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 unresectable colorectal liver metastases, particularly when combined with systemic therapy for conversion to resectability or as salvage therapy after failure of standard chemotherapy regimens. 1

Primary Role: Conversion to Resectability

HAI combined with systemic chemotherapy can convert initially unresectable disease to resectable status, potentially improving survival. 1 The 2023 ESMO guidelines specifically recommend intra-arterial chemotherapy as an option for patients unresponsive to first-line chemotherapy, not only to recover response but also to achieve liver resection 1. The phase II OPTILIV 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 RAS-wild-type patients with extensive disease (median of 10 metastases involving six liver segments) 1.

Technical Approach and Drug Selection

HAI is delivered through intra-arterial ports or pumps placed either surgically or percutaneously 1. The most commonly used agents are:

• Floxuridine (FUDR): FDA-approved for continuous regional intra-arterial infusion at 0.4-0.6 mg/kg/day for hepatic artery infusion, with higher dosages employed because the liver metabolizes the drug, reducing systemic toxicity 2
• Oxaliplatin: European experience predominantly uses intra-arterial oxaliplatin over 2 hours combined with systemic 5-FU-leucovorin over 48 hours, achieving 62% response rates in heavily pre-treated patients 1
• 5-Fluorouracil: Continuous 5-FU infusion has demonstrated disease control rates of 64% in patients refractory to all standard systemic options 3

The 2022 ACR guidelines note that while direct arterial administration results in increased drug concentration within the liver, it can be limited by procedural complexity and liver toxicity 1.

Clinical Efficacy Data

Response Rates and Survival

HAI demonstrates meaningful clinical benefit even in heavily pre-treated populations:

• Response rates: 26.5% in first/second-line settings and 11% in third/fourth-line settings 4
• Median overall survival: 13.5 months in first/second-line and 8.3 months in third/fourth-line treatment 4
• Secondary resection rate: 16.4% of patients initially deemed unresectable achieved R0 resection after HAI, with 80% two-year survival in this subgroup 4
• Disease control rate: 70% in chemotherapy-resistant cases 5

Progression-Free Survival

Median hepatic PFS was 9 months in first/second-line and 6 months in third/fourth-line settings (HR 0.53,95% CI 0.18-0.659, P=0.0037) 4.

Safety Profile and Complications

HAI has acceptable toxicity when performed in experienced centers. 4 Grade 3-4 clinical toxicities occur in 16% of patients, including 9.8% neurotoxicity, while Grade 3-4 biological toxicities occur in 24.6%, primarily neutropenia (22.2%) 4. Catheter-related complications occur in approximately 31% of cases 4. Severe adverse events are rare (2.9%), including hyperbilirubinemia, liver abscess, and myelosuppression 3.

Common pitfall: The 2022 ACR guidelines emphasize that liver toxicity can limit therapy, requiring careful monitoring 1.

Optimal Patient Selection

HAI is most appropriate for:

1. Liver-limited or liver-predominant disease that is unresectable 1
2. Patients who have failed standard systemic chemotherapy (FOLFOX, FOLFIRI, FOLFOXIRI) with or without biologics 1
3. Candidates for potential conversion to resectability with extensive hepatic involvement 1
4. Patients with adequate performance status to tolerate combined regional and systemic therapy 4

The 2023 ESMO guidelines specifically state that patients unresponsive to first-line chemotherapy should not be denied resection or ablation, and intra-arterial chemotherapy could be an option to achieve liver resection 1.

Timing in Treatment Algorithm

HAI should be considered earlier rather than later in the treatment sequence. 1 While effective as salvage therapy, the data suggest better outcomes when used in first or second-line settings rather than after multiple failed systemic regimens 4. Time to initiation of HAI therapy averages 16-19 days post-procedure, with systemic therapy resuming at 34-35 days 6.

Combination with Primary Tumor Resection

Combining colorectal resection with HAI pump implantation is safe and does not delay chemotherapy initiation. 6 Combined procedures result in similar operative times, blood loss, and postoperative complications compared to HAI pump placement alone, though length of stay increases modestly (6 vs 4 days) 6. Importantly, infectious complications are not increased, and there is no delay to initiation of HAI or systemic chemotherapy 6.

Comparison with Other Locoregional Therapies

The 2022 ACR guidelines position HAI alongside other locoregional options but note distinct differences 1:

• TACE/TAE: Provides survival benefit without superiority data over HAI; most beneficial after 0-2 lines of systemic therapy 1
• TARE: No survival benefit as first-line therapy; reserved for salvage in chemo-refractory disease, though subgroup analysis shows benefit for right-sided primaries 1
• Ablation: Best for limited disease (<3 cm, <5 lesions) 1

HAI offers the unique advantage of potential conversion to resectability through high local drug concentrations while maintaining systemic therapy. 1