Ultra-selective radiation segmentectomy for early-stage hepatocellular carcinoma

Background & Aims: Radiation segmentectomy (RS) is an emerging curative-intent therapy for early-stage hepatocellular carcinoma (HCC) when resection or ablation is not feasible. In this study, we evaluated the safety, efficacy, and dosimetric correlates of ultra-selective RS, defined as glass ⁹⁰Y-radioembolization delivered to vessels at least one order beyond parent segmental arteries, targeting <1 Couinaud segment. Methods: This retrospective study included 38 patients with 42 early-stage (BCLC 0–A) HCCs treated with ultra-selective RS from December 2022 to July 2024. All treatments used glass ⁹⁰Y-microspheres with perfused treatment volumes assessed by cone-beam CT. Post-treatment voxel-based dosimetry was conducted using ⁹⁰Y single-photon emission CT (SPECT)/CT. Tumor response and progression-free survival were assessed by modified RECIST. Explant pathology was used to evaluate treatment effect in transplant recipients, and albumin-bilirubin (ALBI) scores were tracked longitudinally. Results: The median tumor size was 2.4 cm with a median perfused treatment volume of 66.3 cc (4.5% of total liver volume). The median administered activity was 1.36 GBq (median absorbed dose 837 Gy). Complete response (CR) was achieved in 87% (n = 33), with only one local progression. Median local progression-free survival was not reached. Among 16 tumors with explant data, 69% showed complete necrosis and 25% extensive necrosis (median 88%). Tumor D₉₅ >300 Gy predicted CR (97% CR vs. 0% CR with D₉₅ <300 Gy; p <0.001), with logistic regression yielding an AUC of 0.98. Models incorporating tumor alignment within high-activity ⁹⁰Y-SPECT regions improved predictive accuracy. Over 82% of patients retained or improved ALBI grade during follow-up, with only 2 of 15 patients with baseline ALBI 2b declining to grade 3. Conclusions: Ultra-selective RS is a feasible and liver-sparing therapy for early-stage HCC. Voxel-based dosimetry confirms dose-response relationships and underscores the importance of tumor coverage. Impact and implications: This study demonstrates that ultra-selective radiation segmentectomy (uRS) with glass ⁹⁰Y microspheres can achieve high rates of complete imaging and pathologic response in early-stage HCC while treating very small liver volumes. These results replicate and extend prior radiation segmentectomy studies, underscoring that the ablative potential of ⁹⁰Y can be maintained with even greater liver parenchymal preservation. These findings are important for patients who are not candidates for surgery or ablation, especially given low rates of liver function decline after uRS. In practice, uRS may serve as a definitive therapy or as a bridge to liver transplantation, while voxel-based dosimetry provides a framework for ensuring adequate tumor coverage and identifying incomplete responders.