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EDITORIAL
Year : 2020  |  Volume : 16  |  Issue : 5  |  Page : 957-959

TATI modality: A new perspective on the treatment of advanced hepatocellular carcinoma


1 Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, China
2 Department of Oncology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong Province, China

Date of Submission24-Jun-2020
Date of Decision28-Jul-2020
Date of Acceptance29-Jul-2020
Date of Web Publication29-Sep-2020

Correspondence Address:
Ping Liang
Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853
China
Xin Ye
Department of Oncology, The First Affiliated Hospital of Shandong First Medical University, 16766 Jingshi Road, Jinan, Shandong Province 250014
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_850_20

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How to cite this article:
Li X, Liang P, Ye X. TATI modality: A new perspective on the treatment of advanced hepatocellular carcinoma. J Can Res Ther 2020;16:957-9

How to cite this URL:
Li X, Liang P, Ye X. TATI modality: A new perspective on the treatment of advanced hepatocellular carcinoma. J Can Res Ther [serial online] 2020 [cited 2020 Dec 5];16:957-9. Available from: https://www.cancerjournal.net/text.asp?2020/16/5/957/296451



The incidence and mortality of primary liver cancers (PLCs) has been rising rapidly and is predicted to continue to rise in the future. In 2018, more than 800,000 new PLCs and 700,000 liver cancer-related deaths (LCRDs) were recorded worldwide, with more than 400,000 new PLCs and LCRDs occurring in China.[1],[2] Based on the annual projections of the World Health Organization, more than 1 million patients will die from PLCs in 2030.[3] Most patients with hepatocellular carcinoma (HCC) are often diagnosed at an advanced stage with main vascular/bile duct invasion and distant metastases and can no longer receive radical treatment by surgery, local ablation, or liver transplantation. These patients have a dismal prognosis with rapid disease progression and short overall survival (OS). The 5-year OS ranges from 10% to 18%, and HCC is the second leading cause of overall cancer-related deaths after pancreatic cancer.[1],[4],[5]

Advanced HCC generally comprises patients at the Barcelona Clinic Liver Cancer-stage C (BCLC-C) and BCLC-B (intermediate-stage) with disease progression after transarterial chemoembolization (TACE) therapies; even patients with BCLC-0 and A stages experience disease progression on curative treatments, and BCLC clinical staging is endorsed in clinical practice guidelines and is a widely accepted benchmark for clinical trial design.[4],[6],[7] The classic drug sorafenib was approved by the Food and Drug Administration in 2007 as the first-line treatment for advanced HCC, which opened the door to molecular-targeted therapies for HCC (median OS of 6.5 months and 6-month OS rate of 53.3%). Although lenvatinib was recommended as a first-line treatment for advanced HCC in 2018, its clinical efficacy was not superior to that of sorafenib (median OS duration of 13.6 months vs. 12.3 months).[8],[9] As a result, regorafenib, cabozantinib, and apatinib were listed as effective options for second-line treatments, but the OS was improved unsatisfactorily.[10],[11],[12] Currently, tyrosine kinase inhibitors (TKIs), such as sorafenib, lenvatinib, regorafenib, apatinib, capmatinib, and remtolumab, have been used as an optional therapy for advanced HCC, but the overall efficacy is limited, and drug resistance and side effects are major concerns.

The pathogenesis of HCC is often related to chronic hepatitis and is a complex process with multiple factors and stages of evolution. A single agent or monotherapy regimens could not be expected to solve this problem; thus, the need for combination therapy to achieve synergistic effects is urgent. Angiogenesis and immune evasion are two hallmarks of cancer including HCC.[13] Most HCCs are hypervascular with vascular endothelial growth factor (VEGF) overexpression, which is linked to disease development, metastases, and recurrence. In addition, the VEGF overexpression in hyperactive angiogenesis also contributes to the immunosuppressive microenvironment by affecting multiple immune steps.[14],[15] Since 2013, cytotoxic T-lymphocyte-associated antigen 4, programmed death (PD)-1, and PD-ligand 1 monoclonal antibodies have been applied in HCC, and only 10%–15% of patients were sensitive, and the objective response rate varies.[16],[17],[18],[19] In recent years, the combination of multiple drugs based on immunotherapy and antiangiogenesis has gradually become a new hotspot in the treatment of HCC. The latest report of the combination of atezolizumab and bevacizumab achieved promising clinical efficiency and good patient tolerance and may be approved as a first-line treatment for HCC. The 12-month survival rate of patients with advanced HCC on atezolizumab plus bevacizumab reached 67.2%, breaking the bottleneck in the treatment for more than a decade.[20] Moreover, the combination therapy of apatinib and camrelizumab from China also provided an intriguing clinical effect with the objective response rate and disease control rate being 50.0% and 93.8%.[21] Therefore, TKIs aim to inhibit angiogenesis and normalize blood vessels through regulating molecular pathways, which are crucial for tumor growth and maintenance, whereas immunotherapy endeavors to stimulate a host immune response that effectuates long-lived tumor destruction. In addition, TKIs affect pathways that are also crucial for immune development and function and might optimize antitumor immune responses from immunotherapy. On the other hand, immunotherapy may consolidate the impressive clinical responses from TKIs into long-lasting clinical remissions.[13] Therefore, combined immunotherapy is expected to shift the paradigm as a first-line treatment option for advanced HCC.

In contrast to other types of tumors, where surgery, radiation therapy, and chemotherapy dominate the therapeutic landscape, locoregional treatments including curative and palliative intent (ablations and TACE) are widely applied in HCC.[22] Interestingly, both TACE and ablation (cryotherapy, microwave, or radiofrequency) have been shown to induce local hypoxia, vascular permeability increased, tumor antigen release, T-lymphocyte infiltration and aggregation, and cytokine release or expression.[23],[24],[25] However, such responses had been thought to be usually weak and to last for a short time and rarely induce tumor regression. Recently, the results of several preclinical and clinical studies have suggested that locoregional treatments can induce therapeutically effective systemic antiangiogenesis and antitumor immune responses; if appropriate, TKIs and immunotherapies are combined. The preliminary data also suggested a further augmentation of the antitumor effect without overlapping toxicity.[26],[27]

At present, the greatest challenge of combination therapy lies in how to combine locoregional treatments, TKIs, and immunotherapy for advanced HCC in clinical practice. Recently, a novel “TATI modality” was put forward by Meng et al.,[28] which consists of TACE, ablation, TKIs, and immunotherapy applied sequentially in advanced HCC. Four patients underwent TACE treatment at the time of disease diagnosis. During follow-up, the patients were treated with microwave ablation because of a residual tumor or recurrence. For tumor control, apatinib (a TKI drug) was administered after ablation. If the tumor was stable or resistant to TKI, apatinib was continued in combination with immunotherapy (camrelizumab–anti-PD-1 antibody). All four patients had better survival benefits, and the longest survival time of 32 months and the shortest of 17 months achieved with no serious adverse effects. Furthermore, the potential mechanism of TATI modality was also speculated. The results are encouraging and may represent a solution for patients with advanced HCC. This is a very important study and a great contribution to the management of advanced HCC. Certainly, this study met with some limitations. The main limitations were a very preliminary clinical result of case reports and its retrospective nature. Therefore, more prospective, multicenter clinical trials with larger samples are needed to verify the safety and efficacy of the TATI modality.

In the near future, we believe that the novel therapeutic modality would provide a long-term survival and better quality of life for patients with advanced HCC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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