Abstract: It is well known that intermediate stage hepatocellular carcinoma (HCC) encompasses the widest class of patients with this disease. The main characteristic of this special sub-group of patients is that it is extensively heterogenous. This substantial heterogeneity is due to the wide range of liver functions of such patients and variable tumor numbers and sizes. Real world clinical data show huge support for transarterial chemo-embolization (TACE) as a therapeutic modality for intermediate stage HCC, applied in 50%–60% of those class of patients. There are special considerations in various international guidelines regarding treatment allocation in intermediate stage HCC. There is an epidemiological difference in HCC in eastern and western cohorts, and various guidelines have been proposed. In patients with HCC, it has frequently been reported that there is poor correlation between the clinical benefit and real gain in patient condition and the conventional way of tumor response assessment after locoregional treatments. This is due to the evaluation criteria in addition to the scoring systems used for treatment allocation in those patients. It became clear that intermediate stage HCC patients receiving TACE need a proper prognostic score that offers valid clinical prediction and supports proper decision-making. Also, it is the proper time to study more treatment options beyond TACE, such as multimodal regimens for this class of patients. In this review, we tried to provide a summary of the challenges and future directions in managing patients with intermediate stage HCC.


Keywords: staging, scores, liver, cancer, TACE, BCLC


INTRODUCTION

Hepatocellular carcinoma (HCC)1 is the second leading cause of global cancer-related deaths, especially in patients with liver cirrhosis, and it is the sixth most common malignancy worldwide. Staging of HCC plays a vital role in treatment strategy assignment according to international guidelines.

Intermediate stage or Barcelona Clinic Liver Cancer (BCLC) stage B HCC includes multiple tumorous lesions confined to the liver without vascular invasion in a patient with preserved liver functions and good performance status. The most common treatment modality for patients in this stage is transarterial chemo-embolization (TACE). Due to the heterogeneity in the population with this stage, the benefits and the outcome of TACE are considered variable.2 Patients with good reservoir of liver functions and small size tumor have better prognosis than those with poor liver functions and larger tumor size. The 2-year survival rate may reach 63% in patients with good matching criteria.3

INTERMEDIATE STAGE HCC AND TACE

It is well known that intermediate stage HCC encompasses the widest class of patients with this disease. The main characteristic of this special sub-group of patients is that it is extensively heterogenous. This substantial heterogeneity is due to the wide range of liver functions of such patients and variable tumor numbers and sizes.

Although the most commonly used therapeutic approach for such patients is TACE,2 there is a wide gap between guidelines and applied clinical practice, many therapeutic approaches, such as downstaging such patients with percutaneous ablation or radio-embolization followed by radical resection, have been reported.4–6

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In general, guidelines have concluded that the limitations of TACE are due to the extensive heterogeneity within the cohorts. The technique has also been found to have varying results as wide differences were noticed regarding range of selectivity of embolization, emulsifying agents, and degree of treatment delivery. These result in the wide range of responses and benefits obtained from TACE. Also, the differences in liver function capacity and tumor burden between subgroups with this intermediate stage resulted in the fact that not all patients were exposed to the same risk. Consequently, the risk benefit ratio in this case is not accurate or easily evidenced from clinical studies.7

Staging systems resemble the corner stone in the process of patient selection and treatment allocation which determine the prognosis. The more efficient the staging or scoring system, the better the outcome. Staging systems such as Okuda, Child-Pugh, TNM, CLIP, and BCLC have been extensively validated in various cohorts. However, they did not properly fit a heterogenous cohort such as intermediate stage HCC patients. It is rare to find a staging system that correlates with prognosis and treatment allocation. Such systems provide more accurate prognosis and survival prediction.8