Raltitrexed in Hepatocellular Carcinoma: Mechanistic Rationale and Clinical Evidence from Arterial-Based Therapies

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide and is frequently diagnosed at an advanced stage, resulting in limited eligibility for curative therapies and suboptimal outcomes with systemic treatment alone. Locoregional arterial therapies, including transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC), therefore remain integral components of treatment for unresectable HCC. Raltitrexed is a quinazoline antifolate that directly and specifically inhibits thymidylate synthase, leading to sustained suppression of DNA synthesis. Compared with 5-fluorouracil, raltitrexed offers distinct pharmacokinetic and practical advantages, including prolonged intracellular retention and a short infusion schedule. Originally developed for colorectal cancer, raltitrexed has been increasingly incorporated into arterial-based treatment strategies for HCC over the past decade. Accumulating evidence from retrospective studies, prospective single-arm trials, and limited comparative analyses suggests that raltitrexed-based regimens demonstrate meaningful antitumor activity in conventional and drug-eluting bead TACE, as well as in oxaliplatin-based HAIC, with objective response rates, disease control, and survival outcomes comparable to established chemotherapy protocols. Notably, raltitrexed-based HAIC substantially reduces infusion time relative to fluorouracil-based regimens, improving treatment convenience without compromising efficacy. More recently, raltitrexed-containing HAIC has been explored in combination with targeted therapy and immune checkpoint inhibitors, yielding encouraging response rates and survival signals in patients with advanced disease. Overall, raltitrexed represents a rational and increasingly utilized component of arterial-based therapies for unresectable HCC. However, current evidence is predominantly derived from retrospective and single-arm studies, and well-designed randomized trials and biomarker-driven approaches are required to define its optimal role in clinical practice.