Hepatic artery infusion in the treatment of colorectal cancer metastases

The most common site of metastasis from colorectal carcinoma is the liver. Surgical resection of hepatic metastases can result in long-term survival. The majority of patients have unresectable disease, however, and even if hepatic metastases are resected, most patients will still experience relapse, often in the liver. Hepatic arterial infusion (HAI) of chemotherapy allows high concentrations of a drug to be delivered directly to hepatic metastases with minimal systemic toxicity. HAI therapy has been used to treat unresectable isolated hepatic metastases of colorectal cancer and has also been investigated as adjuvant therapy after resection. This review examines the role of HAI as therapy for both unresectable and resectable hepatic metastases.     

The role of aggressive regional therapy for colorectal liver metastases

Surgical resection is the most effective treatment modality for liver metastases from colorectal cancer. However, most patients with liver metastases are not candidates for resection due to extensive intrahepatic disease. Approximately one-half of the patients who are able to undergo resection will eventually recur within the remnant liver. Hepatic arterial infusion (HAI) chemotherapy takes advantage of the arterial blood supply of colorectal liver metastases to increase tumor exposure to chemotherapy while minimizing systemic toxicity. HAI chemotherapy has been utilized in patients with unresectable disease in the neoadjuvant setting in an effort to convert them to resectability as well as in patients with resectable disease in the adjuvant setting in an effort to prevent recurrence. This article reviews the roles of HAI chemotherapy in an aggressive approach toward colorectal liver metastases.     

Phase I/II study of hepatic arterial therapy with floxuridine and dexamethasone in combination with intravenous irinotecan as adjuvant treatment after resection of hepatic metastases from colorectal cancer.

PURPOSE: Patients who undergo resection of liver metastases from colorectal cancer have an average 2-year survival of 65%. With hepatic arterial infusion (HAI) plus systemic fluorouracil and leucovorin, 2-year survival increased to 86%. For further improvement in both local and systemic control, combinations of new systemic drugs with HAI are being explored. The purpose of this study was to determine the maximum-tolerated dose (MTD) of systemic irinotecan (CPT-11) and HAI floxuridine (FUDR) plus dexamethasone (DEX) as combination adjuvant therapy after liver resection. PATIENTS AND METHODS: Ninety-six patients who underwent complete resection of liver metastases from colorectal cancer were treated with six monthly cycles of HAI FUDR plus DEX for 14 days of each 4-week cycle plus escalating doses of systemic CPT-11. The primary end points of the phase I/II study were the MTD and efficacy of this regimen. RESULTS: The MTD for combined systemic CPT-11 and HAI FUDR was CPT-11 at 200 mg/m2 every other week and FUDR at 0.12 mg/kg x pump volume / pump flow rate. The dose-limiting toxicities were diarrhea and neutropenia. With a median follow-up time of 26 months, the 2-year survival rate is 89%. All of the 27 patients who were treated at the MTD are alive. CONCLUSION: In patients who undergo resection of liver metastases from colorectal cancer, adding systemic CPT-11 to HAI therapy in an adjuvant regimen is feasible. This regimen seems to have comparable activity to fluorouracil and leucovorin, but further studies are needed to assess whether it improves local control or decreases extrahepatic recurrences.     

Extent of hepatic resection does not correlate with toxicity following adjuvant chemotherapy

BACKGROUND: In patients with liver metastases from colorectal cancer, survival can be increased by hepatic resection. Treatment with hepatic arterial infusion (HAI) and systemic chemotherapy following resection may further increase survival and decrease recurrence, but may also result in hepatic and systemic toxicity. This article will address the question of whether large hepatic resections resulting in a greater loss of healthy liver predisposes patients to developing toxicity from the subsequent chemotherapeutic regimens. DESIGN: Retrospective analysis of 88 patients who underwent liver resection of colorectal metastases followed by adjuvant HAI and systemic chemotherapy and whose computerized tomography (CT) scans were done at Memorial Sloan-Kettering Cancer Center (MSKCC). Liver volumes were calculated from CT scans and used to determine the percentage change in healthy liver volume between the pre- and post-operative CT scans. Hepatic and systemic toxicities were defined according to the Common Toxicity Criteria of the National Cancer Institute. RESULTS: Patients experienced a mean percentage decrease in healthy liver tissue of 17% (range: 57% decrease to 32% increase) at an estimated 1 month after resection and at the initiation of chemotherapy. In a logistic regression model using percentage change in the healthy liver volume as a continuous variable, no significant association was revealed between percentage of healthy liver resected and diarrhea (P = 0.47), leukopenia (P = 0.37), neutropenia (P = 0.31), high bilirubin (P = 0.27), or alkaline phosphatase (P = 0.79). CONCLUSIONS: A greater loss of healthy liver following resection of hepatic metastases from colorectal cancer does not seem to predispose to the development of toxicity from adjuvant HAI and systemic chemotherapy.     

A phase II study of radiofrequency ablation of unresectable metastatic colorectal cancer with hepatic arterial infusion pump chemotherapy

BACKGROUND: Adjuvant hepatic arterial infusion (HAI) chemotherapy has been demonstrated to improve disease-free survival for colorectal cancer liver metastases. It is unclear if this improvement can be extrapolated to unresectable liver metastases that undergo RFA. The aim of this study was to evaluate the combination of RFA and HAI chemotherapy for unresectable liver metastases. METHODS: Phase II study was conducted from November 2000 to July 2003 evaluating the use of complete extirpation by RFA, or resection/ablation with adjuvant HAI consisting of FUDR for 6 months. RESULTS: Twenty-one patients had successful resection and/or RFA with HAI pump, which included treatment for 100 liver metastases (22 resected, 78 ablated; mean 4.8 tumors/patient). Four of 21 patients completed the full 6-month course of HAI. Six of these patients had 12 adverse events related to HAIP, most commonly elevated liver enzymes. After a median follow-up of 24 months, the median liver specific disease-free and overall survival rates for the entire group were 17 and 30 months, respectively. CONCLUSIONS: Given the complications and toxicity associated with HAI pump chemotherapy, adjuvant HAI chemotherapy after RFA of liver metastases may not be warranted as a first line treatment option.     

Evaluation of prophylactic hepatic arterial infusion chemotherapy after curative hepatectomy for metastatic colorectal cancer

We evaluated the effect of hepatic arterial infusion (HAI) chemotherapy after curative resection of liver metastases of colorectal cancer. A total of 161 patients underwent curative resection of liver metastases. Among them, 50 patients underwent HAI of 5-FU, and 111 patients had no HAI therapy. The 50% disease-free survival time (50% DFS) was 758 days and 342 days in the HAI group and the non-HAI group (logrank test, p<0.01), and the 50% overall survival time (50% OS) was 978 days versus 730 days (p<0.05), respectively. Among the 71 patients with multiple resectable metastases (H2 or H3), the HAI group had a significantly superior 50% DFS. HAI therapy seems to be an effective form of adjuvant chemotherapy after hepatic resection of metastatic colorectal cancer.     

Regional chemotherapy for liver-limited metastatic colorectal cancer

This review examines the development of hepatic arterial infusion (HAI) of chemotherapy over the past 40 years. Liver metastases are mainly supplied by the hepatic artery, and high levels of intratumoral drug delivery are achievable with the use of HAI. Floxuridine, 5-fluorodeoxyuridine is commonly used, but intra-arterial oxaliplatin and mitomycin- C also have advantages. The dramatic responses observed with HAI plus systemic therapy offer the possibility of resection and cure in select patients. Resectability of liver-limited colorectal cancer metastases should be considered as an endpoint for all patients. Hepatic arterial infusion may be used in palliative, neoadjuvant, and adjuvant settings. Herein, combinations of systemic chemotherapy with HAI are discussed, along with the role of newer cytotoxic and biologic agents. The first-pass extraction of some drugs given by regional perfusion in the liver limits systemic side effects. Toxicity includes catheter-related complications and biliary and gastrointestinal ulcers. The role of HAI therapy for the treatment of unresectable and resectable disease, as well as the use of other regional strategies such as embolization and ablation, are discussed.     

198例结直肠癌肝转移患者外科治疗的疗效分析

背景与目的:肝脏是结直肠癌常见的转移部位,35%的患者在确诊时已发生肝转移,肝转移患者的预后较差。尽管手术切除、化疗、射频消融术、介入治疗等手段应用于临床,但治疗效果不同。本研究探讨结直肠癌肝转移外科治疗的临床疗效。方法:对我院5年间经病理检查证实的198例结直肠癌肝转移患者的临床资料进行回顾性分析。根据治疗方法的不同进行分组:根治性切除组46例(23.2%)、姑息性切除组43例(21.7%)、手术探查组或最佳支持治疗组29例(14.6%)、肝动脉置泵化疗组41例(20.7%),全身化疗组39例(19.7%);对其生存期进行比较和统计学分析。结果:根治性切除组中位生存期37.1个月,5年生存率为31.2%;姑息性切除组的中位生存期14.3个月,5年生存率为0;肝动脉置泵化疗组的中位生存期21.3个月,5年生存期为7.5%;全身性化疗和探查组或最佳支持治疗组的中位生存期分别为18.7个月、6.3个月,均无5年生存者。根治性切除组与其他组比较,中位生存期有统计学意义(P<0.01)。结论:根治性切除是提高结直肠癌肝转移患者生存率的重要手段;姑息性切除治疗效果并不优于辅助性治疗,对于不能根治性切除的病例可采用肝动脉置泵化疗。     

肝动脉灌注在结直肠癌肝转移治疗中的应用现状及前景

结直肠癌（colorectal cancer ，CRC ）是中国最常见的恶性肿瘤之一，肝转移是其主要的转移模式及治疗关键。相对于全身化疗，肝动脉灌注（hepatic arterial infusion，HAI）给药方式可使肝脏局部药物浓度升高，而外周血液中药物浓度较低，全身不良反应相对较低。HAI 化疗在肠癌肝转移的转化化疗、肝切除术后辅助化疗以及肠癌根治性切除术后的肝转移预防方面显示出一定的应用前景。本文就HAI 在肠癌肝转移的治疗现状及前景做一综述。      

肝动脉药盒灌注氟脲苷联合全身化疗治疗不可切除老年结直肠癌肝转移

目的 探讨经肝动脉药盒灌注（HAI）氟脲苷（FUDR）联合全身化疗治疗不可切除老年结直肠癌肝转移患者的疗效及安全性.方法 对18例不可手术切除的老年结直肠癌肝转移回顾性分析.所有患者采用一种改进的介入方法植入肝动脉药盒,术后第2天开始接受HAI FUDR联合全身化疗.对治疗疗效、毒副反应及随访结果进行分析.结果 18例患者的总有效率为94.4%,其中完全缓解1例（5.6%）,部分缓解16例（88.9%）,疾病进展1例（5.6%）.8例患者转化为可手术切除,转化率为44.4%.中位无进展生存时间为26.0个月,中位总生存时间为30.2个月.结论 HAI FUDR联合全身化疗是治疗不可切除老年结直肠癌肝转移的一种安全有效的方法,可获得较高的手术切除率.     

Hepatic artery chemotherapy for colorectal liver metastases: technical considerations and review of clinical trials

Hepatic artery infusion (HAI) of chemotherapeutic agents for colorectal hepatic metastases is associated with significantly higher response rates compared to systemic chemotherapy. However, response rates have not consistently translated into improved survival. Several randomized trials have evaluated the implantable pump for treating unresectable colorectal hepatic metastases. Meta-analysis of these studies have demonstrated an improved survival advantage with pump therapy as well as improved quality of life. Recent studies of HAI of chemotherapy as adjuvant therapy following liver metastases resection have also demonstrated a potential survival advantage. Toxicities of HAI can be treatment limiting, but measures have emerged for overcoming these side effects. These randomized clinical trials have established HAI as a reasonable therapeutic option in patients with unresectable disease, and as adjuvant therapy in patients with resectable disease.     

An update on hepatic arterial infusion chemotherapy for colorectal cancer

Hepatic metastases are a frequent complication of colorectal cancer (CRC), affecting over half of all CRC patients. Resection of isolated metastases can result in long-term survival, but the majority of patients relapse, and most have unresectable disease. Hepatic arterial infusion (HAI) chemotherapy delivers high concentrations of cytotoxic agents directly to liver metastases with minimal systemic toxicities. Advances in surgical techniques, development of fully implantable pumps, and modification of drug regimens have decreased complications and improved patient tolerability. Randomized trials comparing HAI with systemic chemotherapy have demonstrated superior response rates and times to hepatic progression for unresectable disease, and have shown better times to progression and overall survival rates in the adjuvant setting following hepatic resection. HAI chemotherapy has unique toxicities, including chemical hepatitis and biliary sclerosis, which can be mitigated by the addition of dexamethasone to therapy. In an attempt to prevent extrahepatic progression, combinations of HAI with systemic chemotherapy, including newer agents such as irinotecan and oxaliplatin, are currently being investigated, with promising early results.     

Regional chemotherapy: a focus on hepatic artery infusion for colorectal cancer liver metastases

Regional infusion strategies have been used as a treatment modality in multiple cancers, including ovarian, appendiceal, and colorectal cancers. Perhaps the most illustrative use of regional therapy is that of hepatic arterial infusion (HAI) for liver metastases from colorectal cancer. The administration of chemotherapy by HAI is logical and has theoretic advantages over systemic chemotherapy for the treatment of hepatic metastases from colorectal cancer. With the use of an appropriately chosen chemotherapy agent, HAI can generate an increase in hepatic tumor drug exposure as compared with intravenous delivery of the same agent. This article reviews the pharmacologic benefits of HAI therapy and the contemporary trials performed and underway.     

Hepatic arterial infusion and systemic chemotherapy after multiple metastasectomy in patients with colorectal carcinoma metastatic to the liver: a North Central Cancer Treatment Group (NCCTG) phase II study, 92-46-52

BackgroundPatients with multiple liver metastases from colorectal cancer are at high risk of recurrence after resection. Hepatic artery infusion (HAI) alternating with systemic therapy after surgical resection may improve survival after surgery.MethodsPatients with liver-only metastases from colorectal cancer amenable to resection/cryoablation were eligible. Previous adjuvant chemotherapy for a completely resected primary tumor was allowed. Alternating courses of HAI and systemic therapy included floxuridine (FUDR) by HAI. Systemic chemotherapy consisted of bolus leucovorin (LV) plus 5-fluorouracil (5-FU).ResultsForty-nine patients had complete resection of their liver metastases, with 44% having more than 4 hepatic metastases and 78% having bilobar disease. Thirty-six patients had HAI FUDR alternating with systemic therapy. Patients received a median of 3.5 cycles (range, 1-4) and 3 cycles (range, 0-6) of therapy with HAI FUDR and systemic therapy, respectively. At the time of final analysis the estimated median disease-free survival and hepatic disease-free survival was 1.2 years (95% confidence interval [CI], 0.9-2.1) and 1.8 years (95% CI, 1.8-not available), respectively. Eleven patients (31%) were alive at this writing. All surviving patients had a minimum of 5.5 years of follow-up.ConclusionThis trial of adjuvant chemotherapy in patients who underwent complete resection with unfavorable characteristics demonstrates apparent improvement in outcome compared with historical series treated with surgery alone. However the results of this trial and other randomized trials of HAI do not appear to support its use at this time because of the development of more effective systemic options.     

Role of intra-arterial hepatic chemotherapy in the treatment of colorectal cancer metastases

Hepatic metastases are common with colorectal cancer. The primary blood supply to hepatic metastases is the hepatic artery. Regional chemotherapy utilizing the hepatic artery is one treatment option for liver metastases. The advantage of hepatic arterial chemotherapy is that high concentrations of the therapeutic drug are obtained in the liver with minimal systemic toxicity. Recently, systemic chemotherapy regimens have been added to hepatic arterial infusional chemotherapy to treat hepatic metastases. Due to the high response rates in the liver, resection rates are increasing in patients originally thought to have unresectable liver disease. Hepatic arterial chemotherapy has also been used in the adjuvant setting after resection of all liver metastases in order to minimize hepatic recurrences. The role of hepatic arterial infusional therapy in treating hepatic colorectal metastases includes treating patients with both resectable and unresectable metastases in the adjuvant, neoadjuvant, or palliative settings.     

Combined chemotherapy with oral leucovorin (LV) + tegafur/uracil (UFT) and hepatic arterial infusion (HAI) therapy for liver metastasis of colorectal cancer

The liver is the most frequent metastatic site from colorectal cancer, and the control of liver metastasis is an important issue in the treatment of progressive colorectal cancer. Hepatic arterial infusion (HAI) therapy can achieve a high drug concentration in the liver and relatively low level in the systemic circulation because of the first pass effect of the drug metabolism. With the high response rate, several reports have failed to show a significant survival benefit of HAI monotherapy, partially due to its inability to control extrahepatic metastasis. In this report, we used oral tegafur/uracil (UFT) and Leucovorin (LV) combined with HAI of 5-FU for four patients with liver metastasis of colorectal carcinoma. One of two patients with unresectable multiple hepatic metastases could undergo resectional surgery after 5 courses of this therapy. Two other cases in an adjuvant setting have been surviving free of tumors. In this series, adverse effects of this therapy were acceptable, including one case of grade 3 thrombocytopenia. The benefit of this combined therapy for survival in a case of liver metastasis from CRC remains to be evaluated. We are planning phase I and II clinical studies to evaluate the efficiency and feasibility of this combination therapy.     

Hepatic arterial infusion chemotherapy for colorectal liver metastases

Hepatic metastases are a frequent complication of colorectal cancer. Resection of liver metastases can result in long-term survival. However, the majority of patients have unresectable disease. Alternative methods in Japan for treating these patients are hepatic arterial infusion (HAI) chemotherapy with administration of 1,000 mg/m2 of 5-FU over 5 hours. We summarize the status of HAI chemotherapy in terms of colorectal hepatic metastases today. HAI chemotherapy produced higher response rates compared with systemic chemotherapy, but did not demonstrate elongation of survival time in many trials. Important problems remaining to be solved are the technical aspects of percutaneous implantation of intraarterial catheters connected to a subcutaneous infusion reservoir and studies of combined therapy with systemic chemotherapy. Furthermore, in order to finally determine the position of HAI for colorectal liver metastases, it is necessary to conduct a comparative study versus systemic chemotherapy, using the survival time as the primary end point.     

A pilot study of multimodality therapy for initially unresectable liver metastases from colorectal carcinoma: hepatic resection after hepatic arterial infusion chemotherapy and portal embolization

The prognosis of patients with unresectable liver metastases is poor, even if hepatic arterial infusion chemotherapy (HAI) or systemic chemotherapy is administered. A pilot study was performed to evaluate the feasibility and efficacy of multimodality therapy with hepatectomy after HAI and portal embolization for such patients. Eight patients with colorectal carcinoma and synchronous unresectable liver metastases underwent resection of the primary tumor and placement of a pump, followed by HAI with 5-fluorouracil and mitomycin C. Owing to shrinkage of the liver metastases, two patients could undergo extended right hepatic lobectomy after portal embolization, which was deemed to be essential to prevent post-operative hepatic failure. The median survival time of the eight patients was 30 months, with a response rate of 75%. Complications including sclerosing cholangitis and duodenal ulcer were observed in five patients (63%). Additional hepatectomy could be performed successfully after portal embolization without morbidity in two patients. These two patients are still alive more than 6 years after initiation of HAI and have been free of disease for more than 5 years after hepatectomy. Hepatectomy after HAI and portal embolization is feasible and may be an option to cure selected patients with initially unresectable liver metastases.      

Chemotherapy for liver metastasis of colorectal cancer

In colorectal cancer, liver metastasis is the most common and most important prognostic factor. Although surgical resection is the first choice of treatment for liver metastasis of colorectal cancer, there are many cases we cannot choose the surgical treatment. The chemotherapy is very important in such cases. We examined 18 cases of unresectable liver metastases from colorectal cancer which were adapted a hepatic arterial infusion of 5-FU (HAI) with a weekly high-dose infusion method (WHF) as the first-line treatment, and then systemic chemotherapy of CPT-11 in combination with 5-FU as the second-line treatment. The response rate of this treatment is 72% (13/18) and the 1-, 2-, 3-year survival rates were 100% (16/16), 83% (10/12), and 50% (5/10), respectively. The combination chemotherapy of HAI with systemic chemotherapy using CPT-11 seemed to be an effective treatment method.     

Phase I trial of systemic oxaliplatin combination chemotherapy with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of concurrent systemic oxaliplatin (Oxal) combinations plus hepatic arterial infusion (HAI) in patients with unresectable hepatic metastases from colorectal cancer. PATIENTS AND METHODS: Thirty-six patients (89% previously treated) with unresectable liver metastases were treated with concurrent HAI and systemic Oxal plus irinotecan (CPT-11; group A) or Oxal, fluorouracil (FU), and leucovorin (LV; group B). Systemic chemotherapy was administered every 2 weeks concurrent with 2 weeks of HAI floxuridine (FUDR) and dexamethasone (Dex) every 28 days. RESULTS: The MTD for patients in group A was Oxal 100 mg/m(2), CPT-11 150 mg/m(2), and FUDR 0.12 mg/kg x 30 mL divided by pump flow rate. The MTD for group B was Oxal 100 mg/m(2), LV 400 mg/m(2), and FU 1,400 mg/m(2) by continuous infusion over 48 hours, with the same FUDR dose as in group A. Grade 3 or 4 toxicities in groups A and B included diarrhea (24% and 20%), neutropenia (10% and 7%), neurotoxicity (24% and 20%), and bilirubin more than 3 mg/mL (5% and 7%, respectively). The complete and partial response rate totaled 90% for group A and 87% for group B. Median survival time was 36 and 22 months for groups A and B, respectively. Seven patients in group A were ultimately able to undergo liver resection. CONCLUSION: Combination therapy with HAI FUDR and Dex plus systemic Oxal combinations may be safely administered to patients with colorectal cancer. The high response rate (88%) and the possibility of conversion to resectability, despite disease progression on prior systemic regimens, suggest that these combinations should be evaluated in larger studies as first- or second-line therapy in patients with hepatic metastases from colorectal cancer.