Supplementary Material for: THE CONCEPT OF “CONVERSE THERAPEUTIC HIERARCHY” FOR PATIENTS WITH HEPATOCELLULAR CARCINOMA

Background. The clinical complexity of patients with hepatocellular carcinoma (HCC), the availability of multiple therapeutic options, and clinical therapeutic intents could make it challenging to identify an unequivocal limit between conversion, downstaging/downsizing, and neoadjuvant therapies and curative or palliative intent treatments and to dimension the most proper sequential therapeutic strategy for each patient.
Summary. The concept of converse therapeutic hierarchy could rationally embrace all the different sequential treatment options (e.g., from surgery to systemic therapy) and the different therapeutic clinical intents (e.g., curative, neoadjuvant, downstaging/downsizing, conversion, and palliative), sharing the common goal of converting the patient with HCC from a less to a more favourable condition to improve the chance (higher applicability – conversion or downstaging intent) or the effectiveness (better postoperative outcome – neoadjuvant intent) of “intent-to-cure treatments”. This narrative review aims to introduce and explain the umbrella concept of the converse therapeutic hierarchy as a valuable framework for everyday clinical practice, enabling clinicians to better define ideal candidates and good responders for each sequential strategy.
Furthermore, the converse therapeutic hierarchy concept represents a flexible container that should be continuously filled with new scientific evidence to build different sequential treatment strategies in the multidisciplinary and multi-step management of patients with HCC.
An operative and pragmatic definition of the various sequential treatment strategies, based on the initial probability of intent to cure therapy for patients with HCC, has also been proposed. This probability varies from very high to low. It is related to the initial treatment choice and the multiparametric patient evaluation (e.g., patient’s fitness, tumour features, liver function, and technical aspects) done by an expert multidisciplinary tumour board.
Key messages. The converse therapeutic hierarchy concept represents a valuable and pragmatic framework for everyday clinical practice. It also serves as a flexible container that must be filled with new high-quality evidence and expert consensus to better define the clinical boundaries between the different HCC sequential treatment strategies (e.g., neoadjuvant, downstaging/downsizing, and conversion).

背景：肝细胞癌（hepatocellular carcinoma, HCC）患者的临床复杂性、多种治疗方案的可及性以及临床治疗意图的差异，使得明确界定转化治疗（conversion therapy）、降期/缩瘤治疗（downstaging/downsizing therapy）、新辅助治疗（neoadjuvant therapy）与根治性或姑息性意向治疗之间的清晰边界，并为每位患者制定最恰当的序贯治疗方案，均极具挑战。
总结：逆向治疗层级（converse therapeutic hierarchy）这一伞状概念可合理涵盖所有不同的序贯治疗方案（例如从手术到全身治疗）以及不同的临床治疗意图（例如根治性、新辅助治疗、降期/缩瘤治疗、转化治疗及姑息性治疗），其共同目标是将肝细胞癌患者的病情由不利状态转为更优状态，以提升“根治性意向治疗（intent-to-cure treatments）”的实施可能性（转化或降期意图可扩大适用范围）或治疗有效性（新辅助意图可改善术后结局）。本叙述性综述（narrative review）旨在介绍并阐释逆向治疗层级这一实用框架，助力临床医师在日常临床实践中更精准地明确各类序贯治疗方案的理想候选人群与良好应答者。
此外，逆向治疗层级概念作为一个灵活载体，需持续纳入新的科学证据，以在肝细胞癌患者的多学科、多步骤管理中构建不同的序贯治疗方案。
研究人员还基于肝细胞癌患者初始根治性治疗意向概率，提出了各类序贯治疗方案的可操作且实用的定义。该概率跨度从极高至极低，其与初始治疗选择以及由专家多学科肿瘤会诊团队（multidisciplinary tumour board）开展的多参数患者评估（例如患者体能状态、肿瘤特征、肝功能及技术层面因素）密切相关。
核心要点：逆向治疗层级概念是适用于日常临床实践的实用且有价值的框架。其同时作为一个灵活载体，需持续纳入高质量新证据与专家共识，以进一步明确肝细胞癌各类序贯治疗方案（例如新辅助治疗、降期/缩瘤治疗及转化治疗）之间的临床边界。