Advances in understanding of colorectal liver metastasis and implications for the clinic

Colorectal cancer is one of the most common cancers in both the USA and Europe. Over the course of diagnosis, treatment and surveillance, up to 50% of these patients will develop metastases to their liver. In the past 20 years alone, there have been multiple advances in the management of these colorectal metastases to the liver. These advances have been made in characterization of these tumors, diagnosis and in treatment, both locally and systemically. Because of this progress, there are subsets of patients with this stage IV disease who are cured of their disease. While significant progress has been made, there still exist limitations in the management of metastatic colorectal cancer to the liver. This review outlines current strategies and highlights recent advances in the management of colorectal liver metastases.     

Surgical management of recurrence after resection of colorectal liver metastases

The optimal treatment for recurrent lesions after hepatectomy for colorectal liver metastases is controversial. We report the outcome of aggressive surgery for recurrent disease after the initial hepatectomy and the influence on quality of life of such treatment. Forty-five (70%) of the 64 surviving patients developed recurrence after the initial hepatectomy for liver metastases. The determinants of hepatic recurrence were the distribution and the number of liver metastases. Twenty-eight (62%) of patients with recurrence underwent resection. A second hepatectomy was performed in 20 patients, and a third hepatectomy was done in 5 patients. Ten patients with pulmonary metastasis underwent partial lung resection on 14 occasions, while resection of brain metastases was performed in 3 patients on 5 occasions. There were no operative deaths after resection of recurrent disease. The morbidity rate was 28% after repeat hepatectomy, 21% after pulmonary resection, and 0% after resection of brain metastasis. The Karnofsky performance status (PS) after the last surgery was not significantly different from that after the initial hepatectomy. The 3- and 5-year survival rates after the second hepatectomy were 54% and 14%, respectively. The 3-and 5-year survival rates of the patients undergoing resection of extrahepatic recurrence were both 17%. The survival rate after resection of recurrent disease (n=28) was significantly better than that of patients (n=17) with unresectable recurrence (P < 0.05). For the 66 patients with colorectal liver metastases, the 5-year survival rate after initial hepatectomy was 50%. The distribution and the number of liver metastases and the presence of extrahepatic disease, as single factors, significantly affected prognosis after the initial hepatectomy. Multivariate analysis revealed that only the presence of extrahepatic metastasis and a disease-free interval of less than 6 months were independent predictors of survival after the initial and second hepatectomy, respectively. It is concluded that aggressive surgery is an effective strategy for selected patients with recurrence after initial hepatectomy. Careful selection of candidates for repeat surgery will yield increased clinical benefit, including long-term survival.     

Liver transplantation for the treatment of neuroendocrine liver metastases

Neuroendocrine neoplasms represent a heterogeneous group of cancers arising from a variety of neuroendocrine cell types. In general, these tumors (NET) are asymptomatic and are discovered late once metastatic disease is present (40–80%). The liver is the most common organ involved when metastases occur (40–93%), followed by bone (12–20%) and lungs (8–10%). A number of different therapeutic options are available for patients with hepatic metastases including surgical resection, transplantation, transarterial chemoembolization, radiofrequency and microwave ablation, radioembolization (Y90), chemotherapy, somatostatin analogues and molecular targeted therapies. Surgical resection is still considered the treatment of choice and provides excellent disease control with an overall survival of 47–92%. Liver transplantation has been advocated in selected patients with bilateral unresectable symptomatic liver metastases. The aim of this study is to review the existing literature emphasizing on the role of transplantation to treat patients with liver metastases from NET.     

Clinical research advances in primary liver cancer

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Current surgical management of pancreatic endocrine tumor liver metastases

BACKGROUND: The management of metastatic disease in pancreatic endocrine tumors (PETs) demands a multidisciplinary approach and the cooperation of several medical specialties. The role of surgery is critical, even when a radical excision cannot always be achieved. DATA SOURCES: A PubMed search of relevant articles published up to February 2011 was performed to identify current information about PET liver metastases regarding diagnosis and management, with an emphasis on surgery. RESULTS: The early diagnosis...     

Surgical treatment of liver metastases from pancreatic cancer

Pancreatic cancer is a disease with a poor prognosis. Most patients are diagnosed at an advanced and unresectable stage. Even if the primary cancer is radically removed, postoperative recurrence frequently occurs. Generally, metastatic liver tumors from pancreatic cancer are not indicated for surgical treatment. Here we evaluate the results of performing hepatectomy for liver metastases of pancreatic cancer. In our institute, six patients with liver metastases from pancreatic cancer were treated by partial hepatectomy. Overall 1-, 3- and 5-year survival rates of six patients after hepatectomy were 66.7%, 33.3% and 16.7%, respectively, and one patient was alive for 65.4 months. Performing a hepatectomy for liver metastases of pancreatic cancer, when combined with a pancreas resection, was recently considered to be a safe operation, and one that might offer prolonged survival for highly selected patients with curative resection of liver metastases. In the future, it will be necessary to develop new multi-modality therapies to improve the prognosis of pancreatic cancer.     

Major anatomical hepatic resection with regional lymph node dissection for liver metastases from colorectal cancer

Sixty-four patients with liver metastases from colorectal cancer were studied to clarify the characteristics of the regional spread of liver metastases (secondary invasive factors) and the effects of major anatomical hepatic resection with lymph node dissection on reducing liver recurrence. No secondary invasive factors, i.e., lymph node metastasis, portal or hepatic vein involvement, bile duct involvement, micrometastasis, and direct invasion, were observed in patients with liver metastases less than 3 cm in diameter (5-year survival rate; 100%). Secondary invasive factors were seen in 19.2% of the patients with liver metastases from 3 cm to less than 6 cm (5-year survival rate; 28.7%), and in 45.2% of those with liver metastases 6 cm and over (5-year survival rate; 14.6%). Secondary invasive factors were noted in 45% of the patients with recurrence in the remmant liver. Although 31% of all 64 patients exhibited secondary invasive factors, major anatomical hepatic resection with lymph node dissection achieved a low liver recurrence rate of 31.3%. In conclusion, considering the risks attributed to secondary invasive factors, major anatomical hepatic resection with lymph node dissection is an appropriate surgical procedure for patients with liver metastases exceeding 3 cm in diameter.     

Clinical efficacy analysis and safety evaluation of ultrasonographically guided percutaneous radiofrequency ablation in liver cancers

OBJECTIVE : To assess the clinical efficacy of radiofrequency (RF) ablation in treating liver cancers. The indications, contraindications and side-effects of the technique were also evaluated. METHODS : One hundred and fifty-four patients with liver cancers were treated between May 1999 and July 2000. One hundred and thirty-two cases were hepatocellular carcinomas (HCC) and 22 cases were metastatic liver cancers. The diameter of the cancers ranged from 1.5 to 19.0 cm, with a mean diameter of 7.07 cm. All patients were treated with RF2000TM RF under ultrasonographic guidance and the results and side effects were evaluated. RESULTS : One hundred and fifty-four patients were treated 182 times, with the average number of treatments for each patient being 1.18 and the average number of therapeutic points was 5.74. Symptoms improved after therapy and the levels of α-fetoprotein (AFP) dropped from 1553.68 to 883.70 ng/mL. The AFP level declined in 60.8% of patients, remained unchanged in 32.7% of patients and was elevated in 6.5% of patients. After RF ablation, the size of the tumor was reduced in 87 cases (56.6%), stabilized in 52 cases (33.7%) and enlarged in 15 cases (9.7%). The common side-effects of RF were local pain, fever and leukocytosis; no life-threatening complications were observed. CONCLUSIONS : Percutanous RF ablation of liver cancers is a simple, safe, effective method. It can be curative for small liver cancers but for large liver cancers multiple treatments combined with arterial chemoembolization therapy may be needed to enhance its effectiveness.     

Surgery for liver metastases from breast cancer

Liver metastases develop in approximately half of women with metastatic breast cancer, and are typically associated with metastases at other sites, indicating advanced disease and poor prognosis. Whenever possible, hormonal therapy should be administered, until resistance develops. Several series in the literature have reported a poor effect of chemotherapy alone in patients with metastatic breast cancer, therefore liver surgery could be considered as an adjuvant treatment to systemic therapy in highly selected patients. This study looked at recent case series in the literature, and analysed prognostic factors and indications for surgery.     

Location of liver metastases reflects the site of the primary colorectal carcinoma

Objective. The present study was designed to investigate whether the different venous return of different locations of colorectal carcinomas affects the lobar distribution of metastases to the liver, due to the “streaming” within the portal vein. Material and methods. The site of the primary colorectal carcinoma was divided into the right- and left hemicolon according to the different venous drainage via the superior and the inferior mesenteric/splenic vein. Both groups were analyzed for the distribution of the metastases in the liver. The anatomic site of the liver metastases was detected by intraoperative exploration and differentiated between the two lobes using the Cantlie line. Results. Out of a total of 178 patients, 109 men and 69 women with 264 metastases were eligible for the study. The ratio of metastases in the right and left hemiliver was 3.6:1 for 35 right-sided primary tumors (p=0.002) compared with 2.1:1 for 143 left-sided primary tumors (p=NS). No significant differences were evident for the sub-analysis of involved liver segments. Conclusions. The results of our study support the existence of the “streaming” effect in the portal vein. Right-sided colon carcinomas predominantly involve the right hemiliver, while left-sided colon carcinomas involve the liver homogeneously, considering the size ratio of the right to left liver lobe, which is about 2:1. Knowledge of streaming may help us to understand the spread of abdominal malignancies and may provide a reference concerning the possible primary site depending on metastatic distribution in the liver.     

手术切除与射频消融治疗符合米兰标准的不同肝段多发肝癌的效果分析

目的探讨手术切除与射频消融治疗多发位于不同肝段符合米兰标准肝癌的效果。方法回顾性分析2009年2月-2013年2月在华西医院肝脏外科及肝移植中心行手术切除及射频消融术的多发位于不同肝段的符合米兰标准的158例肝癌患者的临床资料,手术切除110例,射频消融48例。比较两种治疗方法的效果差异。计数资料2组间比较采用χ2检验或Fisher确切检验;计量资料满足正态分布的2组间比较采用t检验,不满足正态分布的2组间比较采用Mann-Whitney U检验;采用Kaplan-Meier分析总体生存率及无瘤生存率,生存率比较采用log-rank检验。采用受试者工作特征曲线(ROC曲线)分析肿瘤分化程度与微脉管侵犯的关系。结果射频消融组患者血红蛋白、Alb较手术切除组低(P值均<0.05),术后住院时间较手术切除组短(P<0.05)。手术切除组与射频消融组患者预后差异无统计学意义(1、3、5年总体生存率分别为94.5%、55.2%、28.8%和83.3%、50.0%、26.5%,χ2=1.161,P=0.281;1、3、5年的无瘤生存率分别为86.4%、42.5%、21.9%和79.2%、37.5%、11.0%,χ2=1.771,P=0.183)。无微脉管侵犯者与有微脉管侵犯的患者预后差异有统计学意义(1、3、5年总体生存率分别为94.6%、59.1%、31.8%和94.1%、33.1%、10.1%,χ2=4.250,P=0.039;1、3、5年无瘤生存率分别为87.1%、48.1%、25.0%和82.4%、17.6%、6.1%,χ2=8.120,P=0.004)。低分化肝癌与非低分化肝癌患者预后差异有统计学意义(1、3、5年总体生存率分别为91.2%、33.7%、4.1%和96.1%、64.5%、39.0%,χ2=19.092,P<0.001;1、3、5年无瘤生存率分别为79.4%、10.3%、3.2%和89.5%、56.6%、31.4%,χ2=25.973,P<0.001)。整块肝肿瘤切除与分开局部切除的1、3、5年总体生存率分别为93.7%、57.7%、29.8%和93.3%、38.9%、23.3%(χ2=1.282,P=0.257),1、3、5年无瘤生存率分别为85.3%、46.0%、23.7%和86.7%、26.7、10.0%(χ2=1.706,P=0.191),二者差异均无统计学意义。手术切除组与射频消融组患者术后并发症无明显差异(χ2=3.088,P=0.079),2组患者在术后30 d内均无死亡。结论对于多发的位于不同肝段的符合米兰标准的肝癌患者,手术切除效果与射频消融效果没有明显差异。在手术切除组,整块切除与分开局部切除的效果无明显差异。肿瘤的微脉管侵犯情况、肿瘤的分化程度对患者的预后存在影响。     

An overview of imaging techniques for liver metastases management

Evaluation of liver metastases is one of the most common indications for liver imaging. Imaging plays a key role in the of assessment liver metastases. A variety of imaging techniques, including ultrasonography, computed tomography, MRI and PET combined with CT scan are available for diagnosis, planning treatment, and follow-up treatment response. In this paper, the authors present the role of imaging for the assessment of liver metastases and the contribution of each of the different imaging techniques for their evaluation and management. Following recent developments in the field of oncology, the authors also present the importance of imaging for the assessment of liver metastases response to therapy. Finally, future perspectives on imaging of liver metastases are presented.     

The role of 18FDG PET/CT in the management of colorectal liver metastases

Introduction

Surgical resection remains the only potentially curative treatment for colorectal liver metastases (CLM). However, involvement of both the hepatic lobes or extrahepatic disease (EHD) can be a contra-indication for resection. The aim of the present study was to examine the addition of combined positron emission and computed tomography (PET/CT) to CLM staging to assess the effects upon staging and management.

Methods

All CLM patients referred to a single centre between January 2005 and January 2009 were prospectively included. All underwent routine staging (clinical examination and computed tomography), followed by a whole body ¹⁸fluoro-deoxy-glucose (¹⁸FDG)-PET/CT scan and Fong clinical risk score calculation.

Results

Sixty-four patients were included [63% male with a median age of 63 years (age range 32–79 years)]. The addition of PET/CT led to disease upstaging in 20 patients (31%) and downstaging in two patients (3%). EHD was found in 24% of low-risk patients (Fong score 0–2) as compared with 44% of high-risk patients (Fong score 3–5) (P = 0.133). There was a trend towards a greater influence upon management in patients with a low score (44% vs. 17%; P = 0.080).

Conclusion

The addition of PET/CT led to management changes in over one-third of patients but there was no correlation between alterations in staging or management and the Fong clinical risk score; suggesting that PET/CT should be utilized, where available, in the pre-operative staging of CLM patients.     

EASL clinical practice guidelines for the management of occupational liver diseases

The Clinical Practice Guidelines (CPG) on Occupational Liver Diseases (OLD) of the European Association for the Study of the Liver (EASL) have been developed to increase awareness, recognition and improve management of patients with OLD. Indeed, although workplace exposure has been associated with virtually the entire spectrum of acute and chronic liver diseases, data on the epidemiology of OLD are scarce. These diseases may be a result of high‐level accidental exposure or prolonged lower level exposure to a variety of chemicals including solvents, pesticides, metals and other agents. While acute liver diseases related to OLD are uncommon and easily recognized, chronic liver diseases are relatively more frequent but often overlooked because of their asymptomatic course and an insidious onset which is often accompanied by comorbidities. Because of the absence of data in observational studies and meta‐analyses or systematic reviews, the evidence and recommendations in these guidelines have been graded according to the Oxford Centre for Evidence‐based Medicine, which assesses evidence according to diagnostic, prevalence, aetiological, prognostic or preventive categories. They can still generate grades of recommendation even when the evidence is inconclusive.     

Long-term survival after surgical management of neuroendocrine hepatic metastases

Background:

Surgical cytoreduction and endocrine blockade are important options for care for neuroendocrine liver metastases. We investigated the long-term survival of patients surgically treated for hepatic neuroendocrine metastases.

Methods:

Patients (n= 172) undergoing operations for neuroendocrine liver metastases from any primary were identified from a prospective liver database. Recorded data and medical record review were used to analyse the type of procedure, length of hospital stay, peri-operative morbidity, tumour recurrence, progression,and survival.

Results:

The median age was 56.8 years (range 11.5–80.7 years). 48.3% of patients were female. Median overall survival was 9.6 years (range 89 days to 22 years). On multivariate analysis, lung/thymic primaries were associated with worse survival [hazard ratio (HR): 15.6, confidence interval (CI): 4.3–56.8, P= 0.002]. Severe post-operative complications were also associated with worse long-term survival (P < 0.001). A positive resection margin status (R1) was not associated with a worse overall survival probability (P∼ 0.8).

Discussion:

Early and aggressive surgical management of hepatic metastases from neuroendocrine tumours is associated with significant long-term survival rates. Radiofrequency ablation is a reasonable option if a lesion is unresectable. R1 resections, unlike many other cancers, are not associated with a worse overall survival.     

The prognostic impact of primary tumor resection in pancreatic neuroendocrine tumors with synchronous multifocal liver metastases

Background

Whether primary tumor resection benefits patients with synchronous multifocal liver metastases from pancreatic neuroendocrine tumors remains controversial. We investigated whether primary tumor resection significantly affects survival in this study.

Two-stage hepatectomy with radioembolization for bilateral colorectal liver metastases: A case report

BACKGROUND Two-stage hepatectomy(TSH) is a well-established surgical technique, used to treat bilateral colorectal liver metastases(CRLM) with a small future liver remnant(FLR). However, in classical TSH, drop-out is reported to be around 25%-40%, due to insufficient FLR increase or progression of disease. Trans-arterial radioembolization(TARE) has been described to control locally tumor growth of liver malignancies such as hepatocellular carcinoma, but it has been also reported to induce a certain degree of contralateral liver hypertrophy, even if at a lower rate compared to portal vein embolization or ligation.CASE SUMMARY Herein we report the case of a 75-year-old female patient, where TSH and TARE were combined to treat bilateral CRLM. According to computed tomography(CT)-scan, the patient had a hepatic lesion in segment VI-VII and two other confluent lesions in segment II-III. Therefore, one-stage posterior right sectionectomy plus left lateral sectionectomy(LLS) was planned. The liver volumetry estimated a FLR of 38%(segments I-IV-V-VIII). However, due to a more than initially planned, extended right resection, simultaneous LLS was not performed and the patient underwent selective TARE to segments II-III after the first surgery. The CT-scan performed after TARE showed a reduction of the treated lesion and a FLR increase of 55%. Carcinoembryonic antigen and CA 19.9 decreased significantly. Nearly three months later after the first surgery, LLS was performed and the patient was discharged without any postoperative complications.CONCLUSION According to this specific experience, TARE was used to induce liver hypertrophy and simultaneously control cancer progression in TSH settings for bilateral CRLM.     

Contrast-enhanced intraoperative ultrasound improves detection of liver metastases during surgery for primary colorectal cancer

Background:

Computed tomography (CT) is the most common staging investigation in colorectal cancer (CRC). Up to 25% of patients are found to have previously undetected hepatic lesions when intraoperative ultrasound (IOUS) of the liver is used during CRC resection. We aimed to assess the ability of IOUS to detect additional liver lesions/metastases at primary colorectal resection, and to evaluate whether contrast-enhanced IOUS (CE-IOUS) improves the detection and characterization of hepatic lesions.

Methods:

We performed a single-centre, prospective pilot study. At CRC resection, patients underwent IOUS of the liver. Contrast-enhanced IOUS of the liver was undertaken using i.v. sulphur hexafluoride micro-bubbles (SonoVue®, 4.8 ml). Findings of CT, non-enhanced IOUS and CE-IOUS were compared. Changes in staging or management were noted. Additional lesions were corroborated with iron oxide magnetic resonance imaging (MRI).

Results:

Among 21 patients, IOUS demonstrated additional lesions in seven (33%). Contrast altered the diagnosis of non-enhanced IOUS in four (20%) and changed the management strategy in three (14%) patients. Thus, IOUS in combination with the contrast agent altered the intraoperative or postoperative management plan in four patients.

Conclusions:

In the first study of its kind, early results suggest that the ability of IOUS to detect additional metastases is improved by CE-IOUS, and that this may impact on surgical staging and management.     

Outcomes in patients with indeterminate pulmonary nodules undergoing resection for colorectal liver metastases

Objectives

This study aimed to assess outcomes in patients who underwent hepatic resection for colorectal liver metastases (CRLM) with subcentimetre indeterminate pulmonary nodules (IPN) and to devise a management pathway for these patients.

Methods

Patients undergoing CRLM resection from January 2006 to December 2010 were included. Survival differences following liver resection in patients with and without IPN were determined.

Results

A total of 184 patients were included, 30 of whom had IPN. There were no significant differences between the IPN and non-IPN groups in terms of demographics, surgery and pathological factors. There were no significant differences between patients with and without IPN with respect to disease-free (P = 0.190) and overall (P = 0.710) survival. Fifteen patients with IPN progressed to metastatic lung disease over a median period of 10 months (range: 3–18 months); six of these patients underwent lung resection. Of the remaining 15 patients with IPN, eight showed no IPN progression and subsequent CT scans did not identify IPN in the remaining seven.

Conclusions

Colorectal liver metastases patients with IPN who have resectable disease should be treated with liver resection and should be subject to intensive surveillance post-resection. Although 50% of these patients will progress to develop lung metastases, this does not appear to influence survival following liver resection.     

CalliSpheres drug-eluting beads transarterial-chemoembolization in the treatment of liver metastases from breast cancer: Initial experience in 14 patients

Breast cancer patients with liver metastases are associated with high mortality. However, no standardized treatment approach is available for these patients who have undergone chemotherapy and hormonal therapy. We aimed to assess the clinical outcomes of patients with breast cancer liver metastases (BCLM) who underwent drug-eluting beads used for transarterial-chemoembolization (DEB-TACE).We retrospectively enrolled 14 patients with 39 lesions who underwent DEB-TACE for liver metastases following mastectomy for primary breast cancer. The incidence of complications, overall survival (OS), and local tumor progression-free survival (PFS) were assessed.A total of 14 patients with 39 liver metastases were treated with DEB-TACE from July 2017 to July 2020. The objective response rates (ORR) and disease control rates (DCR) were 71.4% and 92.8% at the 3-month period and 50% and 71.4% at the 6-month period, respectively. During the follow-up period the local tumor PFS was 8.0 months. The median OS was 20.0 months (range, 8–40 months) and the 1-, 2-year OS rates were 84.4% and 47.4%, respectively. No severe complications caused by this technique were detected.DEB-TACE for BCLM was characterized as a low trauma technique, with a limited number of complications. The results indicated that this method was safe and effective for patients with BCLM and could be widely adopted as a palliative treatment in clinical practice.