1. Congenital anatomical factors
Hepatocellular carcinoma (HCC) is one of the most common malignancies, accounting for 4.7% of all new cancer cases and 8.3% of all cancer-related deaths worldwide, ranking sixth and third in morbidity and mortality, respectively. According to the data released by the National Cancer Center in mainland China, the incidence of hepatocellular carcinoma in 2022 ranked fourth among all tumors, and the mortality rate ranked second. Surgery (surgical resection, radiofrequency ablation and liver transplantation) is the preferred treatment for hepatocellular carcinoma, but due to the insidious onset of hepatocellular carcinoma, most patients with hepatocellular carcinoma in mainland China are already in the middle and advanced stages (CNLC-stage II.b, stage III.a and stage III.b) at the time of initial diagnosis. In order to improve the prognosis of patients with unresectable hepatocellular carcinoma, conversion therapy has emerged as a new treatment modality, that is, to downstage the tumor of patients with unresectable surgery and obtain the opportunity for surgical resection through early treatment. Studies have shown that the 5-year survival rate of patients with unresectable hepatocellular carcinoma who underwent surgical resection with conversion therapy is similar to that of patients who initially underwent surgery.
The conversion regimen for effective down-repulsion consists of the following two factors: (1) high objective response rate (ORR). High ORR is closely related to improving the surgical conversion rate, so as to ensure the degree of tumor shrinkage and pathological necrosis, and create opportunities for subsequent R0 surgical resection. (2) Liver function damage is small, and adverse reactions are small. Since most patients with hepatocellular carcinoma in mainland China have a history of hepatitis or underlying diseases such as liver cirrhosis, the liver function damage and adverse reactions of the switching treatment regimen are relatively small, so as to ensure the smooth operation and perioperative safety after conversion therapy. In the past, the surgical conversion rate of local therapy alone was low, which limited the application and promotion of conversion therapy. In recent years, anti-angiogenic targeted drugs, such as tyrosine kinase inhibitors (TKIs) and large molecule bevacizumab, have been used in combination with immune checkpoint inhibitors to increase the objective response rate by 24.1%~27.3%, bringing new hope for conversion therapy, increasing the conversion rate to 15.9%~30.6%.
In recent years, it has been used more and more in unresectable hepatocellular carcinoma, and the objective response rate has been rising, and it has been reported to reach 40%~60%, which brings more possibilities for the success of surgical transformation, although there is no clinical study of randomized controlled conversion therapy. However, there have been multiple single-arm studies and large retrospective studies reporting the latest data on interventional combined systemic drug therapy. The purpose of this article is to explore the value of interventional and other local therapies combined with systemic therapy in the transformation therapy of hepatocellular carcinoma.
1. Transarterial chemoembolization (TACE) combined with systemic therapy
TACE injects fluid or granular embolic agent through the blood supply artery of the tumor to reach the peripheral blood vessels of the tumor, so that the tumor is ischemic necrosis, carries chemotherapy drugs in the embolic material, and releases high concentrations of chemotherapy drugs in the tumor trophic blood vessels at the same time of embolization, so as to achieve the dual purpose of chemoembolization, and cause necrosis and apoptosis of tumor cells to a greater extent. For intermediate-stage hepatocellular carcinoma (BCLC stage B) (stage II.b), it has been reported that the effect of TACE treatment in stage B2 with tumor burden (tumor size + number) > 7 is significantly lower than that in stage B1 with tumor burden < 7, the overall survival (OS) decreased from 42.3 months to 29.3 months, and the time to TACE progression decreased from 9.5 months to 5.3 months. Wang et al. reported that the survival after TACE treatment was reduced from 32.6 months to 16.8 months after TACE treatment at >12 compared with tumor burden 6~12. Although TACE has a good therapeutic effect on patients with Vp1/2 portal vein cancer thrombus, the treatment effect of HCC patients with major portal vein cancer thrombosis is limited, and it has been reported that TACE alone has an ORR of only 22.7% for advanced hepatocellular carcinoma with Vp3/4 portal vein cancer thrombus. Therefore, it is difficult for most patients with stage B2 disease who require conversion therapy or stage II.b patients with large tumor burden, and stage III.a patients with Vp3/4 portal vein cancer thrombosis to obtain a lasting and effective conversion therapy effect from TACE alone. TACE combined with systemic drug therapy improved the effect of anti-tumor therapy, expanded the population and success rate of conversion therapy.
1.1 TACE combined with targeted therapy
When TACE combined with targeted therapy alone is used in conversion therapy, most of them are combined with TKI-type targeted drugs with a relatively high objective response rate, such as lenvatinib. In the Phase III LAUNCH study of TACE+lenvatinib versus lenvatinib alone as a first-line treatment in patients with advanced hepatocellular carcinoma, 70% of patients had portal vein cancer thrombosis and 55% had extrahepatic metastases; Patients in the TACE+lenvatinib group had a higher ORR [54.1% (92/170) vs 25.0% (42/168), P<0.001] (mRECIST), of whom 26 (15.3%) patients underwent radical surgical resection due to stage reduction, and 2 patients had pathologic complete remission, compared with only 3 patients (1.8%) in the lenvatinib alone group who underwent radical surgery, and none of them had pathologic complete remission. In terms of survival benefit, the median OS was significantly longer in the TACE+lenvatinib arm than in the lenvatinib arm (17.8 versus 11.5 months, HR=0.45, P<0.001), suggesting that the addition of TACE to lenvatinib in advanced hepatocellular carcinoma improved efficacy, surgical conversion rate, and survival.
1.2 TACE in combination with targeted therapy and immunotherapy
More and more studies have found that TACE combined with TKI targeted drugs and immunotherapy can bring more efficacy, higher objective response rate, acceptable safety and higher conversion rate than TACE alone with targeted therapy. Chen et al. retrospectively collected data from three clinical centers to compare the efficacy of TACE+lenvatinib versus TACE+lenvatinib+pembrolizumab in patients with PD-L1-positive initially unresectable hepatocellular carcinoma. The ORR [47.1% (33/70) vs 27.8% (20/72)], disease control rate (DCR) [70.0% (49/70) vs 52.8% (38/72)], and surgical conversion rate [25.7% (18/70) vs 11.1% (8/72)] were significantly higher with triple therapy than with dual therapy. In addition, triple therapy significantly prolonged median OS (18.1 versus 14.1 months, HR=0.56, 95%CI: 0.38~0.83, P=0.004) and reduced the risk of death by 44% compared with dual therapy. Subgroup analysis of PD-L1 expression showed that the combination of TACE+lenvatinib in combination with immunotherapy was more recommended in the high CPS group to improve OS. This retrospective study has preliminarily demonstrated the superiority of topical combination with target-immune triple therapy in selected populations. In a study from Zhongshan Hospital, Fudan University, triple therapy (TACE + lenvatinib + toripalimab) achieved higher ORR (mRECIST) (76.7% vs 47.6%), DCR (mRECIST) (90.0% vs 57.1%), and surgical conversion rate [50.0% (15/30) vs 19.0% (4/21)] than dual therapy (TACE + lenvatinib). In terms of safety, increased ALT/AST was the most common grade 3 adverse reaction in the triple therapy group and was tolerated with pharmacological intervention. A multicenter, prospective, single-arm clinical trial included a total of 55 patients who underwent triple therapy with TACE + lenvatinib + camrelizumab, with an ORR of 76.4% (42/55, complete response rate of 16.4%, partial response rate of 60.0%) and DCR of 85.5% (47/55) (mRECIST criteria). Twenty-nine patients (52.7%) were converted to resectable, with pathologic response (MPR) rates and pathologic complete response (pCR) rates of 65.5% (19/29) and 20.7% (6/29), respectively, and median OS and progression-free survival (PFS) were not reached. Another multicenter retrospective study looked at 187 patients with unresectable hepatocellular carcinoma treated with TACE + lenvatinib + anti-PD-1 antibodies, including camrelizumab, sintilimab, toripalimab, tislelizumab, penpulimab, and pembrolizumab. In the study, 77 patients eventually met the resectable criterion, and 70 patients underwent surgery, with a conversion rate of 38.7%. Twenty-nine patients (41.4 percent) achieved pCR and 59 (84.3 percent) achieved MPR. Perioperative mortality occurred in 2 patients (4.3%) and liver failure after hepatectomy in 16 patients (22.9%) was the most common serious complication, most of which could be improved by medical intervention. Li et al. also paid attention to the therapeutic effect of TACE+lenvatinib + anti-PD-1 antibody (camrelizumab/sintilimab) in conversion therapy, and among the 94 patients treated, the ORR was 87.2%, the DCR was 93.6% (mRECIST), and 32 patients (34.0%) were successfully converted. The investigators further divided the patients into those with early tumor response (n=68, 72.3%) and those without early tumor response (n=26, 27.7%). Subgroup analysis showed that the conversion rate of patients with early tumor response was significantly higher than that of patients without early tumor response (44.1% vs 7.7%, P=0.001), and early tumor response predicted the success of conversion therapy (OR=10.296, 95%CI: 2.076~51.063, P=0.004), and patients with early tumor response could obtain longer PFS and OS (15.4 months vs 7.8 months, P=). 0.005;23.1 months vs 12.5 months, P=0.004). Some investigators applied TACE+lenvatinib+anti-PD-1 antibody to patients with portal vein thrombosis with poor prognosis, and the ORR and DCR were 69.8% (74/106) and 84.0% (89/106), respectively, and the surgical conversion rate was 31.1% (33/106). Median OS was longer than 24 months, and median PFS was 12.53 months. Grade 3/4 treatment-related adverse reactions occurred in 20.8% (22/106) of the patients, and no treatment-related deaths occurred.
TACE combined with bevacizumab and immune checkpoint inhibitors also brings good combination therapy effects, and the global, multicenter, randomized controlled phase III study EMERALD-1 just reported at the 2024 United States Society of Clinical Oncology Gastrointestinal Oncology Symposium enrolled intermediate hepatocellular carcinoma and advanced hepatocellular carcinoma (Vp1 and Vp2 types), randomly divided into 3 groups according to 1:1:1, group A is TACE+durvalumab (D+TACE); The treatment regimen in group B was TACE+durvalumab+bevacizumab (D+B+TACE); Treatment regimen in Group C was TACE + placebo. The primary endpoint was PFS in group B versus group C (RECIST1.1). The study met the primary endpoint, with a median PFS of 15.0 months for D+B+TACE and 8.2 months for TACE (HR=0.77, 95%CI: 0.61~0.98, P=0.032). In terms of secondary endpoints, D+TACE failed to improve PFS compared with TACE (10.0 months vs 8.2 months, HR=0.94, 95%CI: 0.75~1.19, P=0.638). These results suggest that TACE in combination with bevacizumab and PD-L1 immune checkpoint inhibitors is an effective conversion therapy.
2. Hepatic arterial perfusion chemotherapy (HAIC) combined with systemic therapy
HAIC is an interventional technology that uses the arterial chemotherapy regimen applied to hepatocellular carcinoma for oxaliplatin and 5-fluorouracil, cisplatin, cisplatin + 5-fluorouracil, interferon + 5-fluorouracil and other regimens. At present, oxaliplatin and 5-fluorouracil regimens are mostly used in China. HAIC technique: modified hepatic artery kit implantation is recommended, or disposable catheterization can be used, and intrahepatic blood flow redistribution and extrahepatic blood flow redistribution surgery are required to protect the gastrointestinal mucosa while ensuring drug perfusion of the whole liver. HAIC is mainly used for stage III.a hepatocellular carcinoma (especially in patients with Vp3/Vp4 portal vein cancer thrombosis), or stage II.b hepatocellular carcinoma with large tumor burden and unclear borders.
2.1 HAIC combined with targeted therapy
In the phase III study of HAIC + sorafenib versus sorafenib alone in patients with hepatocellular carcinoma with portal invasion, the median OS was 13.37 months in the HAIC + sorafenib arm compared with 7.13 months in the sorafenib alone arm. The ORR of the HAIC + sorafenib group was higher than that of the sorafenib group [51 (40.8%) vs 3 (2.46%), P<0.001], and the conversion rate was also higher [12.8% (16/125) vs 0.8% (1/122), P]. <0.001］。 In another phase II randomized controlled study comparing HAIC + sorafenib versus sorafenib alone in hepatocellular carcinoma complicated with Vp3/4 portal vein aneurysm thrombosis, the HAIC + sorafenib group also achieved longer median survival (16.3 versus 6.5 months) and ORR (41% (13/32) versus 3% (1/32), p<0.001], but only 2 (6%) patients in the HAIC + sorafenib arm were offered surgery, one of whom received a pCR.
2.2 HAIC in combination with targeted therapy and immunotherapy
In a prospective, single-arm study of HAIC + sintilimab + bevacizumab analogue (IBI305), the ORR was 58.6% (17/29) (mRECIST), and a total of 14 patients (48.3%) completed surgical resection, of whom 1 (5.3%) achieved pCR and 5 (26.3%) achieved MPR. Zhang et al. retrospectively studied the conversion effect of HAIC + TKI (apatinib/lenvatinib/sorafenib) + anti-PD-1 antibody (camrelizumab/sintilimab), and the optimal ORR of the triple combination was 96.0% (24/25), and the surgical conversion rate was 60% (15/25), of which 7 patients (28%) achieved pCR. In another retrospective study with a large sample size (n=145), HAIC+TKI (apatinib/lenvatinib/sorafenib) + anti-PD-1 antibody (camrelizumab/sintilimab/tislelizumab) had an ORR of 57.2% (83/145) and a surgical conversion rate of 18.6% (27/145), with 7 achieving pCR.
2.3 TACE+HAIC combined targeting and immunization
The combination of TACE or HAIC with lenvatinib and anti-PD-1 antibody achieved a good ORR, and some studies further observed the transformation effect of the two local treatments using TACE-HAIC + lenvatinib + anti-PD-1 antibody, the overall ORR was 64.3% (18/28), the DCR was 89.3% (25/28), and after 2 cycles of combination therapy, 35.7% (10/28) of patients could achieve R0 resection.
3. Transarterial radioembolization (TARE) combined with systemic therapy
TARE transarterial intervention, usually using yttrium-90 as the labeled nuclide, is perfused with radionuclide-labeled embolic microspheres through the hepatic artery to achieve brachy endoirradiation therapy for tumors. Selective internal radiation radiation therapy (SIRT) is injected into the liver lobe and hepatic arteries, and the tumor can achieve a higher absorbed dose locally and improve the treatment effect. TARE has shown superior efficacy over TACE in stage II.b hepatocellular carcinoma with large tumor burden and stage III.a hepatocellular carcinoma with portal vein cancer thrombus. In European and United States countries, TARE is more commonly used in the downstaging transformation of liver transplantation. In a single-center randomized controlled study, TARE had a longer time to disease progression (17.1 versus 9.5 months, P=0.002) and longer OS (30.2 versus 15.6 months, P=0.006) than D-TACE for unresectable intermediate-stage hepatocellular carcinoma, with 10 of 38 patients in the TARE group being downstaged to liver transplantation compared with only 4 of 34 patients in the control TACE group. Radioactive hepatic segment resection is a new concept proposed in recent years, which uses selective SIRT technology to achieve high-dose internal irradiation in the liver where the tumor is located, and studies have found that the absorbed dose of 400 Gy > tumor is closely related to pathological complete necrosis. Radioactive lobectomy achieves high-dose irradiation in the tumor tissue, and the effective dose (>88 Gy) in the normal liver lobe tissue where the tumor is located is also effective, which can compensate for the proliferation of the remaining liver tissue and help convert it into surgical resection. There are still few studies of TARE in combination with targeted agents, and randomized controlled SORAMIC studies have shown that sorafenib plus SIRT has not shown a longer survival benefit than sorafenib alone in advanced hepatocellular carcinoma. Phase II clinical studies of TARE in combination with PD-1 immunotherapy have shown some combination benefits. In the CA209-67 study, TARE plus nivolumab resulted in an ORR of 30.6%, an intrahepatic tumor ORR of 43.5%, and an OS of 16.9 months. In the I./II.a study reported by Lee et al., TARE in combination with durvalumab, the ORR was 83.3%, and the time to disease progression was 15.2 months.
4. Radiotherapy combined with systemic therapy
Hepatocellular carcinoma is sensitive to radiation therapy, and moderate doses of radiotherapy can achieve a good tumor response rate. Patients with hepatocellular carcinoma who are not candidates for surgical resection may have a longer survival time if they can be converted to surgical resection after radiotherapy. In a recent prospective study exploring the outcomes of TACE + stereotactic radiotherapy + anti-PD-L1 antibody in the treatment of unresectable hepatocellular carcinoma, 12% (4/33) of patients received curative therapy after triple therapy. In another retrospective study, a total of 23 patients with unresectable hepatocellular carcinoma who received radiotherapy + pembrolizumab + bevacizumab were included in a total of 34.8% and 91.3% of patients with unresectable hepatocellular carcinoma (HCC) who received radiotherapy + pembrolizumab + bevacizumab. Two patients (8.7%) with locally advanced unresectable hepatocellular carcinoma eventually underwent radical tumor resection after this triple therapy.
5. Summary and outlook
The ORR and surgical conversion rates of unresectable hepatocellular carcinoma (HCC) with local therapy alone or drug therapy are low, and the existing literature data have shown that local treatment combined with systemic drug therapy can play a synergistic role and improve the ORR and surgical conversion rates. TACE is the standard treatment for intermediate-stage hepatocellular carcinoma, and for stage II.b and/or stage III.a hepatocellular carcinoma with Vp1/2 tumor thrombus, TACE combined with targeted and immunotherapy can improve the anti-tumor treatment effect and improve the success rate of surgical transformation. For stage II.b and III.a hepatocellular carcinoma with large tumor burden and unclear tumor boundaries (especially for patients with Vp3/Vp4 portal vein cancer thrombosis), the conversion effect of HAIC combined with systemic target-immune therapy may be better. TARE may produce a higher surgical conversion rate than TACE in patients with stage II.b and III.a hepatocellular carcinoma, but the data of TARE combined with target immunity are insufficient and need to be confirmed by studies. In the future, it is necessary to further accurately screen the population benefiting from immunotherapy, and more and more effective biomarkers need to be explored in addition to PD-L1 expression. In addition, most of the existing clinical studies are small-sample retrospective studies, and large-sample III. clinical trials with rigorous design are still needed to provide higher-level evidence to determine the best local combination system treatment regimen, combination timing, and optimal beneficiary population.
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引证本文 Citation
ZHU Chaofan, WANG Xiaodong . Value of local therapy combined with systemic therapy in the transformation of hepatocellular carcinoma[J]. Journal of Clinical Hepatobiliary Diseases, 2024, 40(9): 1732-1737
扩展阅读 Read more
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