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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 2  |  Page : 327-334

Transarterial chemoembolization, ablation, tyrosine kinase inhibitors, and immunotherapy (TATI): A novel treatment for patients with advanced hepatocellular carcinoma


1 Department of Oncology, Shandong Provincial Hospital Affiliated, Shandong First Medical University, Jinan, China
2 Department of Oncology, The First Affiliated Hospital of Shandong First Medical University, 16766 Jingshi Road, Jinan, Shandong Province 250014, China

Date of Submission23-Jan-2020
Date of Decision14-Mar-2020
Date of Acceptance28-Mar-2020
Date of Web Publication28-May-2020

Correspondence Address:
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_101_20

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 > Abstract 

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Currently, the main effective treatment options for HCC include resection, liver transplantation, various percutaneous modalities (such as transarterial chemoembolization [TACE] and thermal ablation), and tyrosine kinase inhibitors (TKIs). Herein, we have proposed a novel therapy which consists of TACE, ablation, tyrosine kinase inhibitors, and immunotherapy (TATI) for patients with advanced HCC). We reported the therapeutic effects of TATI in four patients with advanced HCC. All patients underwent TACE treatment at the beginning of disease diagnosis. During follow-up, all patients were treated with microwave ablation because of a residual tumor or recurrence. For tumor control, apatinib, a TKI, was administered after ablation. If the tumor was resistant to the TKI, we continued to apatinib therapy in combination with immunotherapy (camrelizumab). All the four patients had better survival benefits and no serious adverse effects.

Keywords: Ablation, hepatocellular carcinoma, immunotherapy, transarterial chemoembolization, tyrosine kinase inhibitors


How to cite this article:
Meng M, Li W, Yang X, Huang G, Wei Z, Ni Y, Han X, Wang J, Ye X. Transarterial chemoembolization, ablation, tyrosine kinase inhibitors, and immunotherapy (TATI): A novel treatment for patients with advanced hepatocellular carcinoma. J Can Res Ther 2020;16:327-34

How to cite this URL:
Meng M, Li W, Yang X, Huang G, Wei Z, Ni Y, Han X, Wang J, Ye X. Transarterial chemoembolization, ablation, tyrosine kinase inhibitors, and immunotherapy (TATI): A novel treatment for patients with advanced hepatocellular carcinoma. J Can Res Ther [serial online] 2020 [cited 2020 Jul 16];16:327-34. Available from: http://www.cancerjournal.net/text.asp?2020/16/2/327/285177




 > Introduction Top


Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and the fifth most common cancer worldwide.[1],[2] Till date, the main effective treatment options for HCC include resection, liver transplantation, various percutaneous locoregional therapeutic modalities (such as transarterial chemoembolization [TACE] and thermal ablation), and tyrosine kinase inhibitors (TKIs).[3],[4],[5] Resection and liver transplantation are performed for early-stage and oligonodular (five or fewer intrahepatic lesions) HCCs, and only approximately 9%–27% of patients benefit from these surgical therapies.[6] Various percutaneous locoregional therapeutic modalities include TACE, percutaneous ethanol injection, and thermal ablation with radiofrequency ablation, microwave ablation (MWA), laser ablation, or cryoablation. In most patients with HCC, these are palliative treatment options.[3],[4],[5],[6]

MWA is a new treatment method that is faster and covers a larger area than radiofrequency ablation. Ablation is the standard treatment for lesions <3 cm in diameter that is unsuitable for surgery.[7],[8] However, the combination of MWA and TACE increases the complete necrosis rate of HCC >3 cm. Unfortunately, these procedures can stimulate local angiogenesis factors, promote tumor regeneration, and increase the possibility of metastasis.[9],[10]

Some TKIs, including sorafenib and apatinib, that target the vascular endothelial growth factor (VEGFR) can block tumor growth and angiogenesis.[5],[11],[12] Apatinib can inhibit tumor neovascularization after TACE/MWA and thus have an anti-cancer role.[13] Furthermore, apatinib can improve the effect of anti-tumor treatments and reduce recurrence and metastasis. However, the follow-up treatment choice is unclear for drug-resistant tumors. Currently, many clinical trials have evaluated the efficacy of anti-programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) treatments alone or in combination for HCC.[14],[15],[16]

Herein, we have proposed a novel therapeutic modality for patients with advanced HCC, which consists of TACE (T), ablation (A), tyrosine kinase inhibitors (T), and immunotherapy (I)--TATI. We also report the efficacy of TATI in four patients with advanced HCC.


 > Case Reports Top


Case 1

A 72-year-old man visited our hospital 2.5 years ago after multiple masses were detected in his liver during an ultrasound examination at a local hospital. He had a history of hepatitis B infection and liver cirrhosis for more than 4 years and was regularly taking antiviral drugs. In our hospital, we found multiple intrahepatic masses with typical imaging features of liver cancer [Figure 1]a-c]. The α-fetoprotein (AFP) level was 237.9 ng/mL, and the protein-induced by Vitamin K absence or antagonist-II (PIVKA-II) level was 206 ng/mL. The patient was diagnosed with HCC according to the 2010 edition of the classification of digestive system tumors by the World Health Organization (WHO).
Figure 1: (a) A magnetic resonance image of case 1 showing the first lesion in the left hepatic lobe and the second in the right posterior lobe. (b) Focus 3 is located beside the inferior vena cava. (c) Focus 4 is beside the gallbladder. (d and g-k) One month thereafter, a residual tumor signal was observed in the periphery of foci 1 and 4; hence, we performed microwave ablation. (e and f) One month after transarterial chemoembolization, no residual tumor signal was observed in the periphery of foci 2 and 3. (l) One month thereafter, there was no obvious signal of a residual tumor around the first and fourth lesions; accordingly, complete ablation was considered to have been performed. (m and n) At the 1.5-year follow-up, a new lesion was found in the right posterior lobe; there was a recurrence around the lesion in the right lobe. We performed a second ablation. (o-s) One year after immunotherapy, no residual tumor was found. (t and u) Change in tumor marker levels of case 1

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As there was no indication for tumor resection, the patient received TACE on March 2, 2017. During the procedure, 20 mg pirarubicin and 15 mL lipiodol were administered to embolize the feeding arteries. One month after TACE, the AFP level decreased [Figure 1]t and [Figure 1]u, although computed tomography (CT) revealed that some lesions in the liver had residual tumor tissue [Figure 1]d,[Figure 1]e, [Figure 1]f, [Figure 1]g. Therefore, the patient received MWA on April 5, 2017 [Figure 1]h, [Figure 1]i, [Figure 1]j, [Figure 1]k. After ablation, the patient was treated with apatinib once daily at a dose of 250 mg. During the 1-year follow-up, the AFP level decreased gradually and finally stabilized [Figure 1]t and [Figure 1]u, and no new measurable lesions were observed; therefore, the cancer was considered completely ablated [Figure 1]l. The patient developed moderate hypertension and mild hand-foot syndrome, both of which were well controlled after proper treatment without any serious side effects or other treatment-related adverse events.

However, at the 1.5-year follow-up, we found a new lesion in the right posterior liver lobe, a recurrence around the lesion in the right liver lobe [Figure 1]m, and an increase in the AFP level [Figure 1]t and [Figure 1]u. We performed a second ablation for these lesions on September 18, 2018 [Figure 1]n. Considering the drug progression of the patient, we began anti PD-1 antibody immunotherapy after ablation. We administered 200 mg camrelizumab (Jiangsu Hengrui Medicine; Jiangsu, China) every 3 weeks. After 2 months, the patient's skin began to show reactive capillary hemangiomas (RCHs).[17] With the prolongation of the treatment cycle, RCHs increased significantly. After 4 months, we started administering apatinib in combination with camrelizumab. RCHs began to gradually decrease. During the 1-year follow-up of immunotherapy, the AFP level decreased gradually [Figure 1]t and [Figure 1]u, and no new measurable lesions were observed [Figure 1]o, [Figure 1]p, [Figure 1]q, [Figure 1]r, [Figure 1]s. The patient continuously received camrelizumab and apatinib as maintenance therapy.

Case 2

A 55-year-old emaciated man complaining of fatigue since 5 months visited the hospital on May 19, 2018. The patient showed a large tumor on liver abdominal ultrasound and CT examinations in the local hospital. He had a history of hepatitis B infection and liver cirrhosis for more than 10 years and did not take antiviral drugs. In our hospital, we found a huge intrahepatic mass, approximately 16.7 cm × 11.5 cm in diameter, with typical features of liver cancer on magnetic resonance (MR) and CT imaging [Figure 2]a and [Figure 2]b. The AFP level was 4.8 ng/mL, and the PIVKA-II level was 4397.86 ng/mL. Liver puncture biopsy confirmed HCC.
Figure 2: (a and b) Computed tomography and magnetic resonance images from case 2 showing a large lesion in the right liver lobe. (c and d) One month after transarterial chemoembolization, a residual tumor signal was observed in the periphery of the focus; hence, we performed transarterial chemoembolization a second time for this lesion. (e and f) One month thereafter, a residual tumor signal was observed in the periphery of the focus. (g and h) computed tomography images at the time of the first microwave ablation. (i) One month after the first microwave ablation, a residual tumor signal can be observed in the periphery of the focus; therefore, we performed microwave ablation a second time. (j and k) computed tomography images at the time of the second ablation. (l) Five months thereafter, we considered the progression of intrahepatic lesions with a larger enhancement range than before. (m and n) computed tomography image at the third ablation. (o) Two months thereafter, there was no obvious residual tumor signal around the lesion. (p) Six months after immunotherapy, no residual tumor was found. (q and r) Change in tumor marker levels of case 2

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Because of the large size of the lesion, we performed TACE twice, first on May 24, 2018, and then on July 14, 2018 [Figure 2]c, [Figure 2]d, [Figure 2]e, [Figure 2]f. One month after, the second time TACE was performed, the PIVKA-II level decreased [Figure 2]q and [Figure 2]r, but another MR imaging revealed residual tumor tissue around the focal point [Figure 2]e and [Figure 2]f. The patient received MWA twice, first on August 14, 2018, and then on September 25, 2018 [Figure 2]g, [Figure 2]h, [Figure 2]i, [Figure 2]j, [Figure 2]k. After MWA was performed thefirst time, the patient was treated with apatinib once daily at a dose of 250 mg. During the 5 months of follow-up, the PIVKA-II level decreased gradually [Figure 2]q and [Figure 2]r, and no new measurable lesions or residual lesions were observed. There were no serious side effects or treatment-related adverse effects except mild hypertension.

However, on February 19, 2019, the progression of intrahepatic lesions was observed with a larger enhancement range than before [Figure 2]l, and the PIVKA-II level was higher than before [Figure 2]q and [Figure 2]r. We performed ablation for the third time for these lesions on February 21, 2019 [Figure 2]m and [Figure 2]n. After ablation, we administered apatinib in combination with immunotherapy (camrelizumab, 200 mg every 2 weeks). During the 8 months of follow-up after immunotherapy, the PIVKA-II level decreased gradually [Figure 2]q and [Figure 2]r, and no new measurable lesions were observed [Figure 2]o and [Figure 2]p. There was no obvious capillary hyperplasia or treatment-related adverse reactions. The patient continuously received camrelizumab and apatinib as maintenance therapy.

Case 3

A 68-year-old man visited our hospital because multiple masses were found in his liver during ultrasound and CT examinations in a local hospital. He had a history of hepatitis B infection for more than 30 years and cirrhosis for 3 years. In our hospital, we found two intrahepatic masses in the left outer lobe and right posterior lobe with typical MR imaging features; the diameters were 5.2 cm × 4.7 cm and 4.8 cm × 3.4 cm, respectively. The AFP level was 154.7 ng/mL. The patient was diagnosed with primary liver cancer, according to the 2010 WHO classification of digestive system tumors.

First, we performed TACE on February 4, 2017. At the 1-month follow-up, the AFP level decreased, but MR imaging re-examination revealed residual tumor tissue. The patient received MWA twice, first on March 2, 2017, and then on May 8, 2017. After thefirst ablation, the patient was treated with apatinib once daily at a dose of 250 mg. During the 21 months of follow-up, no new measurable lesions or residual lesions were observed. There were no serious side effects or treatment-related adverse effects except mildly increased blood pressure and an oral mucosal ulcer (which was well controlled after appropriate treatment). However, on December 15, 2018, we found a new lesion in the left adrenal gland. In the previous 6 months, the AFP level had been gradually increasing. We performed MWA for the adrenal metastasis on December 20, 2018. After ablation, we administered apatinib combined with camrelizumab (200 mg every 2 weeks). During the 9 months of follow-up, the AFP level decreased gradually, and no new measurable lesions were observed. There were no obvious RCHs or treatment-related adverse reactions. The patient continuously received camrelizumab and apatinib as maintenance therapy.

Case 4

A 69-year-old man visited our hospital 1.5 years ago because a tumor mass was detected in his liver during CT examination at a local hospital. He had a history of hepatitis B infection and liver cirrhosis for more than 30 years and regularly took antiviral drugs. On visiting our hospital, we found a mass in the right liver lobe, with a diameter of 4.3 cm × 3.0 cm. The AFP level was 28230.3 ng/mL, and the PIVKA-II level was 2033.0 ng/mL. The patient was diagnosed with primary liver cancer according to the 2010 WHO classification of digestive system tumors.

We performed TACE on April 14, 2018. After 1 month of follow-up, the AFP level decreased, but MR imaging re-examination showed residual tumor tissue. The patient received TACE for the second time on May 17, 2018. No anti-tumor treatment was performed after TACE. After 2 months of follow-up, MR imaging revealed residual lesions. On July 12, 2018, we performed MWA. After ablation, the patient was treated with apatinib once daily at a dose of 250 mg. During the 11 months of follow-up, no new measurable lesions or residual lesions were observed. No severe toxicities or treatment-related adversities were observed.

However, on June 16, 2019, we found a lesion in the right posterior lobe of the liver adjacent to the diaphragmatic apex larger than the one before. We performed MWA on June 18, 2019. After ablation, we administered apatinib in combination with camrelizumab (200 mg every 2 weeks). During the 4 months of follow-up with immunotherapy, the AFP levels decreased to normal, and no new measurable lesions were observed. No severe toxicities or treatment-related adverse effects were observed. The patient continuously received camrelizumab and apatinib as maintenance therapy.


 > Discussion Top


China is among the countries with a high incidence of HCC. In addition, because most patients are diagnosed with advanced-stage disease, they cannot undergo radical surgery.[18],[19] TACE treatment is a valid option for patients with advanced HCC using a variety of combinations of chemotherapeutic drugs and embolic agents. TACE can effectively prolong the survival time of patients with HCC and improve the 2-year survival rate of patients.[6] However, achieving a complete response for medium, large, or multiple tumors using TACE is difficult. Chen et al.[20] reported that TACE with MWA resulted in a better tumor response and could reduce re-intervention than TACE alone. After TACE, MWA can completely destroy the tumor, thereby ensuring better tumor control and longer survival.

In this study, all the four patients were male [Table 1] and received MWA after TACE; some patients even received MWA three times [Table 2]. MWA is an effective technique for treating HCC. When TACE is combined with MWA, the ablation volume can be increased, and MWA can destroy the residual tumor observed after TACE.[20] MWA is usually performed 3–4 weeks after TACE because patients treated with TACE require time to recover, and lipiodol needs to be eliminated from the normal liver parenchyma to clearly observe the tumor.[20],[21]
Table 1: Patient characteristics

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Table 2: Characteristics of treatment with transarterial chemoembolization, ablation, tyrosine kinase inhibitors, and immunotherapy (i.e., tumour-associated trypsin inhibitor) for the four patients

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After TACE, the expression of VEGF in remnant peripheral tumor tissues becomes higher, and the tumors become more invasive and cause metastasis. As a highly selective VEGFR-2 blocker, apatinib can block the migration and proliferation of vascular endothelial cells, reduce tumor microvessel density, and inhibit tumor growth.[22],[23],[24],[25] In this study, we administered apatinib after MWA to all the four patients at a dose of 250 mg once daily. Considering the efficacy, the benefit time of apatinib administration for patients with Barcelona Grade B HCC was >18 months, and in one case, 21 months. However, for patients with Barcelona Grade C HCC, the benefit time was relatively short, with the longest being 11 months [Table 1] and [Table 2]. The main side effects of apatinib were hypertension, rash, and other minor effects, which were tolerable.

The increased expression of PD-1 and PD-L1 in HCC was significantly correlated with tumor invasiveness and postoperative recurrence risk.[15],[26],[27] Therefore, PD-L1 may be an immunotherapeutic target in HCC. Duffy et al.[28] found that the combination of tremelimumab and interventional radiology procedures (e.g., TACE and MWA) was not only feasible but also resulted in an objective tumor response outside the ablation or embolization area in a patient heavily pretreated with sorafenib. Sangro et al.[29] reported that after trastuzumab monotherapy in a Phase II study of hepatitis C virus-related HCC, the partial remission rate was 17.6%, the median time to progression was 6.48 months, and the median overall survival was 8.2 months. In this study, we used camrelizumab to treat patients who were apatinib-resistant after TACE and MWA. One patient has been taking camrelizumab for 13 months [Table 2] and remains in a stable condition. The main side effect was RCHs, and no other serious complications (such as immune pneumonia) were found.

Camrelizumab is a humanized high-affinity immunoglobulin G4 kappa monoclonal antibody against PD-1. RCHs are a common skin toxicity associated with camrelizumab, for which apatinib seems to be effective.[30],[31] In this study, a patient with RCHs showed rapid remission after apatinib treatment. In addition, there were no symptoms of RCHs in other patients who were treated with camrelizumab in combination with apatinib. Moreover, tumor neovascularization is often distorted, dilated, and accompanied by increased vascular wall permeability and uneven internal blood flow, leading to decreased drug concentrations in tumor tissue. Anti-angiogenic therapy may improve tumor vascular morphology by cutting off distorted vascular branches and reducing gaps between endothelial cells. Moreover, combining low-dose apatinib (VEGFR-2 TKI) with an anti-PD-L1 antibody significantly slowed tumor growth and metastases and resulted in prolonged survival. Apatinib may improve the effective perfusion of tumor vessels in a certain time window by normalizing tumor vessels. The improved vascular structure allows a higher concentration of PD-1 drugs to be delivered from the blood vessels to the tumor, possibly explaining the synergistic effect of anti-angiogenic drugs and immunotherapy.[32]

We speculated that the mechanism of the anti-tumor effect of TATI might be as follows [Figure 3]: TACE and ablation could release cancer cell antigens and reduce tumor loading. Subsequently, cancer antigens are presented on dendritic cells, immune cells are primed and activated (anti-CTLA-4 can promote this step), and T cells are trafficked to tumors to infiltrate them (VEGF inhibitors can potentially promote T-cell infiltration). Finally, cancer cells are recognized and killed by T-cell (anti-PD-L1 or anti-PD-1 antibodies can promote this step).
Figure 3: Schematic of TATI modality in the treatment of advanced HCC

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In short, all four patients with advanced HCC underwent TATI treatment. The longest survival time was 32 months and the shortest was 17 months [Table 2]. Moreover, all the toxicities were tolerable.

In conclusion, 'TATI modality” was effective for treating advanced HCC with clinically acceptable toxicity. Nevertheless, prospective, multicenter clinical trials with a larger sample size are necessary to better clarify the effectiveness and safety of TATI.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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