Downstaging and Resection of Initially Unresectable Hepatocellular Carcinoma with Tyrosine Kinase Inhibitor and Anti-PD-1 Antibody Combinations

Abstract

<b><i>Background:</i></b> Combined therapy with tyrosine kinase inhibitors (TKIs) and anti-PD-1 antibodies has shown high tumor response rates for patients with unresectable hepatocellular carcinoma (HCC). However, using this treatment strategy to convert initially unresectable HCC to resectable HCC was not reported. <b><i>Methods:</i></b> Consecutive patients with unresectable HCC who received first-line therapy with combined TKI/anti-PD-1 antibodies were analyzed. Tumor response and resectability were evaluated via imaging every 2 months (±2 weeks) using RECIST v1.1. Resectability criteria were (1) R0 resection could be achieved with sufficient remnant liver volume and function; (2) intrahepatic lesions were evaluated as partial responses or stable disease for at least 2 months; (3) no severe or persistent adverse effects occurred; and (4) hepatectomy was not contraindicated. <b><i>Results:</i></b> Sixty-three consecutive patients were enrolled. Of them, 10 (15.9%) underwent R0 resection in 3.2 months (range: 2.4–8.3 months) after the initiation of combination therapy. At baseline, these 10 patients had a median largest tumor diameter of 9.3 cm, 7 had Barcelona Clinic Liver Cancer stage C (vascular invasion) disease, 2 had stage B, and 1 had stage A. Before surgery, 6 patients were evaluated as a partial response, 3 stable disease, and 1 partial response in the intrahepatic lesion but a new metastatic lesion in the right adrenal gland. Six patients (60%) achieved a pathological complete response. One patient died from immune-related adverse effects 2.4 months after hepatectomy. After a median follow-up of 11.2 months (range: 7.8–15.9 months) for other 9 patients, 8 survived without disease recurrence, and 1 experienced tumor recurrence. <b><i>Conclusions:</i></b> Combination of TKI/anti-PD-1 antibodies is a feasible conversion therapy for patients with unresectable HCC to become resectable. This study represents the largest patient cohort on downstaging role of combinational systemic therapy on TKI and PD-1 antibody for HCC.

Downstaging Conversion Therapy in Patients With Initially Unresectable Advanced Hepatocellular Carcinoma: An Overview

“…Results from several small sample studies also support c o m b i n a t i o n t h e r a p y w i t h T K I s c o m b i n e d w i t h immunotherapy in the conversion treatment setting in patients with unresectable HCC. For example, Zhu et al reported 63 cases of patients with initially unresectable liver cancer treated with PD-1 inhibitors combined with a TKI, 60 of whom were classed as Child-Pugh A, and the conversion resection rate was 15.9% (19). A further study by Lu et al of 33 patients with unresectable liver cancer with measurable PVTT (by mRECIST) and no extrahepatic metastasis who were treated with PD-1 inhibitors combined with Lenvatinib, reported a conversion rate of 42.4% (22).…”

“…For example, Zhu et al. reported 63 cases of patients with initially unresectable liver cancer treated with PD-1 inhibitors combined with a TKI, 60 of whom were classed as Child-Pugh A, and the conversion resection rate was 15.9% ( 19 ). A further study by Lu et al.…”

Chinese expert consensus on conversion therapy for hepatocellular carcinoma (2021 edition)

“…Conversion therapy for unresectable HCC has been explored many years ago, and successful cases are not rare; there have been multiple reports of successful conversion from small-sample retrospective cohort studies (20,21,(37)(38)(39)(40). However, there remain many controversies and questions.…”

“…At present, the research on conversion therapy mostly comprises small-sample retrospective clinical studies. (39). In clinical practice, the optimal choice of systemic treatment for patients with potentially resectable HCC is still unclear.…”

Recent Advances and Future Prospects in Immune Checkpoint (ICI)-Based Combination Therapy for Advanced HCC

“…In a recently published real-world study, 63 patients with advanced HCC received either lenvatinib-pembrolizumab or camrelizumab-apatinib. In total, 15.9% of patients were able to receive curative resection following systemic treatment [55].…”