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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Anti-PD-1 antibody; Anti-angiogenic therapy; Conversion therapy; Hepatocellular carcinoma.

Fig. 1

Patient flowchart.

Fig. 2

Two representative cases. a Patient 4 was diagnosed with multiple HCCs involving the right liver lobe and invading the main branch of the portal vein (BCLC stage C). The patient received lenvatinib 8 mg/day and sintilimab 200 mg every 3 weeks for 9 weeks. Following systemic therapy, the primary tumors showed no arterial enhancement on contrast-enhanced MRI, and the portal vein tumor thrombosis regressed. Curative liver resection was performed. H&E staining of the surgically resected specimen showed a pCR. b Patient 10 was diagnosed with a solitary HCC lesion involving the right hepatic vein, middle hepatic vein, and right pedicle (BCLC stage A). However, the tumor was unresectable because the ratio of the remnant liver volume was insufficient (the ratio of left external liver lobe volume to standard liver volume was 18.7%). The patient received PVE and lenvatinib 8 mg/day and pembrolizumab 200 mg every 3 weeks. Nine weeks after treatment initiation, the ratio of the residual to standard liver volume increased to 31.5%, and curative liver resection was performed. H&E staining of the surgically resected specimen showed a pCR. HCC, hepatocellular carcinoma; H&E, hematoxylin and eosin; MR, magnetic resonance; CT, computed tomography; BCLC, Barcelona Clinic Liver Cancer; PVE, portal vein embolism; pCR, pathological complete response; MHV, middle hepatic vein; RHV, righ hepatic vein; RPV, right portal vein.

Fig. 3

Pretreatment MR or CT scan showed that the patients (except patients 4 and 10) had a unresectable HCC before systemic treatment and imaging scan before surgery. The major reason of unresectability were tumor invasion into major portal vein (patients 1 and 2), into the first branch of the portal vein (patients 6 and 9), into middle hepatic vein (patient 7), or into right atrium (patient 8; the intrahepatic nodule was not shown on this image) (red arrows); multiple intrahepatic lesions (yellow arrows) (patients 3 and 5) (only 1 nodule was shown on this image for patient 5). Before surgery, obvious tumor regression was observed in all the cases, except sustained stable disease were seen for patient 2, and partial response in the intrahepatic lesion but a new metastatic lesion in the right adrenal gland (green arrow) for patient 9. HCC, hepatocellular carcinoma; MR, magnetic resonance; CT, computed tomography.