Locoregional treatment

Before the advent of effective systemic treatments, TACE was the main method of conversion therapy for unresectable HCC. A single-center randomized controlled trial showed that 21 of 73 patients (28.8%) who received liver transplantation exceeded the Milan standard when first examined and received liver transplantation after downstaging through TACE, and overall survival time of patients receiving liver transplantation after conversion therapy is similar to that of patients receiving liver transplantation who were within the Milan standard (55). Several other RCTs also showed that TACE creates potential resection opportunities for patients with initially unresectable HCC and can bring survival benefits (56-58). In 2016, a retrospective study of 831 Chinese patients with HCC found that for the 82 patients who achieved a partial response (PR) after TACE treatment, those who received surgical excision had a longer overall survival (49 vs. 31 months, P=0.027) and a higher 5-year survival rate (26% vs. 10%) compared with those who received conservative treatment (28). Recently, Li et al. reported a retrospective assessing the efficacy of TACE combined with HAIC on initially inoperable patients with HCC, in which 56.1% of the enrolled patients had tumors ≥10 cm in diameter. The results showed that the conversion rate of TACE combined with HAIC was higher than that of TACE monotherapy (48.8% vs. 9.5%; P<0.001) (59). However, it should also be considered that TACE can have negative effects on liver function or cause liver damage, although these events are rare (60).

The role of TACE in conversion therapy has been explored and widely recognized. However, it should be noted that multiple TACE procedures may cause liver damage, thereby affecting the safety of liver excision after conversion. In future, the conversion success rate can be enhanced by improving TACE treatment methods or utilizing combination therapy strategies. (Evidence-based) (GRADE: strong recommendation, moderate-quality evidence. Agreement: 100%).

In recent years, Chinese scholars have made significant progresses in the field of HAIC treatment of intermediate or advanced HCC. A multi-center RCT showed that the ORR of HAIC treatment among HCC patients with portal vein tumor thrombus was significantly higher than that of sorafenib (mRECIST criteria, 27.6% vs. 3.4%, P=0.001) (61). A retrospective study published by Lyu et al. also found that the ORR of HAIC treatment was higher than that for sorafenib (mRECIST criteria, 47.8% vs. 9.1%, P<0.01). 26.1% of patients in the HAIC treatment group achieved tumor downstaging and had the opportunity to receive local treatment (62). Another RCT study compared the efficacy of combination therapy with HAIC and sorafenib versus sorafenib monotherapy in patients with HCC and portal vein invasion, and the results showed that the overall response rate among the combination therapy group was significantly higher than that of the sorafenib monotherapy group. In addition, 12.8% of the patients in the combination therapy group achieved downstaging after treatment and received radical surgical resection, of which three patients achieved a pathological complete response (pCR) (20). A further retrospective study also showed that, compared with lenvatinib monotherapy, lenvatinib combined with toripalimab and HAIC can achieve a higher ORR and a higher conversion resection rate (12.7% vs. 0%) (63). These studies suggest that systemic therapy combined with local therapy can achieve higher anti-tumor activity, thereby allowing more patients the possibility of receiving resection. A study comparing the efficacy of HAIC and TACE in patients with BCLC stage B HCC with the largest tumor >7 cm in diameter showed that the proportion of patients in the HAIC group who received surgical resection was significantly higher than that in the TACE group (23.9% vs. 11.5%, P=0.004) (51). However, this result may be limited to patients with large tumors, diffuse HCC, and HCC with portal vein tumor thrombus. In other HCC patients with lighter tumor burden, TACE may still have better efficacy (64).

For patients with HCC whose tumor burden is concentrated in the liver or those with portal vein tumor thrombus, multiple clinical studies have confirmed that HAIC treatment has a higher tumor response rate than TACE or systemic therapies. After HAIC treatment, some patients achieve significant tumor burden reduction or large vessel tumor thrombus regression, thus obtaining the opportunity for surgical resection or ablation treatment. HAIC treatment is suitable for patients with tumor burden in the liver and relatively good liver function (Child-Pugh A/B), and the FOLFOX regimen is recommended for chemotherapy. Generally, it is necessary to complete 4 or more consecutive infusion courses to obtain the best chance of conversion. Targeted therapy and immunotherapy combined with HAIC have a higher conversion rate than HAIC alone. (Evidence-based) (GRADE: conditional recommendation, moderate-quality evidence. Agreement: 88.5%).

SIRT is also called transcatheter arterial radioembolization (TARE). So far, there have been no large-scale prospective RCTs of SIRT as conversion therapy for patients with intermediate or advanced HCC. A study published by Lau et al. that included 71 patients with unresectable HCC showed that 26.7% of the patients had tumor shrinkage greater than 50% after SIRT treatment, of which four patients (5.6%) received radical resection and two (2.8%) achieved a pCR (65). In a subsequent study, the same group observed 49 patients with advanced HCC who were successfully downstaged after chemotherapy or SIRT and surgically resected, the results suggested that the 5-year survival rate was as high as 57% (25). Another clinical study reported that the PR rate associated with SIRT in HCC patients with Child Pugh class A liver function and portal vein tumor thrombus was 40%, and in those with Child Pugh class B the PR rate was 25% (66). An RCT comparing the efficacy of TACE and SIRT in the treatment of unresectable HCC showed that SIRT led to a higher ORR than TACE (30.8% vs. 13.3%, P<0.05), and 15.4% of patients in the SIRT group achieved tumor downstaging (38).

Multiple studies have suggested that SIRT effectively causes tumor shrinkage and has a role in conversion therapy. For patients with portal vein tumor thrombus, SIRT has a higher local dose and a more precise delivery than external beam radiotherapy, and it also reduces radiation damage to normal liver tissue (67). However, clinical data for SIRT in China are currently limited and more evidence is needed to verify its role in conversion therapy. (Evidence-based) (GRADE: conditional recommendation, low-quality evidence. Agreement: 96.2%).

Japanese researchers compared the efficacy of radiotherapy followed by surgery and upfront surgery in a group of patients with tumor thrombus in the main portal vein or the major branches. Radiotherapy was only targeted to the tumor thrombus, and the radiation dose was 30–36 Gy/10–12 times. Surgery was performed within 2 weeks after radiotherapy. Post-operation pathology showed that in the radiotherapy and resection group, 5/6 (83.3%) of patients achieved complete pathological necrosis of the main portal vein tumor thrombus. The 5-year survival rate of the radiotherapy and resection group was 34.8%, and that of the upfront surgery group was 13.1% (P=0.0359) (68). For patients with technically resectable CNLC stage IIIa HCC, an RCT reported by Wei et al. compared the efficacy of preoperative radiotherapy followed by resection and upfont resection and found that 20.7% of patients in the radiotherapy group had portal vein tumor thrombus downstaging from Cheng’s type III to Type II or from type II to type I (69). Preoperative radiotherapy followed by resection significantly improved the survival of patients compared with upfront resection (69).

Data also suggest that radiotherapy combined with HAIC may lead to a higher conversion rate. A retrospective study investigated radiotherapy combined with HAIC in the treatment of locally advanced and initially unresectable HCC. A total of 41 patients in this study (16.9%) underwent surgery after tumor downstaging. The 5-year OS rate of the surgical group and the non-surgery group was 49.6% and 9.8% (P<0.001) respectively (70). Another retrospective study showed that in patients with BCLC stage C HCC who received combination therapy with radiotherapy and HAIC, the surgical conversion rate was 10.7% (68/637). The median survival time of surgical and non-surgical patients was 103.8 vs. 11.4 months (P<0.001) and patients receiving a radiotherapy dose >72 Gy had higher conversion rates (71).

For patients with HCC and portal vein tumor thrombus, surgery can be conducted after downstaging through radiotherapy combined with HAIC. Radiotherapy combined with HAIC therapy may achieve a higher conversion rate than either therapy alone. (Evidence-based) (GRADE: conditional recommendation, low-quality evidence. Agreement: 80%).