Supplementary Material for: Lenvatinib-Transarterial Chemoembolization Sequential Therapy as an Effective Treatment at Progression during Lenvatinib Therapy for Advanced Hepatocellular Carcinoma

<b><i>Background:</i></b> The aims of this study were to evaluate the efficacy of additional treatment, especially lenvatinib-transarterial chemoembolization (TACE) sequential therapy, for unresectable hepatocellular carcinoma (HCC). <b><i>Methods:</i></b> Consecutive 56 patients who underwent lenvatinib treatment were reviewed. Oncological aggressiveness of tumor was estimated using a dynamic CT enhancement pattern classification, and clinical impact of subsequent treatment was investigated through analysis of progression-free survival (PFS), post-progression survival (PPS), and multivariate analysis of potential confounders for survival after progression during lenvatinib therapy. <b><i>Results:</i></b> Heterogeneous enhancement patterns (<i>Type-3</i> and <i>-4</i>), which are reportedly associated with higher oncological aggressiveness of HCC, were associated with better objective response to lenvatinib compared to homogeneous enhancement pattern (<i>Type-2</i>) (86 and 85% vs. 53% in modified Response Evaluation Criteria in Solid Tumors), resulting in similar PFS (<i>p</i> = 0.313). Because of significantly worse PPS, overall survival of <i>Type-4</i> tumor was poor compared to <i>Type-2</i> or <i>-3</i> tumors (<i>p</i> = 0.009). However, subgroup of patients who achieved subsequent treatment showed significantly better PPS, regardless of CT enhancement pattern. Multivariate analysis confirmed that use of lenvatinib-TACE sequential treatment after progression during lenvatinib therapy was associated with better PPS (hazard ratio [HR], 0.08; 95% CI, 0.01–0.71; <i>p</i> = 0.023), while <i>Type-4</i> enhancement pattern was correlated with worse PPS (HR, 2.92; 95% CI, 1.06–8.05; <i>p</i> = 0.039). <b><i>Conclusion:</i></b> Oncological aggressiveness of HCC estimated by CT enhancement pattern was predictive of PPS after progression during lenvatinib. Successful subsequent treatment with lenvatinib-TACE sequential therapy may offer survival benefit regardless of CT enhancement pattern of HCC.

<b><i>背景：</i></b> 本研究旨在评估额外治疗方案的疗效，尤其是仑伐替尼（lenvatinib）-经动脉化疗栓塞（transarterial chemoembolization, TACE）序贯疗法针对不可切除肝细胞癌（unresectable hepatocellular carcinoma, HCC）的治疗效果。
<b><i>方法：</i></b> 本研究回顾性分析了56例接受仑伐替尼治疗的连续入组患者。采用动态CT增强分型评估肿瘤的侵袭性，并通过分析无进展生存期（progression-free survival, PFS）、进展后生存期（post-progression survival, PPS），以及对仑伐替尼治疗期间进展后生存的潜在混杂因素开展多因素分析，探究后续治疗的临床影响。
<b><i>结果：</i></b> 研究显示，据报道与肝细胞癌更高侵袭性相关的不均匀强化分型（3型、4型），相较于均匀强化分型（2型），对仑伐替尼的客观缓解率更优：改良实体瘤疗效评价标准（modified Response Evaluation Criteria in Solid Tumors, mRECIST）下分别为86%、85%，而2型仅为53%；二者的无进展生存期无显著差异（p=0.313）。由于4型肿瘤的进展后生存期显著更差，其总生存期相较于2型或3型肿瘤更差（p=0.009）。不过，无论CT增强分型如何，接受后续治疗的患者亚组的进展后生存期均显著更优。多因素分析证实，仑伐替尼治疗期间进展后采用仑伐替尼-TACE序贯治疗与更佳的进展后生存期相关（风险比[HR]=0.08；95%置信区间[CI]：0.01~0.71；p=0.023），而4型强化分型与更差的进展后生存期相关（HR=2.92；95%CI：1.06~8.05；p=0.039）。
<b><i>结论：</i></b> 本研究表明，通过CT增强分型评估的肝细胞癌肿瘤侵袭性，可预测仑伐替尼治疗期间进展后的进展后生存期。无论肝细胞癌的CT增强分型如何，成功采用仑伐替尼-TACE序贯疗法进行后续治疗，均可为患者带来生存获益。