increased number of studies on successful resection after neoadjuvant chemotherapy with initially unresectable liver metastasis has been reported. We evaluated retrospectively the results of 35 patients with unresectable liver only metastases from colorectal cancer treated with capecitabine plus oxaliplatin combination (XELOX). Treatment consisted of IV oxaliplatin 130 mg/m2 day 1 and oral capecitabine 1000 mg/m2 day twice daily on days 1 to 14 followed by 7 days of rest repeated every 3 weeks. After chemotherapy, 13 (37, 2 %) patients showed partial clinical response. Among them, 7 patients were considered suitable for surgery but 2 patients refused the surgery. While one of 5 patients had unresectable disease at surgery, the remaining 4 patients (11, 4 %) had a complete resection. There was one postoperative mortality due to sepsis within 2 months after surgery. Our data suggests that XELOX regimen seems to be useful in unresectable liver only metastases from colorectal cancer because of its activity, feasibility and tolerability. Further studies of XELOX in combination with bevacizumab and/ or cetuximab are warranted in this setting.     

中国结直肠癌肝转移诊断和综合治疗指南(V 2020)

肝脏是结直肠癌血行转移最主要的靶器官,结直肠癌肝转移是结直肠癌治疗的重点和难点之一.为了提高我国结直肠癌肝转移的诊断和综合治疗水平,自2008年开始编写《中国结直肠癌肝转移诊断和综合治疗指南》并后续进行了多次修订,以期指导对结直肠癌肝转移患者进行全面评估,个性化地制定治疗目标,开展相应的综合治疗,达到预防结直肠癌肝转移...     

中国结直肠癌肝转移诊断和综合治疗指南（V2023）

肝脏是结直肠癌血行转移最主要的靶器官，结直肠癌肝转移是结直肠癌治疗的重点和难点之一。为了提高我国结直肠癌肝转移的诊断和综合治疗水平，自2008年起各学组联合编写《中国结直肠癌肝转移诊断和综合治疗指南》并后续进行多次修订，以期指导对结直肠癌肝转移患者进行全面评估，精准地制定个体化的治疗目标，开展综合治疗，达到预防肝转移发生、提高肝转移灶局部毁损率、延长长期生存和改善生活质量的目的。此次修订后的《中国结直肠癌肝转移诊断和综合治疗指南（V2023）》包括结直肠癌肝转移的诊断和随访、预防、多学科团队作用、手术及其他毁损治疗、可达到“无疾病证据”状态结直肠癌肝转移的新辅助和辅助治疗、无法达到“无疾病证据”状态结直肠癌肝转移的综合治疗等六部分，汇集总结国内外该领域的先进经验和最新成果，内容详尽，可操作性强。     

Radioimmunodetection of colorectal carcinoma

BACKGROUND/AIMS: The aim of the study is detection of the recurrences and metastases of colorectal carcinomas using 111In-labeled antibodies B72.3. METHODOLOGY: Fourteen patients underwent planar immunoscintigraphy and/or tomoscintigraphy. RESULTS: With tomography in comparison to planar scintigraphy, we can access better distinction of tumor and estimation of its size. Other imaging methods (computed tomography, ultrasonography) have an advantage in detection of liver metastases, while immunoscintigraphy is more specific for the assessment of malignant abdominal tumors and extrahepatic metastases. CONCLUSIONS: The first results point out that Oncoscint CR-103 can be useful in diagnosis of recurrences and metastases of colorectal carcinoma, viability assessment after radiotherapy and in the choice of the adequate surgical treatment in dependence of the spread of the disease.     

Multiple focal nodular hyperplasias induced by oxaliplatin-based chemotherapy

Focal nodular hyperplasia (FNH) is a benign condition that affects normal liver with low prevalence. Recently, the extensive use of oxaliplatin to treat patients with colorectal cancer has been reported to be associated with the development of different liver injuries, as well as focal liver lesions. The present work describes two patients with multiple bilateral focal liver lesions misdiagnosed as colorectal liver metastases, and treated with liver resection. The first patient had up to 15 small bilateral focal liver lesions, with magnetic resonance imaging consistent with colorectal liver metastases (CLM), and fluorodeoxyglucose (FDG)-positron emission tomography (PET) negative. The second patient had up to 5 small focal liver lesions, with computed tomography consistent with CLM, and FDG-PET negative. They had parenchyma sparing liver surgery, with uneventful postoperative course. At the histology the diagnosis was multiple FNHs. The risks of oxaliplatin-based chemotherapy regimens in development of liver injuries, such as FNH, should not be further denied. The value of the modern multidisciplinary management of patients with colorectal cancer relies also on the precise estimation of the risk/benefit for each patient.     

Evidence-base guideline on management of colorectal liver metastases in the Netherlands

A dutch national evidence-based guideline on the diagnosis and treatment of patients with colorectal liver metastases has been developed. The most important recommendations are as follows. For synchronous liver metastases, spiral computed tomography (CT) or magnetic resonance imaging (MRI) should be used as imaging. For evaluation of lung metastases, imaging can be limited to chest radiography. For detection of metachronous liver metastases, ultrasonography could be performed as initial modality if the entire liver is adequately visualised. In doubtful cases or potential candidates for surgery, CT or MRI should be performed as additional imaging. For evaluation of extrahepatic disease, abdominal and chest CT could be performed. Fluorodeoxyglucose positron emission tomography could be valuable in patients selected for surgery based on CT (liver/abdomen/chest), for identifying additional extrahepatic disease. Surgical resection is the treatment of choice with a five-year survival of 30 to 40%. Variation in selection criteria for surgery is caused by inconclusive data in the literature concerning surgical margins.