Lenvatinib

All patients received lenvatinib (8 mg/day regardless of body weight; Eisai, Inc., Japan) plus anti-PD-1 antibodies. Anti-PD-1 antibodies were intravenously administered as follows: nivolumab (Bristol-Myers Squibb, USA) 3 mg/kg or camrelizumab (Hengrui Medicine, China) 200 mg, [19 (link)] every 2 weeks, or pembrolizumab (MSD, USA) 200 mg, sintilimab (Innovent Biologics, China) 200 mg, [20 (link)] or toripalimab (Junshi Bioscience, China) 240 mg, [21 (link)] every 3 weeks. All patients with active hepatitis B infection received concomitant anti-viral therapy.

All patients received sorafenib (Bayer Pharma, Leverkusen, Germany) or lenvatinib (Eisai, Tokyo, Japan) after TACE refractoriness was determined. sorafenib at a dose of 400 mg was administered orally twice a day. lenvatinib at a dose of 12 mg (bodyweight ≥ 60 kg) or 8 mg (bodyweight < 60 kg) was administered orally once a day. Interruption and dose reduction of TKI was allowed and depended on the presence and severity of toxicities according to the package insert. TKI treatment was continued until intolerable toxicity or disease progression occurred.

All patients in group A received sequential systemic therapy with molecular targeted agents after the TIPS procedure when the symptoms of portal hypertension were controlled. Patients received a daily oral dose of sorafenib (400 mg/bid, Bayer) or lenvatinib (8–12 mg/qd, Eisai Co Ltd). Patients received regorafenib (120–160 mg/qd during weeks 1–3 of each 4-week cycle, Bayer) if they were nonresponders or tolerated sorafenib or lenvatinib. The treatment strategy is shown in Fig. 3.
Fig. 3

Treatment strategy for advanced hepatocellular carcinoma (HCC) with portal vein tumour thrombus (PVTT)–related symptomatic portal hypertension to improve survival. A transjugular intrahepatic portosystemic shunt (TIPS) is used to resolve portal hypertension complications, including variceal bleeding, refractory ascites or hydrothorax, and access to antitumour treatment opportunities (molecular targeted agents)

Oral lenvatinib (Lenvima; Eisai Co., Ltd., Tokyo, Japan) treatment (8 mg/day [<60 kg] or 12 mg/day [≥60 kg]) was started, and the dose was reduced (to 8 mg/day, 4 mg/day, or 4 mg every other day) because of lenvatinib‐related toxicities until the AEs were alleviated or eliminated. If the AEs continued even after dose adjustment, lenvatinib treatment was interrupted until it alleviated or disappeared.
The first DEB‐TACE procedure was performed between 7 and 14 days after the first administration of lenvatinib. After imaging and catheterization of hepatic arteries with standard angiographic protocols and equipment to visualize HCC blood supply, selective catheterization was performed to achieve lobar or segmental chemoembolization. lenvatinib was continuously administered without interruption during DEB‐TACE.
DEB‐TACE was performed as previously recommended.²⁴ We used DC Beads (Biocompatibles UK) or CalliSpheres microspheres (Jiangsu Hengrui Medicine Co., Ltd., Jiangsu, China) with diameters of 100–300 or 300–500 μm. Each vial of these particles (2 ml) was added to 10 mg of idarubicin (Pfizer) with sterilized water for 30 min. The DEB dose was determined by tumor volume (calculation of ellipsoid volume: height × width × length × π/6). The endpoint of primary chemoembolization was complete devascularization of the tumor confirmed via angiography.²⁴ Figure S1 shows a typical patient.