In a groundbreaking comparative study poised to reshape the therapeutic landscape for advanced hepatocellular carcinoma (HCC), researchers have unveiled compelling evidence that combining lenvatinib with radiotherapy (RT) may yield superior local tumor control relative to the established regimen of lenvatinib alongside transarterial chemoembolization (TACE). This new research, published in the prestigious journal BMC Cancer, rigorously evaluated the efficacy of these combination treatments, highlighting a potential paradigm shift in clinical oncology for managing a notoriously challenging malignancy.

Advanced HCC remains a formidable clinical challenge, with limited effective treatment options and a dismal prognosis. Traditionally, systemic therapies like lenvatinib, a tyrosine kinase inhibitor, have been employed to target molecular pathways promoting tumor progression. However, local control of hepatic tumors is crucial for improving patient survival and quality of life. Transarterial chemoembolization has long been a favored loco-regional strategy, leveraging targeted delivery of chemotherapy to the tumor vasculature, yet its efficacy in combination with systemic agents remains contentious.

This retrospective investigation encompassed 32 patients diagnosed with advanced HCC between December 2018 and January 2022 at a single academic institution. Patients were stratified into two cohorts: 17 receiving combined radiotherapy plus lenvatinib, and 15 treated with transarterial chemoembolization plus lenvatinib. The study focused on critical endpoints such as overall survival (OS) and infield control (IFC), a metric assessing tumor control within targeted treatment fields.

Utilizing robust statistical methodologies, including the Kaplan–Meier survival analysis and Cox proportional hazards models, the investigators meticulously accounted for confounders that could skew comparative outcomes. Notably, inverse-probability-of-treatment weighting (IPTW) and Fine–Gray competing risk analyses were applied to correct baseline imbalances and competing event risks inherent in observational studies, thereby enhancing result validity.

The median follow-up period spanned 10.2 months, enabling a substantive evaluation of longitudinal treatment impact. While overall survival did not differ significantly between the RT and TACE cohorts, a pronounced divergence emerged in local tumor control. The RT plus lenvatinib group exhibited substantially prolonged infield control durations, with a statistically significant p-value of 0.010. At the one-year mark, the infield control rate was an impressive 74.7% for the RT group, starkly contrasted with a mere 13.2% for patients undergoing TACE.

Multivariable analyses reinforced these findings by demonstrating that receiving radiotherapy was independently associated with enhanced IFC outcomes. This advantageous effect persisted following IPTW adjustments, underscoring the robustness of the therapeutic benefit attributed to RT when combined with lenvatinib. Additionally, the cumulative rate of infield failure at twelve months was markedly lower in the RT group (14.9%) compared to the TACE cohort (61.0%), providing further quantitative substantiation of the superior local control achieved with radiotherapy.

A pivotal biochemical marker, alpha-fetoprotein (AFP), often elevated in HCC and indicative of tumor burden, underwent significant reductions within three months post-RT treatment. This contrasted with negligible AFP changes following TACE, highlighting RT’s potent antitumor activity at the molecular level. The data suggest that radiotherapy not only physically impedes tumor growth but may also modulate the tumor microenvironment in synergy with lenvatinib’s systemic effects.

From a hepatic function standpoint, the study examined changes in the Child–Pugh score, an established prognostic tool reflecting liver disease severity. The RT group experienced notably less deterioration, with only 5.9% showing a two-point or greater decline, compared to 26.7% in the TACE group. Although this difference approached but did not achieve statistical significance, it suggests better preservation of liver function when radiotherapy is employed, an essential consideration in the management of patients with compromised hepatic reserve.

The mechanistic rationale for these divergent outcomes likely stems from the distinct modes of action intrinsic to radiotherapy and transarterial chemoembolization. Radiotherapy delivers precisely targeted ionizing radiation, inducing DNA damage and tumor cell apoptosis, potentially potentiated by lenvatinib’s antiangiogenic properties that may enhance tumor oxygenation and radiosensitivity. Conversely, TACE relies on ischemic necrosis via embolization, which may inadvertently exacerbate hypoxia-induced survival pathways, potentially attenuating overall efficacy.

This investigation’s implications extend beyond clinical efficacy; it frames a novel therapeutic strategy prioritizing sustained local tumor control while safeguarding hepatic function, which is critical for patient quality of life and eligibility for subsequent therapies. Importantly, the study underscores the value of integrating multidisciplinary approaches, combining systemic pharmacologic agents with precise loco-regional interventions to tackle the complex biology of advanced HCC.

Despite the retrospective design and limited sample size, the methodological rigor employed—including propensity score weighting and competing risk analyses—lends credence to the observed benefits of RT plus lenvatinib. Future prospective, randomized trials with larger cohorts are warranted to confirm these promising findings and explore optimal sequencing, dose parameters, and patient selection criteria to maximize therapeutic gain.

Moreover, the pronounced AFP decline post-radiotherapy invites exploration into biomarker-driven treatment tailoring and the potential use of AFP dynamics as an early surrogate endpoint for therapeutic response evaluation. The preservation of liver function with RT further suggests it could serve as a cornerstone therapy in patients with borderline hepatic reserves, expanding the pool of candidates for effective advanced HCC management.

In the broader context of oncology, this study exemplifies the evolving trend towards combinatorial regimens designed to exploit synergistic mechanisms and overcome resistance pathways. The integration of radiotherapy with targeted systemic agents represents a convergence of precision medicine and traditional therapeutic modalities, potentially heralding a new era in hepatocellular carcinoma treatment paradigms.

To patients and clinicians grappling with the formidable prognosis of advanced HCC, these findings offer a beacon of hope—a refined therapeutic avenue that balances potent tumor eradication with the preservation of hepatic function. As research advances, the convergence of molecular insights, innovative treatment technologies, and rigorous clinical evaluation will be pivotal in transforming the outlook for this challenging malignancy.

Ultimately, the study by Chuang and colleagues delineates a compelling narrative for radiotherapy’s enhanced role when paired with lenvatinib, positioning it as a formidable contender against the historically dominant TACE combination. This evidence not only challenges existing treatment conventions but also enriches the oncologic armamentarium with a strategy that may substantially improve patient outcomes in advanced hepatocellular carcinoma.

Subject of Research: Advanced hepatocellular carcinoma treatment comparing lenvatinib combined with radiotherapy versus lenvatinib combined with transarterial chemoembolization.

Article Title: Lenvatinib in combination with radiotherapy versus lenvatinib with transarterial chemoembolization for advanced hepatocellular carcinoma.

Article References:
Chuang, WY., Shen, PC., Chiu, SH. et al. Lenvatinib in combination with radiotherapy versus lenvatinib with transarterial chemoembolization for advanced hepatocellular carcinoma. BMC Cancer 25, 1449 (2025). https://doi.org/10.1186/s12885-025-14931-1

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14931-1

Keywords: hepatocellular carcinoma, lenvatinib, radiotherapy, transarterial chemoembolization, local tumor control, alpha-fetoprotein, Child–Pugh score, advanced liver cancer, combination therapy