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Hepatic Intra-Arterial Chemotherapy

Department of Surgery, University of Illinois at Chicago, M/C 958, 840 S. Wood Street, Room 435E, Chicago, Illinois 60612

Correspondence: Address correspondence and reprint requests to: N. Joseph Espat, MD, MS, FACS; E-mail: jespat{at}uic.edu.

Key Words: Hepatic arterial infusion • Chemotherapy • Colorectal metastasis • Outcomes

	INTRODUCTION

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The potential value of hepatic intra-arterial chemotherapy (HIAC) can be considered from several different perspectives. A fundamental assumption for this discourse requires that, in this evaluation, HIAC is being provided with the intent of providing regional hepatic therapy for metastatic hepatic disease. With the exception of colorectal cancer (CRC), there are only limited published data for HIAC evaluation for noncolorectal metastases, and, as such, the terms cancer and hepatic metastasis are specific to CRC in this discussion. It is the aim of this review to summarize the HIAC literature in terms of (1) hepatic drug/agent delivery, (2) clinical applicability and potential outcome benefits/consequences, and (3) novel applications of the HIAC concept as a neoadjuvant/prophylactic approach for the prevention of CRC hepatic metastases.

Despite advances in CRC screening, surgical techniques, and several novel adjuvant agents, CRC continues to be a significant medical challenge. In the United States, approximately 130,000 cases of colon cancer are diagnosed annually. Of these patients, approximately 60% will ultimately develop metastatic disease, and <30% of the initial patient population will have disease confined to the liver.¹ Hepatic resection for CRC metastasis with the potential for cure is achievable in approximately 30% of patients.^2,3 However, for diverse reasons, many patients are not candidates for hepatic resection. Whether resected or not, ultimately the liver is the most common site of subsequent disease progression or recurrence. Historically, with 5-fluorouracil (5-FU)–based systemic chemotherapy, the 5-year survival rate for patients with hepatic CRC metastasis is not greater than 3% with a median survival of approximately 23 to 25 months.^4–6 Conceptually, regional hepatic chemotherapy by means of intra-arterial drug delivery was developed to potentially improve outcomes for these patients.

Although we are presently in the era of oxaliplatin-based systemic regimens and monoclonal antibody therapies, we lack long-term data for these new therapeutic regimens to supplant the historical experience described previously. It is the aim of this article to consider the value of HIAC, and this can be accomplished only with the data set already completed. Discussion of the potential effects of these novel regimens and the long-term outcomes, which are pending, is outside of the scope of this article.

	IS THERE EVIDENCE IN SUPPORT OF HIAC AS AN EFFECTIVE ROUTE OF ADMINISTRATION?

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Options for the route of chemotherapy delivery for patients with hepatic metastases include systemic venous, portal venous, and hepatic arterial. There is a significant body of pharmacokinetic evidence that supports the HIAC route of delivery as superior compared with either systemic or portal venous if the aim of drug delivery is to enhance hepatic drug concentration and to deliver drug into measurable hepatic tumors.⁷

Physiologically, it is well recognized that most blood flow into the liver occurs via the portal vein (70%–80%), whereas most oxygen-rich blood is delivered via the hepatic arteries, which constitute approximately 20% to 30% of blood flow. The challenge of which route of chemotherapy administration may be a beneficial method of drug delivery has been studied from a tumor vascularization perspective.⁸

Radiographically invisible hepatic metastases, otherwise termed micrometastatic disease, derive a blood supply from the portal vein.⁸ Administration of chemotherapy into the portal vein circulation has been reported in at least 10 studies; however, no conclusive evidence of decreased hepatic metastases or a survival advantage has been demonstrated by randomized trial meta-analysis for portal vein infusion therapy.⁹

In contradistinction to micrometastatic disease, measurable hepatic metastases are predominantly vascularized by the hepatic artery. ⁸ Delivery of chemotherapy into tumor is preferentially achieved by this route. Floxuridine (FUDR), which is the primary agent used for HIAC, achieves a 400-fold increased intratumoral concentration after hepatic arterial delivery as compared with systemic infusion and a 15-fold increase compared with portal vein infusion.^7,10

Beyond enhanced delivery of the drug into the liver by arterial infusion, a further factor and key component of hepatic regional drug activity is the potential requirement for an agent (i.e., 5-FU) to be converted into an active metabolite (FUDR). Hepatic extraction between these drugs is widely variable (i.e., FUDR > 5-FU), such that when HIAC infusion is used, FUDR therapy achieves higher hepatic concentrations and is almost completely first-pass extracted, with limited systemic spill, thus resulting in lessened side effects.¹⁰

These data support that the HIAC route of administration has value in achieving enhanced hepatic drug concentrations compared with systemic venous and portal vein delivery, that HIAC enables drug delivery into hepatic tumors based on the tumor vascular supply, and that different drugs have differential extraction within the liver once infused. In the next section, the significance of these observations within a clinical context will be discussed.

	WHAT IS THE EVIDENCE FOR THE CLINICAL APPLICABILITY AND POTENTIAL OUTCOME BENEFITS/CONSEQUENCES FOR HIAC?

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The clinical application of HIAC has been considered over the last four decades, from 1965, when Sullivan and Zurek ¹¹ initially described ambulatory hepatic chemotherapy, to 2004, when Cheng et al.¹² described successful laparoscopic placement of HIAC pumps in a series of patients. Over this interval, the evaluation of optimal regional hepatic drug delivery for CRC patients has included systemic versus portal venous versus hepatic arterial; devices such as indwelling automatic delivery systems (pumps); and liver-directed nonresectional procedures such as cryoablation or radiofrequency ablation. Further potentially confounding the analysis has been the recent and almost explosive availability of agents such as irinotecan, oxaliplatin, and monoclonal antibody systemic therapies with potential hepatic activity, which have been introduced at a rate faster than ever before.

Central to this ongoing discussion has been how to select patients who should be treated with HIAC. Initially, the selection was based on hepatic-only meta-static disease versus extrahepatic disease, such that only the former were candidates for regional hepatic therapy. Subsequently, as resection and ablation modalities became popularized, potential HIAC candidates were further divided into patients with unresectable metastases treated in a palliative approach with or without systemic chemotherapy or patients with resected disease undergoing HIAC as an adjuvant to resection. Most recently, with limited data, HIAC has become a component of cytoreductive therapy in combination with radiofrequency ablation or resection, either independently or in combination.

In this section, the data from HIAC in the treatment of unresectable disease and HIAC as an adjuvant to resection are presented to assess the value of HIAC in these different clinical scenarios. Purposely, HIAC as a component of cytoreductive therapy has been omitted. To facilitate this section, the fundamental assumption is made that value is assessed by the clinical practice terms of radiographic hepatic response, overall survival, or quality of life (QOL).

	HIAC IN THE TREATMENT OF UNRESECTABLE DISEASE (PALLIATION)

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The role of HIAC for the treatment of hepatic colorectal metastases was first studied in the late 1970s.^13–16 In these trials, the inclusion criteria selected patients with CRC metastases that were isolated to the liver and unresectable. Although these small studies lacked randomization and proper control groups, tumor radiographic response rates of 35% to 83% were still consistently reported. After these studies, phase III trials comparing HIAC with intravenous chemotherapy were performed to confirm the advantages of HIAC. Since 1979, nine prospective randomized controlled trials have been conducted to compare HIAC with intravenous chemotherapy for the treatment of unresectable hepatic colorectal metastases (Table 1).^2,17–24

All six of these trials (HIAC to intravenous chemotherapy alone^17–21,24) reported no significant difference in overall survival. However, these studies also had several major disadvantages that were unfavorable to the HIAC treatment arm, including small patient sample sizes, crossing over of patient treatment from intravenous chemotherapy to HIAC in cases of intrahepatic progression, and high rates of no treatment among patients randomized to the HIAC treatment arm.

The remaining three single trials had varied study designs, with resulting different outcomes. The study by Grage et al.²³ randomized patients to receive either one course of 5-FU via HIAC followed by intravenous chemotherapy or intravenous chemotherapy alone. This study did not demonstrate a survival advantage in the HIAC arm, but a criticism of this study was that there was only a single course of HIAC before intravenous chemotherapy.

The studies conducted by Rougier et al.² and Allen-Mersh et al.²² are the only single trials to demonstrate both a statistically significant radiographic tumor response rate and a survival benefit gained by patients treated with HIAC. The important differences in these studies were as follows: (1) patients did not cross over from one treatment arm to another treatment arm, and (2) the treatment for the control group to receive intravenous chemotherapy was at the discretion of the patient or the treating physician. In the studies conducted by Rougier et al.² and Allen-Mersh et al.,²² a major criticism was that only 50% and 22% of the control patients, respectively, received systemic chemotherapy, and, therefore, their results were potentially biased toward a survival advantage for the HIAC treatment arm. However, Rougier et al. argued that the 1-year survival rate of their control group (44% ) was higher than that reported in historic controls, and they believed that bolus 5-FU intravenous chemotherapy did not affect survival.² Moreover, they based their improved survival outcome on decreased hepatic toxicity from regional instead of systemic chemotherapy delivery, improved patient selection, and prevention of extrahepatic metastases by a combination of systemic chemotherapy with HIAC. This last point is important to note because this study permitted the patients in the HIAC treatment arm to receive systemic 5-FU if extrahepatic progression occurred. Similarly, Allen-Mersh et al.²² found a 3-fold increase in the development of extrahepatic disease in HIAC-treated patients compared with controls and commented that survival may have been further improved in the patients treated with HIAC if occult extrahepatic disease had been controlled with concurrent effective systemic chemotherapy.

To overcome some of these single-trial design disadvantages, three meta-analyses including these six studies were performed to reevaluate the data concerning HIAC versus systemic intravenous chemotherapy.^26–28 All three meta-analyses revealed a statistically significant improvement in the radiographic tumor response rate with HIAC and also a significant increase in median survival time; one study reported a mean gain of 3.2 months in life expectancy.²⁸

Although there are mixed results from these numerous studies, the evidence supports that the value of HIAC in the setting of unresectable hepatic colorectal metastases is dependent on:

1. The chemotherapeutic agent chosen for HIAC, because several of the studies that do not demonstrate a difference in overall survival rate highlight how the mode of drug delivery may not be as important, but that the ability of the drug to prevent the appearance of extrahepatic metastasis may be a greater factor in dictating survival.
   
2. Combining regional treatment with systemic treatment instead of HIAC alone, because this has provided the most promising survival data.
   
3. The prevention of procedure/device complications and diminishing the toxicity of the chemotherapeutic agent to avoid inadequate and incomplete treatment resulting in poor outcome.
   

For unresectable disease, the potential role for HIAC in the treatment of metastatic CRC is far from resolved. Although a superior hepatic radiographic response rate has been reported in a variety of single-institutional studies (up to 80% ), meta-analysis of published HIAC trails fails to demonstrate an overall survival advantage. Present-day treatment of metastatic CRC with 5-FU and irinotecan (FOLFIRI) or oxaliplatin (FOLFOX) is associated with hepatic response rates of 34% to 51%, which are at least equivalent to those shown in the HIAC meta-analysis ^29,30 and single HIAC trials.^2,17–24

	QOL AND HIAC

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Although the role of HIAC in tumor progression and survival benefit remains the focus of most studies in the current literature, patient QOL is another point in the evaluation of HIAC, especially in studies measuring the benefit of HIAC as palliative therapy. Unfortunately, the body of literature concerning HIAC and QOL is limited.

The study by Allen-Mersh et al.²² measured QOL in patients receiving HIAC for unresectable liver metastases by using general QOL instruments, the Rotterdam checklist, and the Hospital Anxiety and Depression scale. In this study, it was noted that patients undergoing HIAC were able to maintain a normal QOL and that there were no significant differences in anxiety or depression scores between the HIAC and control patients. In comparison, the more recent trial by Kerr et al.²⁴ hypothesized that as a result of a reduction in liver metastases, the HIAC group would show improvement in QOL. Instead, they found that patients in the HIAC group reported worse physical function, appetite loss, increased fatigue, and an overall poorer QOL at 13 weeks after randomization and treatment with HIAC. By 14 weeks, however, the questionnaires did not demonstrate a difference in QOL between the two groups. The authors of this trial recommended caution in the interpretation of these results because only 30% to 60% of patients in each group returned the QOL questionnaires.

Because of the limited available QOL data for patients undergoing HIAC, a further pilot study was performed by Blair et al.³¹ in 2003. In this study, it was observed that although the treated patients believed HIAC to be convenient and reassuring, HIAC treatment limited their ability to perform vigorous exercise.

In summary, these studies report variable end points, from maintenance of QOL, decreased QOL, or both. As such, the effect of HIAC on QOL remains unclear. Future HIAC studies will need to incorporate the QOL and use appropriate and comparable survey instruments to potentially define the role of HIAC from the QOL perspective.

	ADJUVANT TREATMENT AFTER RESECTED HEPATIC COLORECTAL METASTASES

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After complete resection for CRC hepatic metastases, there is a reported 25% to 35% 5-year survival rate.^3,32 Unfortunately, up to 70% of these potentially cured patients will have recurrence, and of these, more than half will occur in the liver.⁵ The observation that HIAC is a potentially beneficial hepatic regional therapeutic approach has led to the several studies investigating the adjuvant to resection role of HIAC.

The use of HIAC after hepatic resection has been studied in five prospective randomized trials since the early 1990s (Table 2).^25,33–36 The results of these five studies can be divided into two groups. The two studies from Germany (Lorenz et al.²⁵ and Rudroff et al.³⁶) concluded that there was no benefit and even an increased risk of death associated with HIAC treatment. In contrast, two studies from the United States (Kemeny et al.^34,35) and one trial from Japan (Tono et al.³³) demonstrated a significant improvement in disease recurrence, liver disease-free survival, and overall survival.³⁵

The larger study performed by the German Cooperative on Liver Metastases ²⁵ randomized 226 patients to HIAC with 5-FU versus no treatment and reported no significant difference in disease-free status and a decreased median survival among patients who had HIAC. In fact, this study was discontinued early after an interim analysis of the data. However, a key problem with this study was that although 113 patients were randomized to the HIAC treatment, only 84 patients actually received the treatment. It is interesting to note that when the data were analyzed, comparing the HIAC-treated group with controls, the median time to progression in the liver was nearly doubled (44.8 versus 23.3 months). The median overall survival was also increased to 44.8 months, compared with 39.7 months in the control group, but this was not statistically different.²⁵

The remaining three randomized trials performed by Kemeny et al.^34,35 and Tono et al.³³ demonstrated a statistically significant increase in the median disease-free interval after hepatic resection. One explanation for this improved median disease-free interval is the use of systemic chemotherapy and HIAC instead of treatment with HIAC alone. The resultant improvement in tumor-free survival from the addition of systemic chemotherapy mimics the improved survival rates in the studies of HIAC for unresectable hepatic colorectal metastases. Although overall survival was not found to be significantly improved in the two of the three studies (Tono et al.³³ and Kemeny et al.³⁴), these two studies were also not powered enough to be able to demonstrate a survival difference. The larger study by Kemeny et al.³⁵ randomized 156 patients between HIAC with systemic therapy versus systemic therapy alone. This study reported a statistically significant overall survival improvement in the HIAC treatment group at 2 years.

The different study designs of these five trials along with the variable results make it difficult to make an absolute conclusion concerning the value of HIAC as an adjuvant therapy after resected hepatic colorectal metastases. However, we can conclude that HIAC is an effective adjuvant treatment for regional control to reduce the risk of hepatic recurrence after resection that does not consistently translate into a survival benefit.

It is important to include in this discussion the summary of the recent Cochrane group meta-analysis on the role of HIAC after hepatic resection.³⁷ In this meta-analysis, the proposed objective was:

To assess the effect of post hepatic resection hepatic artery chemotherapy on overall survival. Secondary objectives include adverse events related to the chemotherapy, the risk of intra-hepatic tumour recurrence and tumour free survival.

In this analysis, 7 randomized trials totaling 592 patients were evaluated. Measuring overall survival and calculating survival on the basis of intention to treat, an 8.9% survival advantage in favor of the control group (non-HIAC) was demonstrated. In considering the secondary objective, adverse events related to the hepatic artery therapy were common, including five therapy-related deaths. Hepatic tumor recurrence was more frequent in the control (non-HIAC) group (97 patients vs. 43 in the HIAC group). Although recurrence in the remaining liver was less likely in the HIAC group, overall survival was not improved. These results led the Cochrane group to conclude that there is no significant advantage for hepatic artery chemotherapy after liver-focused treatment.³⁷ Similar to the data presented in the setting of unresectable hepatic colorectal metastases, the potential survival benefit seems to be dependent on systemic disease control rather than the regional hepatic response.

	IS THERE A ROLE FOR HIAC IN THE PREVENTION OF CRC HEPATIC METASTASIS?

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Recently, a randomized controlled trial performed by Sadahiro et al.³⁸ evaluated HIAC as prophylactic therapy in CRC patients who did not yet have hepatic colorectal metastases. Because 60% to 80% of patients with advanced colon cancer develop recurrent disease in the form of liver metastases,³⁹ this study was performed to determine the role of HIAC for patients who had not yet developed hepatic metastases.

In this study, 316 patients scheduled for colon resection were randomized to HIAC or control arms.³⁸ HIAC patients received 3 weeks of continuous-infusion HIAC 5-FU (1 week of HIAC before colon resection and 2 weeks after surgery). Control patients underwent colon resection alone. Adjuvant chemotherapy in both arms (HIAC vs. control) beyond the 3 weeks after surgery was not dictated by the study but was left to the discretion of the physician. Patients enrolled in the study but who did not receive HIAC therapy were analyzed on an intention-to-treat basis and compose the HIAC-2 group. With a median follow-up of 59 months, HIAC treatment resulted in significantly improved disease-free survival, overall survival, and liver metastasis–free survival for stage III patients. Prophylactic HIAC therapy reduced the risk of disease recurrence and overall death by 60% . Consistent with these results, recurrence in the liver was also reduced significantly in the HIAC-treated patients (P = .002). It is interesting to note that when patients with stage II and stage III disease were analyzed separately, only patients with stage III disease were found to have statistically significant improvement in disease-free and overall survival.

Further data from the study describe the site of first recurrence in the HIAC arm to be the liver (4% ), lungs (5% ), and local (5% ) compared with the control arm of the study, in which the sites of first recurrence were the liver (15% ), lungs (6% ), peritoneum (5% ), and local (4% ); only the liver as the site of first recurrence was significantly different between arms (P = .002). Patients enrolled in the study and randomized to the HIAC arm who did not get HIAC therapy (HIAC-2 intent-to-treat) had a 16% rate of liver site of failure, which was comparable to that the control arm patients, thus further indicating that the benefit of the HIAC therapy regimen was a treatment-specific reduction in the rate of hepatic metastasis. Because the site of failure differed only for the liver, the improvements in disease-specific and overall survival were associated with the reduction in hepatic failure.

Sadahiro and colleagues’³⁸ results support a novel application of HIAC to potentially achieve risk reduction in recurrence, hepatic metastasis-free survival, and overall disease-free survival in the treatment of CRC patients,⁴⁰ although it is clear that further confirmatory studies using this approach are necessary.

	CONCLUSIONS

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The analysis of the value of HIAC in the treatment of CRC hepatic metastases supports several conclusions. Ample evidence exists in support of HIAC as the preferred route of administration of regional hepatic chemotherapy: it achieves higher intrahepatic drug concentrations and excellent tumor response rates when compared with other routes of administration. HIAC is an effective form of regional chemotherapy for hepatic metastases. Nearly all studies demonstrate a tendency toward or a significant decrease in hepatic tumor progression when HIAC is used. It is also clear from the data reviewed that regional control of hepatic disease without or independent of systemic disease control does not confer a survival advantage.

To date, the QOL of patients undergoing HIAC has not been adequately evaluated or compared with other treatment modalities. The studies available do not permit any conclusions about the QOL of patients receiving HIAC. Future studies should include QOL among the secondary outcomes in evaluating HIAC.

Regarding HIAC after liver resection, the data generally support the benefit of HIAC for local disease control. The studies again emphasize the need for effective systemic therapy in combination with HIAC to achieve any potential survival advantage associated with HIAC. Meta-analyses of available trials do not support the existence of a survival advantage with adjuvant HIAC after resection. The analysis of these data is, however, hampered by the widely variable study designs, control arms, and overall lack of uniformity among trials. The definitive randomized controlled trial of HIAC in the adjuvant setting has yet to be performed.

Recent trials of HIAC in the neoadjuvant or prophylactic setting are intriguing. Thus far, the data do suggest that HIAC in this setting confers a survival advantage and reduces the occurrence of hepatic metastases in CRC patients with stage III disease.

With the advent and widespread use of multiple new chemotherapeutic and biologic agents, as well as ablative techniques, the role of HIAC requires further study. Future trials in comparison to and in combination with these new strategies will define HIAC’s place in our armamentarium as we continue to refine the treatment of hepatic metastases.

Received for publication January 5, 2005. Accepted for publication August 22, 2005.

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