Neoadjuvant Three-Dimensional Conformal Radiotherapy for Resectable Hepatocellular Carcinoma With Portal Vein Tumor Thrombus: A Randomized, Open-Label, Multicenter Controlled Study

Abstract

Purpose: To compare the survival outcomes of neoadjuvant three-dimensional conformal radiotherapy (RT) followed by hepatectomy with hepatectomy alone in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT).

Patients and methods: A randomized, multicenter controlled study was conducted from January 2016 to December 2017 in patients with resectable HCC and PVTT. Patients were randomly assigned to receive neoadjuvant RT followed by hepatectomy (n = 82) or hepatectomy alone (n = 82). The modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines were used to evaluate the therapeutic effects of RT. The primary end point was overall survival. The expression of interleukin-6 (IL-6) in patients' serum before RT and in surgical specimens was correlated with response to RT.

Results: In the neoadjuvant RT group, 17 patients (20.7%) had partial remission. The overall survival rates for the neoadjuvant RT group at 6, 12, 18, and 24 months were 89.0%, 75.2%, 43.9%, and 27.4%, respectively, compared with 81.7%, 43.1%, 16.7%, and 9.4% in the surgery-alone group (P < .001). The corresponding disease-free survival rates were 56.9%, 33.0%, 20.3%, and 13.3% versus 42.1%, 14.9%, 5.0%, and 3.3% (P < .001). On multivariable Cox regression analyses, neoadjuvant RT significantly reduced HCC-related mortality and HCC recurrence rates compared with surgery alone (hazard ratios, 0.35 [95% CI, 0.23 to 0.54; P < .001] and 0.45 [95% CI, 0.31 to 0.64; P < .001]). Increased expressions of IL-6 in pre-RT serum and tumor tissues were significantly associated with resistance to RT.

Conclusion: For patients with resectable HCC and PVTT, neoadjuvant RT provided significantly better postoperative survival outcomes than surgery alone. IL-6 may predict response to RT in these patients.

FIG 1.

CONSORT diagram of the randomized clinical trial. HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; PVTT, portal vein tumor thrombus; RT, radiotherapy.

FIG 2.

(A) Overall survival (OS) and (B) disease-free survival (DFS) curves for the neoadjuvant three-dimensional conformal radiotherapy (RT) plus surgery and surgery-alone groups.

FIG A1.

Tumor and extent of portal vein tumor thrombus (PVTT) before and after neoadjuvant three-dimensional conformal radiotherapy (RT) on computed tomography scan and three-dimensional reconstructed images (with hiding of irrelevant anatomic structures) in a representative patient with partial remission to neoadjuvant RT. (A) A 55-year-old male with an original 4 × 3.5-cm hepatocellular carcinoma with PVTT (arrow), which had extensively invaded the right-side branch, bifurcation, and left-side branch of the portal vein (Cheng’s type III) before RT. (B) Four weeks after RT, tumor size shrunk to 2.5 × 2.5 cm, and the PVTT (arrow) was confined to the right side ipsilateral of the portal vein (type II).

FIG A2.

Kaplan-Meier analysis of patient survival with various types of portal vein tumor thrombus (PVTT) in the neoadjuvant radiotherapy (RT) plus surgery and surgery-alone groups. (A) Overall survival (OS) and (C) disease-free survival (DFS) among patients with Cheng’s type II PVTT in the neoadjuvant RT and surgery-alone groups. (B) OS and (D) DFS among the patients with type III PVTT in the neoadjuvant RT and surgery-alone groups.

FIG A3.

Interleukin-6 (IL-6) expression in patients with different responses to radiotherapy (RT). (A) Comparison of baseline IL-6 levels in serum evaluated by enzyme-linked immunosorbent assay (progressive disease v partial remission/stable disease; P = .047). (B) Comparison of IL-6 expression in hepatocellular carcinoma (HCC) tissues by immunohistochemistry scoring (P = .018). (C) Representative slides of immunohistochemistry (magnification, ×200).