Correlation of radiotherapy, targeted therapy, and immunotherapy with hepatocellular carcinoma recurrence

Table 1 The mechanism of action of radiotherapy, efficacy in hepatocellular carcinoma recurrence, main limitations and relevant improvement strategies

Type	Treatment	Mechanism	Efficacy	Limitations	Strategies	Ref.
External beam radiotherapy	3-DCRT	Adjust the direction of radiation beams based on the shape and location of the HCC lesion	3-DCRT significantly reduces the mortality and recurrence rates in resectable HCC patients with postoperative PVTT	Unsuitable for tumors with complex shapes or those located near critical organs	Replace with IMRT	Kim et al[18]; Wei et al[19]
	IMRT	Adjust the spatial distribution of a single radiation beam	The OS and RFS of patients with close surgical margins combined with IMRT are comparable to those of patients with wider surgical margins	Patients need a high number of treatment sessions and poor liver function exhibit poor tolerance	IMRT + SBRT	Wang et al[21]; Kim et al[24]
	SBRT	High-dose and high-selectivity radiation	Repeated SBRT for intrahepatic recurrent HCC is both safe and effective, with an overall 5-year local recurrence rate of only 6.3% (95%CI: 2.2%-13.4%)	High risk of liver damage outside the target area for multiple recurrent lesions	IMRT + SBRT; Repeated attempts at local control with close monitoring of liver function	Kimura et al[22];Kim et al[23];Kim et al[24];Ding et al[25]
Internal radiotherapy	IVBT (I-125)	γ-rays	Patients with high recurrence risk HCC, especially those with PVTT, demonstrate favorable treatment outcomes, with an ORR of 90% after one course of treatment	Poor systemic effects and inability to control micro-metastases; Incomplete radiation coverage; Patients with immunosuppression	TACE + sorafenib + I-125; Combined irradiation stent; 125I + CIK cells	Zhang et al[26];Huanget al[27];Lu et al[28];Zhang et al[29]
	SIRT (Y-90)	β-rays	In patients with PVTT, SIRT has been shown to significantly improve tumor response rates compared to sorafenib (19% vs 12%). Additionally, patients treated with Y-90 demonstrate a significantly reduced recurrence rate of HCC following LT and are more likely to achieve CPN	High cost; A certain risk of adverse events	Comprehensive pre-operative assessment	Gulec[30]; Hermann et al[32];Palmer et al[33];Chow et al[34];Dai et al[35];Agopian et al[36]

3-DCRT: Three dimensional-conformal radiotherapy; IMRT: Intensity-modulated radiotherapy; SBRT: Stereotactic body radiotherapy; SIRT: Selective internal radiotherapy; IVBT: Intravascular brachytherapy; HCC: Hepatocellular carcinoma; Y-90: Yttrium-90; I-125: Iodine-125; PVTT: Portal vein tumor thrombus; OS: Overall survival; RFS: Recurrence-free survival; ORR: Overall response rate; CI: Confidence interval; CPN: Complete pathological necrosis; CIK: Cytokine-induced killer; LT: Liver transplantation; TACE: Transarterial chemoembolization.

Table 2 The mechanism of action of targeted therapy, efficacy in hepatocellular carcinoma recurrence, main limitations and relevant improvement strategies

Type	Treatment	Mechanism	Efficacy	Limitations	Strategies	Ref.
First-line treatment; Second-line treatment	Sorafenib	Inhibit VEGFR, PDGFR-β, and the RAF/MEK/ERK pathway	Sorafenib significantly improved the median overall survival (10.7 months vs 7.9 months; P < 0.001) and radiographic progression-free survival (5.5 months vs 2.8 months; P < 0.001) in patients with advanced HCC	The use of sorafenib as monotherapy in adjuvant treatment and the prevention of HCC recurrence after surgery has no significant efficacy	TACE + sorafenib/TACE + sorafenib + radiotherapy; Switch to other effective medications	Wilhelm et al[40];Rimassa and Santoro[41];Bruix et al[42];Li et al[43];Jiang et al[44];Peng et al[45];Fan et al[46]
	Lenvatinib	Inhibit VEGFR 1-3, FGFR 1-4, PDGFR-α, RET and KIT	Lenvatinib has a superior ORR compared to sorafenib in HCC; The median overall survival in the lenvatinib group for the treatment of recurrent hepatocellular carcinoma after liver transplantation was significantly longer (15.0 months vs 7.8 months, P = 0.02)	Individual differences and resistance exist	TACE + lenvatinib/pembrolizumab + lenvatinib; Switch to other effective medications	Yamamoto et al[48]; Al-Salama et al[49]; Kudo et al[51]; Magyar et al[52];Peng et al[53];Liang et al[54];Zhang et al[55];Lv et al[56]
Second-line treatment	Regorafenib	Inhibit VEGFR1-3, TIE2, FGFR, PDGFR-β, KIT, RET and p38MAPK/Creb1/Klf4	Regorafenib has demonstrated good anti-tumor activity and effectively prolonged survival in HCC patients who experienced recurrence or progression after sorafenib treatment	Severe toxic side effects with a high incidence	Adopt a stepwise dosing strategy	Eso and Marusawa[58]; Ou et al[59]; Bruix et al[60]; Bruix et al[61]; Finn et al[62]; Bekaii-Saab et al[63]
	Cabozantinib	Inhibit VEGFR1-3, MET and AXL	The phase III clinical trial was positive, with an overall ORR of 4%	The overall efficacy is limited	Cabozantinib + nivolumab; Screening for sensitive patients	Argentiero et al[64]; Abou-Alfa et al[65]; Yang et al[66]

VEGFR: Vascular endothelial growth factor receptor; PDGFR: Platelet-derived growth factor receptor; FGFR: Fibroblast growth factor receptor; TIE2: Angiopoietin-1 receptor; MAPK: Mitogen-activated protein kinase; ORR: Objective response rate; HCC: Hepatocellular carcinoma; TACE: Transarterial chemoembolization.

Table 3 The mechanism of action of immunotherapy, efficacy in hepatocellular carcinoma recurrence, main limitations and relevant improvement strategies

Type	Treatment	Mechanism	Efficacy	Limitations	Strategies	Ref.
ICIs	PD-1/PD-L1 inhibitors	Inhibiting PD-1/PD-L1 weakens the suppression of T cells by cancer cells	The results of the CheckMate 040 and KEYNOTE-224 trials showed that nivolumab and pembrolizumab significantly improved ORR, OS, and PFS in HCC	Drug resistance and individual population differences	Atezolizumab + bevacizumab/nivolumab + ipilimumab	El-Khoueiry et al[81];Zhu et al[82];Qin et al[85];Finn et al[86]
	TIM3-targeted therapy	Blocking the binding of TIM-3 to its ligand reduces its inhibition of immune cells	Higher expression of TIM-3L is often associated with shorter survival and a higher likelihood of recurrence	The complexity of the microenvironment	Radiotherapy + immunotherapy + AZD6738	Yang et al[88]; Wang et al[89]; Khan et al[90]; Chew et al[91]; Kim et al[92]; Li et al[93]; Cheng et al[94]; Chen et al[95]; Sheng et al[96]
Adoptive cell therapy	TILs	T cells extracted from tumor tissue are expanded in vitro and reinfused	In a phase I clinical trial involving 15 HCC patients, only 3 patients experienced recurrence after a median follow-up of 14 months	The current clinical trials have small sample sizes and lack higher-phase clinical trials	Further clinical trials and studies on combination therapy	Jiang et al[99]; Liu et al[100]
	CAR-T	Modify, expand and reinfuse T cells	GPC3 T cell therapy for GPC3-positive advanced hepatocellular carcinoma patients has shown a significant decrease in AFP levels and prolonged survival in some patients	Adverse events are common, and the clinical benefits for solid tumors remain unclear	Monitor adverse events, especially to prevent CRS; Identify more effective therapeutic targets	Maalej et al[101];Jiang et al[102];Beatty et al[103]; Ruella and Kalos[104]; Shi et al[105]
	NK cell therapy	Modify, expand and reinfuse NK cells	Multiple allogeneic NK cells infusion was associated with better prognosis to advanced HCC	The limited availability of mature NK cell sources and the restricted efficacy of single-agent NK therapy remain challenges	NK cells can be generated by culturing CD34 + stem cells, and combination therapies, such as NK cells combined with chemotherapy	Cai et al[106]; Lin et al[107]; Ohira et al[108]
Tumor vaccines	DNA vaccines	Introduce the DNA encoding tumor-associated antigens into the host cell nucleus	A total of 36 patients with advanced HCC underwent combination therapy with PTCV, PD-1 inhibitors, and IL-2. The ORR reached 30.6%, with 8.3% of patients achieving complete remission	Limited efficacy as a standalone treatment; Low bioavailability; Risk of unintended integration of foreign genetic material into the host cell genome	Combine with other immunotherapies; Use nanocarriers/RBC-nano-vaccines for targeted delivery; Replace with mRNA vaccines	Rice et al[112]; Butterfield et al[113]; Wu et al[114]; Hobernik et al[105]; Yarchoan et al[116]
	mRNA vaccines	Introduce the mRNA encoding tumor-associated antigens into the host cell cytoplasm	The combination of pembrolizumab and mRNA-4157 significantly reduces the recurrence rate in patients with high-risk melanoma	Limited efficacy as a standalone treatment; Low bioavailability	Combine with other immunotherapies; Use lipid nanoparticles for delivery	Cagigi and Douradinha[117]; Huang et al[118];Weber et al[119]
Cytokine therapy	IL-2, IFN	Enhance the body’s anti-tumor immune response	After IL-2 treatment, the survival rate of unresectable HCC patients increased; IFN can reduce the mortality and early recurrence rates of HCC patients after curative treatment	Severe side effects and the inability to accumulate sufficiently effective drug concentrations within the tumor	Search for new or artificially modified cytokines and further studies on combination therapy	Bertelli et al[120];Zhang et al[121]; Charych et al[122]; Walker et al[123]

ICIs: Immune checkpoint inhibitors; IFN: Interferon; IL-2: Interleukin-2; PD-1: Programmed cell death protein 1; PD-L1: Programmed cell death ligand 1; TIM3: T-cell immunoglobulin and mucin domain-containing molecule 3; TILs: Tumor-infiltrating lymphocytes; CAR-T: Chimeric antigen receptor-T; NK: Natural killer; mRNA: Message RNA; ORR: Objective response rate; HCC: Hepatocellular carcinoma; OS: Overall survival; RFS: Recurrence-free survival; GPC3: Chimeric antigen receptor-glypican-3; AFP: Alpha-fetoprotein; PTCV: Personalized neoantigen cancer vaccine; CRS: Cytokine release syndrome; CD: Cluster of differentiation; RBC: Red blood cell.