Efficacy of the Combination of Systemic Sequential Therapy and Locoregional Therapy in the Long-Term Survival of Patients with BCLC Stage C Hepatocellular Carcinoma

Abstract

Background: The aim of this study was to evaluate the clinical impact of a combination of systemic sequential therapy and locoregional therapy on the long-term survival of patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC).

Methods: Sixty-four consecutive patients with intrahepatic target nodules who had initially received systemic therapy (lenvatinib and atezolizumab plus bevacizumab) were reviewed. The clinical impact of the combined use of systemic sequential therapy and locoregional therapy was evaluated by determining overall survival (OS). The combined use of systemic sequential therapy with more than two agents and locoregional treatment was defined as multidisciplinary combination therapy (MCT), while only systemic sequential therapy and repeated locoregional-treatment was defined as a single treatment procedure (STP).

Results: R0 resection, MCT, and STP resulted in significantly better OS compared with no additional treatment (median OS, not reached vs. 18.2 months and 12.6 vs. 8.1 months, respectively; p = 0.002). Multivariate analysis confirmed that the use of R0 resection and MCT were associated with better OS (hazard ratio [HR]; 0.053, p = 0.006 and 0.189, p < 0.001, respectively) compared with that for STP (HR; 0.279, p = 0.003).

Conclusions: MCT is may effective in patients with BCLC stage C HCC and intrahepatic target nodules who have previously received systemic therapy-based treatment.

Keywords: atezolizumab plus bevacizumab; combination therapy; hepatocellular carcinoma; lenvatinib; locoregional treatment; systemic therapy.

Figure 1

Overall survival outcomes of the HCC patients treated with systemic therapy.

Figure 2

Overall survival outcomes of the HCC patients treated with systemic therapy grouped by (a) tumor burden (estimated using the Up-to-7 criteria), (b) presence of macrovascular invasion, (c) presence of extrahepatic spread, (d) mALBI grade, (e) liver disease etiology, and (f) systemic therapy type. UT7—up-to-7; MVI—microvascular invasion; EHS—extrahepatic spread; mALBI—modified albumin-bilirubin.

Figure 3

Overall survival curves of the HCC patients treated with systemic therapy, grouped by subsequent treatment during the treatment period. (a) Grouped by with or without subsequent treatment and (b) by type of subsequent treatment.

Figure 4

Adjusted overall survival curves of the HCC patients treated with systemic therapy, grouped according to the type of subsequent treatment selected during the treatment period. HR—hazard ratio; CI—confidence interval.

Figure 5

Relationship between overall survival and the types of subsequent treatment and number of treatments in patients with BCLC stage C HCC, grouped by MVI status. MVI—macrovascular invasion.

Figure 6

The flow of a multidisciplinary treatment approach for a patient with rapidly progressing advanced HCC after initial systemic therapy. The patient showed rapid progression of HCC after first-line Atezo/Bev therapy and received lenvatinib as second-line treatment. After initiation of lenvatinib, the tumor showed extensive necrosis and good tumor control in combination with subsequent DEB-TACE. Atezo/Bev—atezolizumab plus bevacizumab; DEB—drug-eluting beads; ¹⁸F-FDG-PET/CT—¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography; TACE—transarterial chemoembolization.

Figure 7

Verification of the efficacy of lenvatinib added after treatment with atezolizumab plus bevacizumab, based on LDH trends during the course of treatment.

Figure 8

The flow of a multidisciplinary treatment approach for a patient with extremely advanced hepatocellular carcinoma. The patient showed massive portal vein invasion (Vp4) with ¹⁸F-FDG-PET/CT positive and multiple small lung metastases before the initiation of systemic therapy. We considered the most important prognostic factor was tumor thrombus and, therefore, selected lenvatinib as first-line systemic therapy with the combined use of the “L-TACT” method. After several treatment courses, shrinkage of the tumor was observed, and the tumor thrombus changed from ¹⁸F-FDG-PET/CT positive to negative. However, the relative dose of lenvatinib was decreased due to its side effects. Therefore, we performed conversion surgery on the liver tumor and tumor thrombus to manage intrahepatic tumor control. However, the recurrence of the tumor thrombus occurred during the withdrawal of lenvatinib. Therefore, we changed systemic therapy from lenvatinib to Atezo/Bev as second-line treatment, which resulted in good control of the tumor thrombus. The size and number of the multiple small lung metastases were also stable during the treatment period. The red arrow shows the tumor thrombus, and the red dotted arrow indicates the time course of the tumor thrombus during lenvatinib-based treatment. The yellow dotted arrow indicates the time course of the recurrence of the tumor thrombus. The red circle indicates lung metastases, and the red dotted circle indicates the time course of the lung metastases. Atezo/Bev—atezolizumab plus bevacizumab; ¹⁸F-FDG-PET/CT—¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography; L-TACT—lenvatinib-transhepatic arterial cisplatin infusion sequential therapy.