The concept of therapeutic hierarchy for patients with hepatocellular carcinoma: A multicenter cohort study

Abstract

Alessandro Vitale and Fabio Farinati equally contributed to this work.Prognosis and designing a treatment modality in patients with hepatocellular carcinoma (HCC) are extremely complex because, in most cases, this neoplasm is accompanied by the cirrhotic liver and other comorbidities. 1 Thus in such cases, tumour stage, the degree of liver function and general conditions of patients are the major deterministic factors. 2,3 A common and promising approach linking prognostic variables with therapeutic choice is to analyse large patient cohorts and, using treatment selection as the main endpoint, identify the fundamental treatment rules. An example of such a data-based approach is the HCC treatment schedule recently proposed by the Hong Kong Liver Cancer (HKLC) group. In this approach, Yau et al 4 applied an algorithm based on classification and regression tree statistical methodology to link the main treatment decision rules with HKLC tumour stages. The main limitation of this approach, however, was that the Key points• Using a large consecutive cohort of patients with hepatocellular carcinoma from Italy (n = 4,867), we showed that a clear therapeutic hierarchy exists irrespective of tumour stage, live function, patient general conditions and treatment period.• This therapeutic hierarchy, in order of survival benefit gain, follows liver transplantation, liver resection, ablation, intra-arterial therapies, systemic therapy and best supportive care.• The results of this study suggest that a personalized approach based on the therapeutic hierarchy concept should be pursued in the context of a multidisciplinary evaluation, for each patient with hepatocellular carcinoma, irrespective of the stage of the disease. AbstractBackground: The Italian Liver Cancer (ITA.LI.CA) prognostic system for patients with hepatocellular carcinoma (HCC) has recently been proposed and validated. We sought to explore the relationship among the ITA.LI.CA prognostic variables (ie tumour stage, functional score based on performance status and Child-Pugh score, and alpha-fetoprotein), treatment selection and survival outcome in HCC patients. Patients and Methods:We analysed 4,867 consecutive HCC patients undergoing six main treatment strategies (liver transplantation, LT; liver resection, LR; ablation, ABL; intra-arterial therapy, IAT; Sorafenib, SOR; and best supportive care, BSC) and enrolled during 2002-2015 in a multicenter Italian database. In order to control pretreatment imbalances in observed variables, a machine learning methodology was used and inverse probability of treatment weights (IPTW) was calculated. An IPTWadjusted multivariate survival model that included ITA.LI.CA prognostic variables, treatment period and treatment strategy was then developed. The survival benefit of HCC treatments was described as a hazard ratio (95% confidence interval), using BSC as a reference value and as predicted median survival.Results: After the IPTW, the six treatment groups became well balanced for most baseline characteristics. In the IPTW-adjust...

Treatment of Hepatocellular Carcinoma in the Precision Medicine Era: From Treatment Stage Migration to Therapeutic Hierarchy

“…(5) The peculiarity of patients with HCC (i.e., multiple fundamental prognostic variables besides tumor features and the availability of several evidence-based treatments) has prompted the introduction of another approach, which associates prognostic variables to the treatment decision, thereby creating prognostic systems that simultaneously suggest treatment indications. (1,(6)(7)(8) In 1999, the Barcelona Clinic Liver Cancer (BCLC) group proposed the seminal treatmentdictating staging system for HCC, which associated each stage (or substage) to a specific treatment. (6) The BCLC classification was generated following the analysis of the results of randomized controlled studies which evaluated a particular treatment modality against the placebo between patients with comparable tumor characteristics and liver function.…”

“…(42) A detailed description of the existence of a "therapeutic hierarchy" for HCC has been reported recently by the Italian Liver Cancer group (ITA.LI.CA). (8) Working with a large consecutive cohort of patients with HCC (n = 4,867), the authors identified, on the basis of survival benefit observed in clinical practice, a distinct therapeutic hierarchy irrespective of tumor stage, liver function, patient's general condition, and calendar period. This finding was obtained using a multivariate model adjusted with the inverse probability weight method to control for pretreatment imbalances of the baseline variables, thereby eliminating treatment selection bias arising from the survival analysis.…”

Monofocal hepatocellular carcinoma: How much does size matter?

“…In large HCC, thermal ablation with radiofrequency is unable to achieve response rates and outcomes comparable to those observed in smaller tumours, 1 and the efficacy of transarterial chemoembolization is debatable 25,26 . Recently, a therapeutic hierarchy (determined by the decreasing survival benefit starting from LT, through progressively less radical treatments, to best supportive care [BSC]) has been demonstrated, irrespective of stage 27 …”

Therapeutic hierarchy in hepatocellular carcinoma: A dispute of evidence versus practice

“…In assessing cancer patients, every clinician responsible for therapeutic decision making is routinely faced with a fairly chal- In their seminal paper published in this issue of Liver International, Vitale et al take a rather innovative approach by reporting survival outcomes of a large multi-centre patient dataset on the basis of six therapeutic strategies ranging from liver transplantation to best supportive care. 5 As stage classifier, they utilise ITA.LI.CA., a validated prognostic system that takes into account size and number of HCC nodules, vascular invasion, alpha-foetoprotein (AFP) levels, Child-Pugh score and performance status. 6 The rather provocative finding that emerges from this study is the documentation of a clear gradient in overall survival across therapeutic modality independent of stage.…”

“…In their seminal paper published in this issue of Liver International, Vitale et al take a rather innovative approach by reporting survival outcomes of a large multi‐centre patient dataset on the basis of six therapeutic strategies ranging from liver transplantation to best supportive care . As stage classifier, they utilise ITA.LI.CA., a validated prognostic system that takes into account size and number of HCC nodules, vascular invasion, alpha‐foetoprotein (AFP) levels, Child‐Pugh score and performance status …”