Liver-directed therapies in liver metastases from neuroendocrine tumors of the gastrointestinal tract

Presence of liver metastases in neuroendocrine tumors is a major factor altering both quality of life and prognosis. Surgery is recognized as the sole curative treatment. When it is not possible, radiological directed therapies are crucial, particularly in liver metastases from the small bowel. Thermal ablative therapies as radiofrequency ablation and microwave are alternative treatments alone or in combination with surgery. Hepatic artery embolization or chemoembolization, as radioembolization, has been shown to have good clinical, biochemical, and morphological responses when liver burden does not permit ablative therapies. However, technical issues are multiple and there is no randomized study to compare their efficacy. The choice of management depends on liver burden and metastases pattern, but also on origin of the primary tumor, tumor differentiation, and tumor proliferative activity. These patients should benefit of a multidisciplinary management to limit morbidity and mortality.     

Liver-directed therapies in colorectal cancer

Colorectal cancer is the third leading cause of cancer-related deaths in the United States. Historically, the majority of patients that presented with metastatic disease to the liver were treated with systemic chemotherapy only but advances in imaging, surgical techniques, and non-resectional approaches have expanded the indications for liver-directed interventions. Current approaches used in patients with liver-only or liver-dominant metastatic disease include surgical resection, direct tumor ablation strategies, the use of intra-arterial infusions, and radiation therapies. The use of these liver-directed therapies in selected patients with colorectal liver metastases has led to significant improvements in overall survival. We review the clinical data and progress using liver-directed therapies in the treatment of colorectal liver metastases.     

Liver-directed therapies in colorectal cancer

The liver is the most common site of metastatic colorectal cancer (CRC) and the status of this organ is an important determinant of overall survival in patients with advanced disease. Complete resection of hepatic CRC metastases can provide a long-term cure for some patients, but the majority of liver metastases are not amenable to such surgery. Furthermore, most patients after curative resection ultimately suffer from recurrence, and the majority of such failures occur in the liver. Various ablative techniques can achieve local control of tumor after incomplete resection or for palliation. Tumor ablation currently has a secondary therapeutic role, as there is no evidence that it can achieve long-term survival comparable to surgical resection. Regional chemotherapy delivers tumoricidal agents in a selective fashion, minimizing systemic toxicity and damage to normal liver cells. Chemotherapy agents delivered through the hepatic artery can extend time to liver recurrence after curative resection and may prolong survival both in the adjuvant setting and when given to patients with unresectable disease. Molecular-based therapies, such as gene delivery and oncolytic viruses, provide promise for curative outcomes in patients with advanced disease.     

Liver-directed therapies in metastatic colorectal cancer

Colorectal cancer (CRC) is a major health concern in the United States (US) with over 140,000 new cases diagnosed in 2012. The most common site for CRC metastases is the liver. Hepatic resection is the treatment of choice for colorectal liver metastases (CLM), with a 5-year survival rate ranging from 35% to 58%. Unfortunately, only about 20% of patients are eligible for resection. There are a number of options for extending resection to more advanced patients including systemic chemotherapy, portal vein embolization (PVE), two stage hepatectomy, ablation and hepatic artery infusion (HAI). There are few phase III trials comparing these treatment modalities, and choosing the right treatment is patient dependent. Treating hepatic metastases requires a multidisciplinary approach and knowledge of all treatment options as there continues to be advances in management of CLM. If a patient can undergo a treatment modality in order to increase their potential for future resection this should be the primary goal. If the patient is still deemed unresectable then treatments that lengthen disease-free and overall-survival should be pursued. These include chemotherapy, ablation, HAI, chemoembolization, radioembolization (RE) and stereotactic radiotherapy.     

Liver-directed therapies in patients with advanced neuroendocrine tumors

Neuroendocrine tumors (NETs) are increasing in incidence. Incidental NETs that may have little clinical significance, such as gastric and rectal primaries, are often identified because of increased screening efforts and advanced imaging modalities. Although NETs are biologically indolent cancers, many patients present with incurable metastatic disease to the liver at initial diagnosis. Some literature suggests a delay averaging almost 5 years in making the correct diagnosis based on clinical symptoms. Although surgical resection offers the only potentially curative therapy, liver-directed therapies, such as embolization and ablation, offer effective alternatives to control symptoms and potentially impact overall survival. This article reviews the latest liver-directed approaches to the management of advanced NETs.     

Liver-directed therapies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. This disease can be treated through several surgical and nonsurgical approaches. Although the only curative options for patients with HCC are surgical (resection or transplantation), most patients unfortunately present with advanced neoplastic disease or experience the effects of chronic liver disease, making surgical resection implausible. Several additional options are available for treating this population. Ablative therapies such as percutaneous ethanol injection, cryotherapy, radiofrequency ablation, laser ablation, and microwave hyperthermic ablation can be used with varying degrees of success. Transarterial chemoembolization can be used in patients with advanced disease or advanced chronic liver disease that cannot be treated with resection or ablation. This article explores the various liver-directed therapies, including surgical resection, and defines morbidity, mortality, and survival for each.     

Liver-directed therapies for metastatic neuroendocrine tumors

Neuroendocrine tumors, despite being indolent, frequently cause significant morbidity and mortality from hepatic metastatic lesions. It is possible to directly target these liver lesions with embolization/chemoembolization, radiofrequency ablation, or other therapies. The observational studies that exist seem to indicate a prolongation of survival. Liver-directed therapies are also able to decrease symptoms in most patients. The value of these therapeutic interventions therefore lies mainly in their palliative capabilities. Coupled with aggressive use of octreotide, local ablative techniques may frequently control symptoms of hormone excess and tumor bulk. Because of the possible adverse effects of these interventions, however, careful patient selection is essential to minimize the morbidity and mortality of the procedures.     

Techniques and therapies for primary and metastatic liver cancer

In summary, of the 460 patients of primary carcinoma of the liver admitted to the University Surgical Unit at the Queen Mary Hospital over a period of 12 years, more than 40% could not be treated, and only 91 of the patients were candidates for curative resection. The cure rate is very small; a1-to 2-year survival was obtained in 46% of 15 resections. From 1964 to 1969, out of 22-patients with resections, 3 are still alive more than 5 years after the operation. Lin³⁰ reported a 19.1% 5-year survival.When the hepatoma has ruptured and bleeding takes place, surgical treatment is obligatory to control the hemorrhage.Ninety-eight patients underwent a clinical trial of 5 categories: hepatic dearterialization, hepatic arterial cannulation and infusion of 5-FU, hepatic arterial ligation and portal venous infusion of 5-FU, radiotherapy and no treatment. The results show that the advantage of each form of treatment when compared with no treatment is marginal. Thus, a gloomy picture of primary hepatoma is held.Since the operative mortality of hepatic resection for a solitary secondary carcinoma of the liver is negligible, it should be done in each instance because a long-term survival may be possible. This is especially true with primary carcinoma of the colon.     

Locally ablative therapies for primary and metastatic liver cancer

Locally ablative therapies have an increasing role in the effective multidisciplinary approach towards the treatment of both primary and metastatic liver tumors. In patients who are not considered surgical candidates and have low volume disease, these therapies have now become established into consensus practice guidelines. A large range of therapeutic options exist including percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation, percutaneous laser ablation (PLA), irreversible electroporation (IRE), stereotactic body radiation therapy (SBRT) and high intensity focused ultrasound (HIFU); each having benefits and drawbacks. The greatest body of evidence supporting clinical utility in the liver currently exists for RFA, with PEI having fallen out of favor. MWA, IRE, SBRT and HIFU are relatively nascent technologies, and outcomes data supporting their use is promising. Future directions of ablative therapies include tandem approaches to improve efficacy in the treatment of liver tumors.     

Non-operative therapies for colorectal liver metastases

Locoregional therapies for colorectal liver metastases complement systemic therapy by providing an opportunity for local control of hepatic spread. The armamentarium for liver-directed therapy includes ablative therapies, embolization, and stereotactic body radiation therapy. At this time, prospective studies comparing these modalities are limited and decision-making relies on a multidisciplinary approach for optimal patient management. Herein, we describe multiple therapeutic non-surgical procedures and an overview of the results of these treatments.     

Ablative therapies for colorectal liver metastases

Ablative therapies remain a useful adjunct in the multidisciplinary treatment of patients with colorectal liver metastases not amenable to hepatic resection. This review summarizes the rationale, underlying mechanisms, techniques, complications, and outcomes of current and emerging ablative modalities.     

结直肠癌肝转移的术前化疗

结直肠癌在西方国家占肿瘤患者死亡的第2位,发病率为56.1/10万。我国结直肠癌发病率约为20.6/10万,占肿瘤患者死亡的第5位。Parkin等[1]报道,2002年,全世界新诊断结直肠癌为l 020 000例,占发病率第3位,死亡529 000例,占死亡率第4位。     

Prognostic factors for patients with hepatic metastases from breast cancer

Median survival from liver metastases secondary to breast cancer is only a few months, with very rare 5-year survival. This study reviewed 145 patients with liver metastases from breast cancer to determine factors that may influence survival. Data were analysed using Kaplan-Meier survival curves, univariate and multivariate analysis. Median survival was 4.23 months (range 0.16-51), with a 27.6% 1-year survival. Factors that significantly predicted a poor prognosis on univariate analysis included symptomatic liver disease, deranged liver function tests, the presence of ascites, histological grade 3 disease at primary presentation, advanced age, oestrogen receptor (ER) negative tumours, carcinoembryonic antigen of over 1000 ng ml(-1) and multiple vs single liver metastases. Response to treatment was also a significant predictor of survival with patients responding to chemo- or endocrine therapy surviving for a median of 13 and 13.9 months, respectively. Multivariate analysis of pretreatment variables identified a low albumin, advanced age and ER negativity as independent predictors of poor survival. The time interval between primary and metastatic disease, metastases at extrahepatic sites, histological subtype and nodal stage at primary presentation did not predict prognosis. Awareness of the prognostic implications of the above factors may assist in selecting the most appropriate treatment for these patients.British Journal of Cancer (2003) 89, 284-290. doi:10.1038/sj.bjc.6601038 www.bjcancer.com     

原发性肝癌综合介入治疗的疗效分析

目的探讨原发性肝癌综合介入治疗的疗效。方法回顾性分析1126例原发性肝癌患者手术前后行经导管肝动脉化疗栓塞术(TACE)、TACE后射频消融(RFA)治疗、TACE或经导管肝动脉化疗灌注治疗(TAI)后辅以中药和生物治疗的临床资料,分析患者肝功能、肿瘤标志物、癌灶影像资料和生存率等,比较各种综合介入治疗的价值。结果全组患者1、3、5年生存率分别为67.8%、28.7%和18.8%。其中术前TACE组1、3、5年生存率分别为74.7%、41.4%和36.9%,术后TACE组1、3、5年生存率分别为78.9%、40.4%和37.5%;TACE RFA组的近期有效率为93.4%,1、3年生存率分别为74.5%和36.8%;TACE组的近期有效率为83.2%,1、3、5年生存率分别为69.3%、21.7%和8.4%;TAI治疗的近期有效率为27.5%,1、3年生存率分别为11.6%和0。TACE RFA组和TACE组间肝功能Child降级、瘤内与瘤周血流信号消失和甲胎蛋白转阴率差异均无统计学意义,TACE RFA组、TACE组与TAI组肝功能Child降级差异无统计学意义。结论原发性肝癌手术切除前后TACE效果最佳,手术前与手术后行TACE疗效相近;TACE RFA疗效优于TACE;TAI疗效较差。     

结直肠癌肝转移经肝动脉栓塞及持续灌注化疗的临床疗效

背景与目的：结直肠癌肝转移患者经肝动脉介入栓塞或静脉持续滴注化疗药物,治疗效果有所提高,但尚存肿瘤局部化疗药物浓度不够高,化疗药物对肿瘤细胞的杀伤力不够强,晚期结肠直肠癌的治疗效果仍然不够好的缺陷。本文将动脉介入与持续灌注化疗药物两种方法相结合,观察结直肠癌肝转移患者经肝动脉介入栓塞或持续灌注化疗的临床疗效。方法：对26例结直肠癌肝转移患者经肝动脉介入治疗93次,单用肝动脉持续灌注化疗42次,肝动脉介入栓塞联合持续灌注化疗51次。化疗药物选用阿霉素（ADM）、顺铂（DDP）、丝裂霉素（MMC）、醛氢叶酸（CF）和5-氟尿嘧啶（5-FU）。先将ADM30mg/m^2和MMC6mg/m^2加入超液化碘油10-30ml中进行肝动脉灌注栓塞,然后留置导管进行持续动脉滴注。方案为CF200mg/m^2,d1-3,静脉滴注;DDP80mg/m^2d1,如肾功能改变则改用Vp-1660mg/m^2,d1-3,应用电动输液泵动脉滴注;5-FU2500mg/m^2,采用便携式输液泵将5-FU持续动脉滴注72h。结果：近期疗效以实体瘤疗效评价标准评价,CR1例,CR率3.85%;PR14例,PR率53.84%,总有效率为57.69%。本组0.5、1、2、3和5年生存率分别为92.31%、76.92%、38.46%、23.07%和3.85%,肝转移后中位生存期为11.5个月。全组病人出现的不良反应主要有肝功能损害、胃肠道反应和骨髓抑制,经护肝、制酸、止呕、水化和应用升白细胞药物对症治疗后可缓解。结论：经肝动脉持续灌注化疗及栓塞是治疗结直肠癌肝转移瘤的较好方法,能提高治疗效果。     

Clinical trial of prophylactic hepatic arterial chemotherapy for liver metastases in patients with Dukes' C colorectal cancer

Preliminary results of a prospective non-randomized trial of prophylactic hepatic arterial chemotherapy for liver metastases from colorectal cancer are presented. Twenty-two colorectal cancer patients (infusion group) in Dukes' C stage were given hepatic arterial infusion of 5-FU (500 mg/body for 1 hr per week, repeated 50 times) and peroral UFT-E (2.0 g/body, daily). Informed consent was obtained from all patients. Adverse effects and postoperative recurrence in the infusion group were compared with those of patients with UFT-E alone (control group). Complications related to hepatic arterial infusion in the infusion group were also demonstrated. There was no adverse effect in the control group, while diarrhea (grade 1) developed in one patient (5%) and pigmentation in five (24%) in the infusion group. Complications related to infusion were found in five patients (5%). Three patients in the infusion group presented with metachronous hepatic lesions, two of which were resected successfully. In the control group, one patient died of marked hepatic metastases, and one developed ovarian metastasis with lymph node involvement. Our regimen appears hematologically safe, however, the high frequency of pigmentation should be kept in mind. The oncological benefit of this chemotherapy would be clarified by a larger series of cases and longer follow-up.