Supplementary Material for: The impact of radiation dose and tumour burden on outcomes in hepatocellular carcinoma: 11-year experience in a 413-patient cohort treated with yttrium-90 resin microsphere radioembolisation

Introduction
Transarterial radioembolisation (RE) using yttrium-90 (Y-90) microspheres is a widely used locoregional therapy for a broad spectrum of HCC given its favourable safety profile. We evaluated the real-world outcomes of unresectable HCC treated with resin Y-90 RE and the relationship between tumour absorbed dose and subsequent curative therapy with survival.
Methods
Included were consecutive patients treated with Y-90 resin microspheres RE for unresectable HCC between January 2008 and May 2019 at the National Cancer Centre Singapore /Singapore General Hospital. The outcomes were stratified by tumour burden, distribution, presence of portal vein invasion (PVI) and liver function to improve prognostication.
Results
The median overall survival (OS) evaluated on 413 included patients was 20.9 months (95% CI 18.2 – 24.0). More than half of the patients (214/413, 51.8%) had HCC beyond up-to-seven criteria, and 37.3% had portal vein invasion (154/413, 37.3%). Majority (71.7%) had dosimetry calculated based on the partition model. Patients who received ≥150 Gy to tumour had significantly better outcomes (OS 32.2 months, 95% CI 18.3 – 46.4) than those who did not (OS 17.5 months, 95% CI 13.7 – 22.7, p < 0.001). Seventy patients (17%) received curative therapies after tumour was downstaged by Y-90 RE and had better OS of 79.7 months (95% CI 40.4 – NE) compared to those who did not receive curative therapies (OS 17.1 months; 95% CI 13.5 – 20.4, p < 0.001). Radioembolisation-induced liver injury was observed in 5.08% of the patients while 3.2% of the patients had possible radiation pneumonitis but none developed Grade 3-4 toxicity. For HCC without PVI, overall survival differed significantly with performance status, ALBI grade, tumour distribution, and radiation dose; for HCC with PVI, Child-Pugh class and AFP were significant predictors of survival.
Conclusions
Treatment outcomes for unresectable HCC using Y-90 RE were favourable. Incorporating tumour burden and distribution improved prognostication. Patients who received tumour absorbed dose above 150 Gy had better OS. Patients who subsequently received curative therapies after being downstaged by Y-90 RE had remarkable clinical outcomes.

引言
采用钇-90（yttrium-90, Y-90）微球行经动脉放射性栓塞术（radioembolisation, RE）是一类应用广泛的局部区域治疗手段，可用于多种亚型肝细胞癌（hepatocellular carcinoma, HCC），因其安全性表现优异。本研究评估了接受树脂基Y-90微球放射性栓塞术治疗的不可切除肝细胞癌患者的真实世界结局，同时分析了肿瘤吸收剂量与后续根治性治疗及患者生存之间的关联。

方法
纳入2008年1月至2019年5月期间，于新加坡国家癌症中心/新加坡总医院接受树脂基Y-90微球放射性栓塞术治疗的连续入组不可切除肝细胞癌患者。研究结局按肿瘤负荷、肿瘤分布、是否合并门静脉侵犯（portal vein invasion, PVI）及肝功能状态进行分层，以优化预后评估效能。

结果
本研究共纳入413例患者，其评估所得中位总生存期（overall survival, OS）为20.9个月（95%置信区间（confidence interval, CI）：18.2~24.0）。超过半数患者（214/413，51.8%）的肝细胞癌超出up-to-seven标准（up-to-seven criteria），37.3%的患者合并门静脉侵犯（154/413，37.3%）。绝大多数患者（71.7%）的剂量学计算基于分割模型。肿瘤吸收剂量≥150戈瑞（Gray, Gy）的患者生存结局显著更优（中位OS为32.2个月，95%置信区间：18.3~46.4），相较于未达到该剂量的患者（中位OS为17.5个月，95%置信区间：13.7~22.7，p<0.001）。70例患者（17%）在经放射性栓塞术降期后接受了根治性治疗，其中位OS达79.7个月（95%置信区间：40.4~未达到），显著优于未接受根治性治疗的患者（中位OS为17.1个月，95%置信区间：13.5~20.4，p<0.001）。5.08%的患者出现放射性栓塞相关肝损伤，3.2%的患者出现疑似放射性肺炎，但无患者发生3~4级毒性反应。对于未合并门静脉侵犯的肝细胞癌患者，其总生存期与体力状态评分、ALBI分级、肿瘤分布及放射剂量显著相关；对于合并门静脉侵犯的肝细胞癌患者，Child-Pugh分级与甲胎蛋白（alpha-fetoprotein, AFP）水平是显著的生存预测因素。

结论
采用Y-90微球放射性栓塞术治疗不可切除肝细胞癌的临床结局表现优异。纳入肿瘤负荷与分布特征可优化预后评估效能。肿瘤吸收剂量≥150 Gy的患者总生存期更优。经放射性栓塞术降期后接受根治性治疗的患者可获得显著的临床获益。