Defining the role of hepatic arterial infusion chemotherapy in metastatic colorectal cancer

The use of hepatic arterial infusion (HAI) chemotherapy in patients with liver-only colorectal metastases is based on the pharmacologic principle that the regional administration of some drugs can lead to higher drug concentrations at the site of the metastases and avoid systemic toxicity. Early randomized trials resulted in high response rates but did not lead to a survival advantage with HAI. More recent trials have utilized improved surgical techniques and strict guidelines regarding dose reduction or cessation of HAI chemotherapy, resulting in a significant reduction in toxicity. In patients with unresectable liver metastases, two recent European trials using HAI fluorouracil (5-FU) again failed to demonstrate an improvement in survival, but both were plagued by a high complication rate with an associated high proportion of patients failing to receive the assigned treatment. In contrast, the preliminary results of a recent Cancer and Leukemia Group B trial did demonstrate a survival advantage with HAI floxuridine when compared to systemically administered 5-FU. Trials investigating the use of HAI chemotherapy in the adjuvant setting have yielded mixed results. Moreover, in light of improved response rates and overall survival with newer more active chemotherapeutic and novel agents, the absolute role of HAI chemotherapy remains undefined.     

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.     

Hepatic arterial infusion chemotherapy for metastatic colorectal cancer: a concise overview

Patients with colorectal cancer commonly succumb to the sequelae of hepatic metastases. Response to systemic therapy is inadequate. Hepatic arterial infusion (HAI) exposes liver metastases to high local concentrations of drug. Herein, we review the randomized trials of HAI in colorectal cancer. Data for this review were identified by searches of MEDLINE and references from relevant articles using the search terms "infusion intra-arterial" and "colorectal cancer." Abstracts and reports from meetings were included only when they related directly to previously published work. Only papers published in English between 1966 and 2003 were included. Randomized trials (5-fluorouracil- (5-FU-) or fluordeoxyuridine- (FUDR-) based regimens) often demonstrated superior response rates for HAI as compared to systemic chemotherapy (primary treatment or post-resection). Enhanced survival has, however, shown only when HAI was combined with systemic chemotherapy in the post-resection setting. For 5-FU-based and perhaps other regimens, randomized trials of combined regional and systemic therapy versus systemic treatment alone may be needed in order to determine whether or not there is a survival advantage after HAI in unresectable patients, as has been recently demonstrated in resectable patients. A variety of agents other than 5-FU have also been given by HAI to patients with liver metastases from diverse cancers. Such regional therapy often yields encouraging response rates and impact on survival therefore merits investigation.     

Hepatic artery infusion of chemotherapy as a treatment for hepatic metastases from colorectal cancer

Hepatic artery infusion (HAI) of chemotherapy as a treatment for hepatic metastases from colorectal cancer has become more commonly used after the introduction of the totally implantable hepatic artery pump in the early 1970s. Floxuridine (FUDR) is the generally used chemotherapy agent in the pump because of its high solubility and high extraction rates by the liver on the first pass of the chemotherapy through the hepatic circulation. HAI has been used mainly to treat unresectable liver metastases in patients who have liver metastases only. The other scenario for pump use has been as an adjuvant therapy after resection of all metastatic disease inthe liver. The rationale for HAI includes the unique dual blood supply of the liver allowing chemotherapy given into the artery and sparing the normal cells, which get their predominant blood supply from the portal vein. The details of pump design will be reviewed. Complications from HAI are specific for this therapy and will be reviewed. Treatment of unresectable liver metastases with HAI has been the subject of a number of prospective randomized studies. These will be presented, along with newer phase II studies. Three randomized studies on the usefulness of HAI after hepatic resection will be presented.     

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.     

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.     

Current role of hepatic artery infusion and isolated liver perfusion for the treatment of colorectal cancer liver metastases

There are many treatment options for patients with metastatic colorectal carcinoma confined to the liver. Surgical resection alone can result in significant prolongation of survival in patients with favorable prognostic factors. Randomized studies of hepatic artery infusion therapy after complete resection of liver metastases have demonstrated improvements in hepatic recurrence-free survival but no impact on overall survival. Randomized trials evaluating the treatment of unresectable disease with hepatic artery infusion therapy have demonstrated higher response rates (31%-50%) than those seen with systemic chemotherapy (8%-20%) but no survival benefit. Vascular isolation and perfusion of the liver with chemotherapy with or without biologic agents under hyperthermic conditions is another regional modality that has been explored for the treatment of unresectable colorectal cancer liver metastases. Large series report high partial response rates (68%-77%), with responses being achieved in patients with advanced tumor burden and in those who have disease progression through prior treatment of hepatic metastases.     

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.     

Hepatic artery infusion chemotherapy for metastatic colorectal carcinoma

Hepatic metastases are a major cause of morbidity and will affect up to 80,000 new patients annually in the United States. Up to 20% of these patients will die with metastatic disease localized to the liver. Hepatic arterial infusion (HAI) therapy has a sound anatomical and pharmacological rationale. A number of randomized clinical trials in patients with unresected metastases have demonstrated that HAI is associated with a complete response rate in 5% of patients and partial responses up to 60%. In comparison, systemic chemotherapy is associated with a partial response in 20% of cases. No investigation comparing systemic chemotherapy with HAI has demonstrated an improvement in survival following HAI, since all investigations either allowed crossover, were under-powered with respect to survival statistics, or included patients with extrahepatic disease in the HAI arm. However, a recent investigation utilizing HAI with systemic chemotherapy following hepatic resection demonstrates improved local and systemic disease control and overall survival. This approach offers new promise for the curative treatment of the patients with metastatic colorectal carcinoma.     

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.     

Regional and systemic chemotherapy for primary hepatobiliary cancers and for colorectal cancer metastatic to the liver

Hepatic arterial infusional (HAI) chemotherapy is based on the premise that primary and metastatic tumors derive their blood supply from the hepatic artery, whereas normal liver derives its blood supply from the portal vein. This approach has been extensively studied in liver-only colorectal metastasis patients, with 10 published prospective randomized clinical trials comparing fluoropyrimidine-based HAI therapy with systemic chemotherapy. Most of these studies showed a statistically significant superior response rate and improved disease-free survival with HAI chemotherapy compared with systemic fluoropyrimidine-based chemotherapy alone. More advanced chemotherapeutic regimens including biologically targeted agents have clearly impacted survival in metastatic colorectal cancer patients and are currently under investigation with HAI-based trials. In contrast, hepatobiliary tumors remain difficult to treat with overall poor response and survival with systemic chemotherapy. Few clinical trials have attempted to address the role of HAI-based therapy for these regional tumors, although encouraging response rates up to 60% have been reported. Therefore, the regional approach for hepatobiliary tumors deserves further investigation as well as randomized trials for adequate comparison to new systemic chemotherapies.     

Current strategies using hepatic arterial infusion chemotherapy for the treatment of colorectal cancer

In recent years, a number of phase III clinical trials have reported median survival times approaching 20 months using modern combination chemotherapy for metastatic colorectal cancer (CRC). Despite the advances in systemic therapy, this approach is still considered palliative because long-term survival or cure is extremely rare. Surgery or the use of ablative techniques may result in prolonged survival for patients with liver metastases, but only a minority of cases are suitable for local therapy. Hepatic arterial infusion (HAI) therapy involves local delivery of drug to liver metastases, resulting in higher intrahepatic drug levels and a consequent doubling in response rates compared with systemic chemotherapy. Despite higher response rates, demonstrating a survival advantage for HAI has been more challenging. Recently, a number of studies have been published that appear to address some of the inadequacies of earlier trials and have demonstrated encouraging results. This review assimilates the current data on HAI for CRC and includes an assessment of new chemotherapeutic agents delivered via HAI, neoadjuvant HAI, HAI combined with systemic chemotherapy, the use of HAI for early-stage colorectal cancer, and future trials. Continued progress in the field of HAI therapy may reduce the morbidity and mortality associated with CRC, so continued research in this area should be encouraged.     

Hepatic arterial chemotherapy in metastatic colorectal patients.

Hepatic metastases are a major cause of morbidity and mortality for patients with colorectal cancer (CRC). The rationale for hepatic arterial chemotherapy has both an anatomical and pharmacological basis. Several randomized clinical studies of fluoropyrimidine showed higher response rates in all trials when the drug was given as an hepatic arterial infusion (HAI) versus systemic administration. However, the studies did not accurately define survival for the following reasons: (1) some allowed a crossover; (2) some were too small; and (3) some used inadequate systemic chemotherapy. Patients who have failed to respond to previous systemic chemotherapy have an approximately 50% response rate with HAI treatment. Hepatic toxicity, especially biliary sclerosis, is the dose-limiting toxicity, occurring in 6% to 25% of patients. Adding dexamethasone to HAI fluoropyrimidine decreases the hepatobiliary toxicity. The therapeutic benefit of HAI in one study was also demonstrated by an increased time with normal quality of life. To truly define the role of regional therapy in patients with CRC confined to the liver, the current Cancer and Leukemia Group B (CALGB) study is randomizing patients to HAI versus systemic therapy without a crossover to demonstrate if HAI improves survival and/or quality of life in addition to response rates.     

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.      

Experience with continuous regional chemotherapy and hepatic resection as treatment of hepatic metastases from colorectal primaries. A prospective randomized study

Sixty-five patients with hepatic metastases from colorectal primaries were studied in a prospective randomized fashion. The five patients with solitary metastases all had resection of metastases and 50% were randomized to pump therapy. Of the 16 patients with multiple resectable metastases, 7 had pump only and 9 had resection plus pump. Although the difference was not significant, there was a trend of improved survival for the patients with resection plus pump. For the patients with unresectable disease, those patients with positive portal nodes had poor survival matching those patients with extra hepatic metastases. Patients with unresectable disease treated with pump had a 73% therapeutic response rate and a median survival of 22 months. Significant complications included chemical hepatitis and biliary stenosis. The long-term efficacy of continuous hepatic artery infusion versus the hazards of treatment and the financial cost will need further investigation.     

Kirsten rat sarcoma (KRAS) oncogene mutation predicts magnitude of response and outcomes in hepatic arterial infusion pump therapy of unresectable colorectal liver metastases

BackgroundThe Kirsten rat sarcoma (KRAS) mutation predicts negative outcomes following resection of colorectal liver metastases (CRLM) and adjuvant hepatic arterial infusion (HAI) pump chemotherapy. Less is known on the effects of KRAS mutation on tumor response in patients with unresectable CRLM undergoing HAI chemotherapy with floxuridine.MethodsThis is a retrospective cohort study investigating the effects of KRAS mutation on tumor response in patients with unresectable CRLM treated with HAI chemotherapy. Primary endpoint was objective response rate (ORR), secondary endpoints included overall tumor response and conversion to resectability.ResultsTwenty-five patients with unresectable liver metastases from colorectal cancer were treated with HAI chemotherapy between 2017–2019. Median number of liver lesions was 12 (range, 1–59) and almost all (n=24) had prior chemotherapy before starting HAI therapy. Median number of cycles administered via HAI pump was 6 (range, 3–12). Overall decrease in liver tumor burden was 63.5% (median; range, −257–100%) with an ORR of 20/25 (80%) and 10 (40%) patients converting to resectable status. Eleven (44%) patients had KRAS positive tumors. When compared to wild-type, KRAS positive tumors had less overall percent decrease (58% vs. 70%; P=0.04) and ORR (7/11 vs. 13/13; P=0.03). Fewer patients with KRAS positive tumors converted to resectable status during HAI therapy (2/11 vs. 8/13; P=0.05). At a median follow-up of 14.6 months (range, 4.0–36.6 months), overall survival is 45% among KRAS-positive and 77% for wild type patients.ConclusionsKRAS mutational status in patients with unresectable liver metastases from colorectal cancer predicts worse response to HAI chemotherapy compared to wild type.     

Hepatic arterial infusion of chemotherapy for hepatic metastases from colorectal cancer.

BACKGROUND: Sixty percent of colon cancer patients develop liver metastasis. Only 25% of those have potentially resectable hepatic metastases, and approximately 58% of those patients relapse. METHODS: We review the indications and the technical aspects of hepatic artery infusion (HAI) of chemotherapy, as well as the efficacy, morbidity, and outcomes. RESULTS: HAI of chemotherapy has been used following hepatic metastasectomy, in patients with unresectable metastases, or in combination with other agents. Floxuridine, the chemotherapeutic agent most studied, is administered through an implantable subcutaneous infusion pump connected to a surgically placed hepatic artery catheter, which delivers the chemotherapeutic agents at a slow fixed rate. Treatment-related toxicities include chemical hepatitis, biliary sclerosis, and peptic ulceration. Some trials report a survival benefit for HAI over systemic chemotherapy with acceptable toxicity. CONCLUSIONS: Regional perfusion chemotherapy can be logistically and technically complicated to deliver. The development of newer systemic agents with superior efficacy in the treatment of metastatic colorectal cancer will likely diminish the role of regional perfusion therapy in the future.     

Arterial chemotherapy as adjuvant and palliative treatment of hepatic colorectal metastases: an update

Regional hepatic chemotherapy with FUDR significantly improves local recurrence rates and may impact overall survival in patients with hepatic colorectal metastases. The results of prospective randomized trials confirm that careful patient selection, a thorough knowledge of intricate hepatic arterial anatomy, and an understanding of the pharmacokinetics and delivery of FUDR optimize treatment efficacy. A multimodality approach that includes adjuvant therapy in addition to cytoreductive surgery offers promise for the treatment of unresectable hepatic metastases. Because many tumors recur in extrahepatic sites, the addition of novel systemic agents such as CPT-11 may further reduce recurrences. Molecular analysis of the tumor may ultimately help select patients who are good candidates for regional chemotherapy.     

Systemic chemotherapy for advanced colorectal cancer with liver metastasis

We report the progress of systemic chemotherapy for advanced colorectal cancer with liver metastasis. It must be noted that the purpose of this treatment is to prolong the symptom-free period. Review of hepatic arterial infusion (HAI) compared with systemic chemotherapy for the treatment of unresectable liver metastases from colorectal cancer showed that was attained with HAI a much higher response rate and survival benefit than systemic chemotherapy. However, systemic chemotherapy has shown progress since that time. Regarding administration methods, continuous injection is better than bolus injection for 5-FU. New modulators of 5-FU have also became available, such as leucovorin, CPT-11, and I-OHP. Futhermore, many studies of 5-FU-based combination therapy have shown that the mean survival time (MST) and response rate (RR) are now close to those of HAI. Finally, the combination with HAI with systemic chemotherapy using CPT-11 resulted in the highest RR of 74%. Further trials of such combination therapy will be performed in the future.     

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.