Transarterial chemoembolization refractoriness in hepatocellular carcinoma: Chinese College of Interventionalists definition and consensus statement

Transarterial chemoembolization (TACE) is recommended as the first-line approach for intermediate hepatocellular carcinoma (HCC), and it is the most widely applied method for advanced HCC in real-world clinical practice.[1,2] According to the China Liver Cancer (CNLC) staging system, TACE is recommended as the first-line therapy for stages IIb and IIIa, while it is also recommended as a major approach for stages Ib, IIa, and IIIb.[3] Despite its confirmed treatment efficacy and safety, repeated TACE is sometimes unbeneficial for some patients due to the high heterogenicity of HCC, manifesting as liver function deterioration and occupying the optimal occasion of other therapies. Accordingly, the concept of "TACE refractoriness" has been introduced by various societies around the world to avoid ineffective repeated TACE.[4] Nevertheless, there is no widely accepted consensus on the definitions of "TACE refractoriness" and some controversies have yet to be resolved. In addition, whether the existing definitions of "TACE refractoriness" are suitable for Chinese HCC is still doubtful. Currently, three versions of "TACE refractoriness" definitions have been introduced by the Japan Society of Hepatology (JSH) (Kyoto, Japan), the International Association for the Study of the Liver (Shanghai, China), and a European expert panel. Among them, the 2014 updated version of "TACE refractoriness" introduced by the JSH is most widely applied in clinical trials.[4] Different from Western countries and Japan in patient with HCC, Chinese HCCs are mostly diagnosed at more advanced stages and patients treated with TACE generally have a higher tumor burden.[5] Therefore, it is doubtful and remains to be discussed whether the currently definitions of "TACE refractoriness" are suitable for Chinese HCCs. To obtain a comprehensive understanding of the recognition of TACE refractoriness in China, the Chinese College of Interventionalists (CCI) carried out a survey in 2020.[6] A total of 257 physicians with more than 10 years of experience in the treatment of HCC attended the survey. Nearly three quarters (74.3%, n = 191) of the attending interventionalists agreed that the concept of "TACE refractoriness" has scientific and clinical significance. Nearly half (47.1%, n = 121) of the participants disagreed with the perspective that new occurrence of intrahepatic lesion(s) should be regarded as TACE refractoriness and, by contrast, only a fraction (16.3%, n = 42) of participants held opposite opinion. Notably, many of the participants (29.2%, n = 75) agreed that progression of the treated lesion(s) after three consecutive TACE sessions should be regarded as TACE refractoriness and thereafter triggered other therapies. Whereas, most interventionalists insisted that repeated TACE still be beneficial for intrahepatic lesion(s) even in cases of post-TACE macrovascular invasion (94.2%, n = 242) or extrahepatic metastasis (98.4%, n = 253) for patients with preserved liver function. As such, most participants (91.4% n = 235) believed that none of the existing "TACE refractoriness" definitions were suitable for Chinese HCC, and thus it was urgent to redefine this concept to meet the need for TACE management of HCC in China. Based on the available evidence and opinions from experts in China, the CCI definition and consensus statement on "TACE refractoriness" was introduced by the CCI TACE Refractoriness Collaboration Group in 2021. The formulation of the CCI definition and consensus statement on "TACE refractoriness" aims to introduce more reliable concepts of "TACE refractoriness" to better guide the clinical practice of TACE for patients with HCC in China. The evidence quality and recommendation level of the consensus statement were based on the grading method of the U.S. Preventive Services Task Force (https//www.uspreventiveservicestaskforce.org/uspstf/about‑uspstf/methods‑and‑processes/grade‑definitions). At the annual congress of CCI (congress president: Dr. Gao-Jun Teng) held on July 15–18, 2021 in Nanjing, China, a seminar to discuss and evaluate the proposed definition was held on July 17. A total of 31 physicians with senior professional titles who had been engaged in the treatment of HCC for more than 15 years participated in the seminar. All the participating physicians were from tertiary teaching hospitals in China, and the monthly average number of HCC cases treated in their departments was more than 50. They discussed and compared the CCI definition and consensus statement with other existing definitions during the seminar. All the participating physicians agreed that the CCI definition and consensus statement on "TACE refractoriness" had strong rationality and was currently the most suitable "TACE refractoriness" criteria for patients with HCC in China. Recommended Grades According to the US National Clinical Diagnosis and Treatment Guidelines Database Grading System, the evidence is graded [Supplementary Table 1, https://links.lww.com/CM9/B984]. CCI Definition and Consensus Statement on TACE Refractoriness Consensus 1: The CCI TACE refractoriness definition is as follows: After three or more consecutive standardized and precision TACE sessions, the target tumor(s) was still in a progressive disease (PD) state (according to modified Response Evaluation Criteria in Solid Tumors [mRECIST] criteria seen on contrast enhanced computed tomography/magnetic resonance imaging [CT/MRI] at 1-3 months after the latest TACE) compared with that before the first TACE session. Repeated TACE should be terminated after occurrence of TACE refractoriness and other treatments should be considered. Consensus 2: TACE is widely applied for the treatment of unresectable HCC as palliative therapy in clinical practice in China. For patients with a low intrahepatic tumor burden along with uncomplicated tumor blood supply, TACE has the potential to act as a curative approach by superselective embolization (evidence IIb, recommendation B). The global HCC BRIDGE (Bridge to Better Outcomes in HCC) study, a multiregional large-scale longitudinal cohort study including 18,031 patients from 14 countries, has shown that TACE is the most widely used approach for HCC across BCLC stages, especially in intermediate and advanced stages. Differ from the conditions in Western countries and Japan, the majority of HCCs in China have a relatively high tumor burden with the background of hepatitis B virus infection, and therefore, TACE is mainly applied as a palliative approach for HCC in China. Notably, several reported studies have shown that TACE can act as a curative approach by superselective embolization for patients with a low intrahepatic tumor burden and relatively simple blood supply for tumor. Consensus 3: The concept of TACE refractoriness has clinical significance, but it requires rigorous definition and scientific assessment to avoid subjective factors that reduce the actual role of TACE in the treatment of HCC (evidence IIb, recommendation B). As mentioned above, most participants in the survey carried out in 2020 by the CCI agreed that the concept of "TACE refractoriness" has scientific and clinical significance, whereas none of the existing TACE refractoriness definitions were suitable for Chinese HCCs. Blind introduction of existing definitions of "TACE refractoriness" to evaluate the potential benefit of repeated TACE for Chinese HCC patients may lead to a negative long-term prognosis. Consensus 4: Occurrence new intrahepatic lesion(s) post-TACE should not be considered as disease progression, and therefore, it cannot be applied as the criterion for "TACE refractoriness". In such cases, repeated TACE with/without other treatments is recommended (evidence Ib, recommendation A). It is accepted that the occurrence of new intrahepatic lesion(s) is the biological features of HCC and should not be regarded as disease progression[7]. In the TACTICS trial, the occurrence of new intrahepatic lesion(s) was no longer defined as disease progression. Under such conditions, patients could continue to underwent TACE monotherapy or TACE combined with molecular target agents (sorafenib, lenvatinib, donafenib), which was considered as the key reason for the positive results of the trial. Consensus 5: The occurrence of macrovascular invasion and/or extrahepatic metastasis post-TACE should not be applied as the criterion for TACE refractoriness. The concept of TACE refractoriness mainly refers to intrahepatic target lesion(s). Repeated TACE combined with other treatments is recommended even if post-TACE macrovascular invasion and/or extrahepatic metastasis occur while the previous TACE procedure(s) was effective for intrahepatic target lesion(s) (evidence IIb, recommendation B). Several studies have confirmed that patients with macrovascular invasion and/or extrahepatic metastasis post-TACE could still benefit from repeated TACE combined with systemic therapies.[8] For Chinese HCCs with portal vein tumor thrombosis (PVTT), brachytherapy with 125I seed implantation combined with TACE could improve survival benefits. Specifically, for patients with branch PVTT, percutaneous 125I seed or seed strand implantation directly into the portal vein or PVTT should be considered. While for patients with main PVTT, radioactive stents with 125I seed or seed strand placement or helical 125I seed implant should be considered. Consensus 6: At present, any strong and clear evidence has yet to be provided regarding the association between the elevation of HCC-related tumor marker and the occurrence of TACE refractoriness. Further work is warranted to explore such an association (evidence IIb, recommendation B). Several HCC-specific serum tumor markers, such as alpha-fetoprotein (AFP) and Protein Induced by Vitamin K Absence II (PIVKA-Ⅱ), have been widely applied in early diagnosis and prognostic prediction in clinical practice. It has been identified that post-TACE elevation of these markers is an independent risk factor for disease progression for patients treated with TACE. Whereas, the values on changes in serum biomarkers for assessment of tumor response are under investigation and several studies found that patients could still benefit from repeat TACE even with post-TACE elevation of serum tumor markers. Consensus 7: The TACE procedure must be performed with standardization and precision (evidence IIb, recommendation A). Standardization of TACE in clinical practice is difficult to achieve despite the wide application of TACE. The concept of precision TACE has been introduced with the aim of maximizing the standardization of TACE. Precision TACE incorporates careful pretreatment preparation, patients' specific condition, accurate implementation, close follow-up, and whole-process management. Consensus 8: Considering that Chinese HCCs are initially diagnosed with high tumor burden, the "six-and-twelve" score is more suitable for prognostic stratification of intermediate HCCs in China than other models such as up-to-seven criteria (evidence IIb, recommendation B). As mentioned above, Chinese HCCs treated with TACE generally have a higher tumor burden accompanying with chronic liver diseases. Therefore, whether the tumor burden classification criteria, such as the up-to-seven criteria that are mainly widely applied in Western countries and Japan, are still suitable for Chinese HCC remains to be discussed. The six-and-twelve score, which was established based on cohorts from China, is more suitable for prognostic stratification of TACE for Chinese HCCs. Consensus 9: Apart from TACE refractoriness, the concept of TACE unsuitable that indicates termination of repeated TACE should also be emphasized. TACE unsuitable is defined as any of the following conditions: (1) unable to perform catheterization due to occlusion of the feeding arteries; (2) severe decompensated liver function (Child–Pugh C, severe jaundice, overt hepatic encephalopathy, refractory ascites, hepatorenal syndrome); (3) performance status score >2; or (4) diffuse hepatic artery-portal vein/hepatic vein fistula. Repeated TACE should also not be considered for patients meet TACE unsuitable (evidence IIb, recommendation A). Tumor response assessment and treatment strategy after three or more consecutive TACE sessions According to the CCI definition of TACE refractoriness, the Collaboration Group divided the tumor response after three or more consecutive TACE sessions into two groups: TACE refractoriness and TACE effectiveness. In addition, a new algorithm for TACE is proposed with the aim of improving its fit for HCC in China [Figure 1].Figure 1: The algorithm decision tree and evaluation strategy for conventional TACE after three or more consecutive TACEs. aIntrahepatic target lesion(s) including tumor(s) at diagnosis and new intrahepatic tumor(s) emerging after 1st or 2nd TACE treatment; bAdditional therapy and cother therapy including systematic therapy (molecular targeted agent and immune checkpoint inhibitor), locoregional therapy (drug-eluting beads TACE, hepatic artery infusion chemotherapy, selective internal radiation therapy, targeting-intratumoral-lactic-acidosis TACE, ablation therapy, helical Iodine-125 [125I] seed implant, 125I seed or seed strand implantation and 125I irradiation stent) and combined therapy. CR: Complete response; EHS: Extrahepatic metastasis; HCC: Hepatocellular carcinoma; PD: Progression disease; PR: Partial response; PVTT: Portal vein tumor thrombosis; SD: Stable disease; TACE: Transarterial chemoembolization.