What is the role of hepatic artery infusion (HAI) in treating colorectal liver metastases (mets)?

Hepatic Artery Infusion for Colorectal Liver Metastases

Hepatic artery infusion (HAI) chemotherapy is an effective treatment option for patients with unresectable, liver-limited or liver-predominant colorectal metastases, particularly those who have failed first-line systemic chemotherapy or require conversion to resectable disease. 1

Primary Indications for HAI Therapy

HAI should be considered for patients with liver-limited or liver-predominant disease that is unresectable and unresponsive to first-line systemic chemotherapy. 1 The FDA-approved agent floxuridine is specifically indicated for palliative management of gastrointestinal adenocarcinoma metastatic to the liver when given by continuous regional intra-arterial infusion in carefully selected patients considered incurable by surgery or other means. 2

Key patient selection criteria include:

• Disease confined to the liver or liver-predominant burden 1
• Unresectable metastases despite systemic therapy 1
• No extensive extrahepatic disease beyond what can be infused via a single artery 2
• Adequate hepatic function to tolerate potential liver toxicity 1

Conversion to Resectability: The Primary Goal

HAI combined with systemic chemotherapy can convert initially unresectable disease to resectable status, which is the most important outcome for improving survival. 1 The OPTILIV phase II study demonstrated that HAI with irinotecan-oxaliplatin-5-FU combined with intravenous cetuximab achieved conversion to R0-R1 hepatectomy in 29.7% of heavily pre-treated patients with extensive disease. 1

In patients who achieve secondary resection after HAI:

• R0 resection becomes possible in approximately 16.4% of cases 3
• Two-year survival reaches 80% in those who undergo successful resection 3
• This represents a dramatic improvement over palliative therapy alone 3

Technical Approach and Drug Regimens

The optimal HAI regimen combines intra-arterial chemotherapy with concurrent systemic therapy to maximize both local and systemic disease control. 1

European Approach (Preferred for Heavily Pre-treated Patients)

• Oxaliplatin administered intra-arterially over 2 hours combined with systemic 5-FU-leucovorin over 48 hours 1
• Achieves 62% response rates in heavily pre-treated patients 1
• Can be combined with intravenous cetuximab or other biologics 1

FDA-Approved Regimen (Floxuridine)

• Dosing: 0.4 to 0.6 mg/kg/day by continuous arterial infusion for hepatic artery administration 2
• Higher dosage ranges are employed for hepatic artery infusion because the liver metabolizes the drug, reducing systemic toxicity 2
• Therapy continues until adverse reactions appear, then may be resumed after resolution 2

Alternative 5-FU Based Regimens

• Continuous 5-FU infusion via hepatic artery is feasible with acceptable toxicity 4
• Can be combined with systemic chemotherapy or molecular-targeted agents 3

Clinical Efficacy by Treatment Line

HAI demonstrates superior efficacy when used earlier in the treatment algorithm rather than as salvage therapy. 3

First- and Second-Line Setting:

• Tumor response rate: 26.5% 3
• Median overall survival: 13.5 months 3
• Median progression-free survival: 9 months 3

Third- and Fourth-Line Setting (Salvage):

• Tumor response rate: 11-12.4% 3, 4
• Median overall survival: 4.8-8.3 months 3, 4
• Disease control rate: 64-70% 5, 4
• Still provides meaningful palliation with improved quality of life in 80% of patients 5

Safety Profile and Monitoring Requirements

Liver toxicity is the primary limitation of HAI therapy and requires careful monitoring, though severe adverse events are relatively uncommon with proper technique. 1

Common Toxicities:

• Grade 3-4 clinical toxicities: 16% of patients 3
• Neurotoxicity (with oxaliplatin): 9.8% 3
• Grade 3-4 neutropenia: 22.2% 3
• Hyperbilirubinemia: 2.9% 4
• Catheter-related complications: 31.1% 3

Critical Technical Considerations:

• Coiling of the gastroduodenal artery must be performed to prevent drug influx and reduce gastrointestinal toxicity 5
• Appropriate pump systems are required to overcome arterial pressure and ensure uniform infusion 2
• Direct arterial administration complexity and liver toxicity can limit therapy 1

Surgical Timing and Combined Procedures

Combining colorectal primary resection with HAI pump implantation is safe and does not delay initiation of chemotherapy. 6

Combined HAI pump placement with primary resection versus pump alone shows:

• Similar operative time and blood loss 6
• Slightly longer length of stay (6 vs 4 days) 6
• No increase in postoperative or infectious complications 6
• No delay to initiation of HAI therapy (19 vs 16 days) or systemic therapy (34 vs 35 days) 6

Positioning Within Treatment Algorithm

HAI should be integrated with systemic chemotherapy rather than used as monotherapy, and positioned strategically based on resectability assessment. 1

For unresectable disease:

• Consider HAI after failure of first-line systemic chemotherapy as a conversion strategy 1
• Combine with systemic agents (FOLFOX, FOLFIRI) and biologics when appropriate 1, 3
• Reassess for resectability every 2-3 cycles 1

For initially resectable disease:

• HAI combined with systemic chemotherapy post-resection has demonstrated survival advantage 7
• This is the only setting where enhanced survival has been consistently shown 7

Mechanism of Benefit

HAI achieves dramatically higher local drug concentrations in liver metastases compared to systemic administration, overcoming chemotherapy resistance. 1 Direct arterial administration results in increased drug concentration within the liver, which can induce apoptosis and cell death even in anticancer drug-resistant colorectal cancer cells in a concentration-dependent manner. 5 This explains why HAI can be effective even in patients refractory to multiple lines of systemic therapy. 5, 4