The Evolving Scenario in the Assessment of Radiological Response for Hepatocellular Carcinoma in the Era of Immunotherapy: Strengths and Weaknesses of Surrogate Endpoints

Abstract

Hepatocellular carcinoma (HCC) is a challenging malignancy characterised by clinical and biological heterogeneity, independent of the stage. Despite the application of surveillance programs, a substantial proportion of patients are diagnosed at advanced stages when curative treatments are no longer available. The landscape of systemic therapies has been rapidly growing over the last decade, and the advent of immune-checkpoint inhibitors (ICIs) has changed the paradigm of systemic treatments. The coexistence of the tumour with underlying cirrhosis exposes patients with HCC to competing events related to tumour progression and/or hepatic decompensation. Therefore, it is relevant to adopt proper clinical endpoints to assess the extent of treatment benefit. While overall survival (OS) is the most accepted endpoint for phase III randomised controlled trials (RCTs) and drug approval, it is affected by many limitations. To overcome these limits, several clinical and radiological outcomes have been used. For instance, progression-free survival (PFS) is a useful endpoint to evaluate the benefit of sequential treatments, since it is not influenced by post-progression treatments, unlike OS. Moreover, radiological endpoints such as time to progression (TTP) and objective response rate (ORR) are frequently adopted. Nevertheless, the surrogacy between these endpoints and OS in the setting of unresectable HCC (uHCC) remains uncertain. Since most of the surrogate endpoints are radiology-based (e.g., PFS, TTP, ORR), the use of standardised tools is crucial for the evaluation of radiological response. The optimal way to assess the radiological response has been widely debated, and many criteria have been proposed over the years. Furthermore, none of the criteria have been validated for immunotherapy in advanced HCC. The coexistence of the underlying chronic liver disease and the access to several lines of treatments highlight the urgent need to capture early clinical benefit and the need for standardised radiological criteria to assess cancer response when using ICIs in mono- or combination therapies. Here, we review the most commonly used clinical and radiological endpoints for trial design, as well as their surrogacy with OS. We also review the criteria for radiological response to treatments for HCC, analysing the major issues and the potential future perspectives.

Keywords: HCC; RECIST 1.1; endpoints; hepatocellular carcinoma; immunotherapy; mRECIST; radiological criteria; systemic therapy.

Figure 1

Therapeutic algorithm of systemic therapies proposed by the Italian Association of Liver Diseases (AISF) [29].

Figure 2

Evaluation of the benefit of sequential therapies: overall survival is the result of the sum of progression-free survival of different subsequent lines of therapy.

Figure 3

A 61-year-old man with infiltrative hepatocellular carcinoma and tumour thrombosis of the inferior vena cava: On baseline contrast-enhanced CT ((A), arterial phase; (B), portal venous phase), the largest tumour diameter measures 12.8 cm. CT follow-up ((C), arterial phase; (D), portal venous phase) after three months of atezolizumab–bevacizumab demonstrates a decrease in the size of the lesion, with a total tumour diameter of 10.8 cm (continuous line), consistent with stable disease according to the RECIST 1.1 criteria, but with a residual internal enhancing component of 6.1 cm (dashed line), consistent with a partial response according to the mRECIST criteria.

Figure 4

Radiological response according to RECIST 1.1.

Figure 5

Radiological response according to mRECIST.