Supplementary Material for: Factors affecting an increase in spleen volume and association of spleen volume variation with the clinical outcomes of atezolizumab and bevacizumab treatment for hepatocellular carcinoma: A retrospective analysis

Introduction: Gastrointestinal varices rupture is considered to be prone to occur during atezolizumab and bevacizumab (Atez/Bev) treatment. This study aimed to investigate predictive factors affecting the increase in spleen volume (SpV) and the association of SpV variation with the clinical outcomes of Atez/Bev.
Methods: A total of 164 HCC patients were included in this retrospective multicenter study. We measured SpV based on CT scans obtained before treatment and at evaluations. We used the inverse probability of treatment weight to address the imbalance between patient characteristics.
Results: The median pretreatment SpV was 184 (130-257) cm3 and the median SpV variation was 27 (9-60) cm3. An increase in the SpV was observed in 140 patients (85.4%). Age <74 years (p = 0.03), mALBI grade 2b or 3 (p = 0.03), and pretreatment SpV ≥184 cm3 (p < 0.001) were significantly associated with increased SpV. There were no significant differences in progression-free survival (PFS) or overall survival (OS) between patients with SpV variation <25 cm3 and those with SpV variation ≥25 cm3 in the crude (p=0.3 and 0.7) and IPTW-weighted cohorts (p = 0.08 and 0.8, respectively). Regarding pretreatment SpV, there were no significant differences in PFS or OS between patients with and without pretreatment spleen enlargement in the crude (both p = 0.3) and IPTW-weighted cohort (p = 0.6 and 0.3, respectively).
Conclusion: Caution is warranted to detect the aggravation of portal hypertension when administering Atez/Bev to young patients or patients with an impaired liver function or pretreatment spleen enlargement. The impact of spleen modulation by Atez/Bev appears to be limited on clinical efficacy.

引言：胃肠道静脉曲张破裂被认为在阿替利珠单抗联合贝伐珠单抗（atezolizumab and bevacizumab, Atez/Bev）治疗期间易发生。本研究旨在探讨影响脾脏体积（spleen volume, SpV）升高的预测因素，以及脾脏体积变化与阿替利珠单抗联合贝伐珠单抗治疗临床结局的关联。
方法：本回顾性多中心研究共纳入164例肝细胞癌（hepatocellular carcinoma, HCC）患者。我们基于治疗前及评估时点的计算机断层扫描（computed tomography, CT）影像测量脾脏体积。采用治疗权重逆概率法（inverse probability of treatment weight, IPTW）以校正患者特征间的不均衡性。
结果：治疗前脾脏体积的中位数为184（130~257）cm³，脾脏体积变化量的中位数为27（9~60）cm³。140例患者（占比85.4%）出现脾脏体积升高。年龄＜74岁（p=0.03）、改良白蛋白-胆红素分级（modified albumin-bilirubin grade, mALBI）2b级或3级（p=0.03），以及治疗前脾脏体积≥184 cm³（p＜0.001）均与脾脏体积升高显著相关。在原始队列与治疗权重逆概率加权队列中，脾脏体积变化量＜25 cm³与≥25 cm³的患者，其无进展生存期（progression-free survival, PFS）及总生存期（overall survival, OS）均无显著差异（原始队列p值分别为0.3与0.7，加权队列p值分别为0.08与0.8）。针对治疗前脾脏体积，无论患者治疗前是否存在脾脏增大，在原始队列（两组p值均为0.3）及治疗权重逆概率加权队列（p值分别为0.6与0.3）中，其无进展生存期与总生存期均无显著差异。
结论：对于年轻患者、肝功能受损患者或治疗前已存在脾脏增大的患者，在给予阿替利珠单抗联合贝伐珠单抗治疗时，需警惕门静脉高压症的加重。阿替利珠单抗联合贝伐珠单抗对脾脏的调节作用，对临床疗效的影响似乎较为有限。