The Concept of "Converse Therapeutic Hierarchy" for Patients with Hepatocellular Carcinoma

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.

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.

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).