HAIC-first sequential therapy for unresectable hepatocellular carcinoma.

Dear Editor,

We read with interest the study by Wan et al[1] investigating sequential hepatic artery infusion chemotherapy (HAIC) and transarterial chemoembolization (TACE) combined with targeted therapy and immunotherapy in unresectable hepatocellular carcinoma (uHCC). This work significantly advances multidisciplinary management by demonstrating that initiating quadruple therapy with HAIC before TACE (HTTI regimen) optimizes drug delivery, tumor response rates, progression-free survival (PFS), and overall survival (OS) compared to TACE-first approaches (THTI) or triple therapy. Notably, the strategy proved particularly effective for high-risk uHCC patients—including those with portal vein tumor thrombosis (PVTT) and bilateral lesions—achieving superior objective response rates (ORR 81.97% vs. 64.28%) and disease control rates (DCR). This addresses an urgent clinical need, as such patients typically respond poorly to standard systemic therapies.
Mechanistically, HAIC-induced immunogenic cell death may remodel the tumor microenvironment (TME), enhancing subsequent TACE, immunotherapy, and anti-angiogenic efficacy. These insights align with recent literature where Yuan et al[2] and Hou et al[3] validated similar TACE-HAIC combinations with tyrosine kinase/PD-1 inhibitors for PVTT patients, reporting improved survival over TACE alone. Hu et al[4] further established HAIC’s foundational role, showing neoadjuvant FOLFOX-HAIC significantly improved 5-year OS (64.7% vs. 53.8%) in resectable large HCC, collectively reinforcing HAIC’s utility as a backbone for integrated locoregional-systemic strategies[5].
Despite these contributions, the retrospective, single-center design limits generalizability. Residual confounding persists despite propensity score matching, and patient heterogeneity or variability in targeted/immunotherapy agents may impact reproducibility. Sample size imbalances across cohorts also warrant consideration.
Future research should prioritize multicenter randomized trials to validate the HTTI sequence and optimize drug selection/dosing. Concurrent investigations should identify predictive biomarkers[6], evaluate long-term outcomes including resistance mechanisms, and incorporate patient-reported quality-of-life metrics.
In conclusion, Wan et al[1] provide compelling evidence that HTTI has the potential to reshape the management of uHCC. Their “HAIC-first” paradigm could establish a new standard of care, pending validation in prospective studies. We eagerly anticipate further research to translate these findings into precision therapy.