Systemic therapy for hepatocellular carcinoma (HCC) is currently indicated for use in patients with advanced-stage Barcelona Clinic Liver Cancer (BCLC) stage C disease. However, increasing evidence suggests benefit of using upfront systemic therapy in some patients with intermediate-stage HCC. At the Hong Kong College of Radiologists’ 28th Annual Scientific Meeting, Dr Stephen Chan of the Department of Clinical Oncology, Chinese University of Hong Kong, discussed this paradigm shift in treatment and the role of lenvatinib (Lenvima®, Eisai) for improving survival in patients with intermediate-stage HCC.

Limitations of TACE in HCC

Transarterial chemoembolization (TACE) is currently the standard-of-care for intermediate-stage BCLC stage B HCC, which encompasses a heterogeneous population with considerable differences in tumour burden and liver function. While TACE is highly effective in some patients, a number of patients do not benefit from this treatment.

Subgroup analysis of clinical studies showed significant survival benefit with TACE vs symptomatic treatment in patients with unresectable HCC and tumours ≤5 cm (p=0.003), but not in those with tumours >5 cm. [Hepatology 2002;35:1164-1171] Moreover, real-world data support the use of TACE in only 50–60 percent of patients classified as intermediate-stage HCC. [J Hepatocell Carcinoma 2019;6:105-117]

Preserving liver function is equally important for improving survival in HCC. Studies have reported that treatment with TACE can impair hepatic function and lead to poorer prognosis. “Patients are typically treated with multiple cycles of TACE until they develop TACE failure or refractoriness, before systemic therapy is considered,” said Chan. “However, multiple unselective TACE procedures can lead to deterioration of liver function, which can impact patients’ eligibility for subsequent systemic therapy.”

Better candidate selection for TACE

The up-to-7 criteria are defined as the sum of the size of the largest tumour in centimetres and the total number of tumours in the absence of microvascular invasion. “Patients who fall within the up-to-7 criteria and have preserved hepatic function were shown to benefit the most from TACE,” said Chan. [Liver Cancer 2018;7:104-119] “In real-world analysis, greater hepatic dysfunction and earlier impairment were seen in patients with tumour burden beyond the up-to-7 criteria who received TACE. As systemic therapy can help preserve hepatic function, upfront systemic therapy should be considered in patients who are unsuitable for TACE.” [Cheng AL, et al, ILCA 2018, abstract P-34]

Systemic therapy for intermediate-stage HCC

Subgroup analyses of randomized clinical trials have previously shown efficacy with systemic therapy in patients with intermediate-stage HCC. In the randomized phase III REFLECT study, lenvatinib treatment was associated with similar overall survival (OS) benefit vs sorafenib in patients with unresectable BCLC stage B and BCLC stage C HCC (hazard ratio [HR] for BCLC stage B, 0.91; 95 percent confidence interval [CI], 0.65 to 1.28) (HR for BCLC stage C, 0.92; 95 percent CI, 0.77 to 1.08). [Lancet 2018;391:1163-1173]

In another study, atezolizumab plus bevacizumab provided similar benefit in progression-free survival (PFS) vs sorafenib in patients with BCLC stage B and BCLC stage C HCC (HR for BCLC stage B, 0.65; 95 percent CI, 0.33 to 1.30) (HR for BCLC stage C, 0.58; 95 percent CI, 0.45 to 0.75). Data from both trials suggest that a spectrum of patients with intermediate and advanced HCC may benefit from systemic therapy. [N Engl J Med 2020;382:1894-1905]

Improved survival with lenvatinib

Lenvatinib is a multikinase inhibitor that has demonstrated noninferiority to sorafenib for OS (13.6 months vs 12.3 months; HR, 0.92; 95 percent CI, 0.79 to 1.06) in unresectable HCC. [Lancet 2018;391:1163-1173]

In these patients, lenvatinib also demonstrated statistically significant and clinically meaningful improvements in PFS (7.3 months vs 3.6 months; HR, 0.64; 95 percent CI, 0.55 to 0.75; p<0.0001), time-to-progression (7.4 months vs 3.7 months; HR, 0.60; 95 percent CI, 0.51 to 0.71; p<0.0001) and objective response rate (ORR) (40.6 percent vs 12.4 percent; odds ratio [OR], 5.01; 95 percent CI, 3.59 to 7.01; p<0.0001) vs sorafenib (all values cited are from masked independent imaging review according to modified response evaluation criteria in solid tumors [mRECIST]). [Lancet 2018;391:1163-1173]

Based on these data, lenvatinib was assessed as upfront systemic therapy vs conventional TACE in a proof-of-concept study in patients with intermediate-stage HCC. Patients in the retrospective, propensity score–matched study had unresectable HCC exceeding the up-to-7 criteria, no vascular invasion, no extrahepatic spread, no prior treatment with TACE or systemic therapy, and Child-Pugh A liver function. [Cancers (Basel) 2019;11:1084]

This proof-of-concept study was the first to demonstrate a significant improvement in survival with first-line systemic therapy vs standard-of-care TACE in patients with intermediate-stage HCC and no prior TACE treatment. Median OS was 37.9 months with lenvatinib vs 21.3 months with TACE (HR, 0.48; 95 percent CI, 0.16 to 0.79; p<0.01). (Figure) Patients receiving lenvatinib also experienced significantly longer PFS (median, 16.0 months vs 3.0 months; HR, 0.19; 95 percent CI, 0.10 to 0.35; p<0.001) and significantly higher ORR (73.3 percent vs 33.3 percent; OR, 0.18; 95 percent CI, 0.07 to 0.48; p<0.001) vs TACE recipients. (Figure)

Importantly, lenvatinib was associated with better preservation of liver function vs TACE both during and after the 4-month treatment course. Change in albumin-bilirubin (ALBI) score was from -2.61 at baseline to -2.61 at the end of treatment (p=0.254) in lenvatinib group, compared with significant worsening from -2.66 to -2.09 (p<0.01) in TACE recipients.

Based on current evidence, the Asia-Pacific Primary Liver Cancer Experts Consensus Statement recommends treatment with superselective conventional TACE in intermediate-stage HCC patients eligible for effective or curative TACE. In patients who are ineligible for TACE, systemic therapy is recommended as the first choice of treatment. [Liver Cancer 2020;9:245-260]