Application of Transcatheter Arterial Embolization Sequential Surgery in the Treatment of Liver Cancer


 Background Preoperative transcatheter arterial embolization (TACE) is conducive to improve the surgery rate and prognosis of hepatocellular carcinoma (HCC) patients. This study aimed to evaluate the reasons and treatment effects of preoperative TACE as well as its influence on the surgery outcome.Method A total of 22 HCC patients (aged 36–68) undergoing TACE sequential surgery were retrospectively reviewed in our centers between January 2018 and August 2020. The parameters reasons, response of tumor to TACE, objective remission rate (ORR) and disease control rate (DCR), downstaging rate, abdominal adhesion and arterial injury were statistically analyzed.Results The reasons of preoperative TACE included downstaging (45.5%, 10/22), bridging therapy (22.7%, 5/22), individual choice (13.7%, 3/22), definite diagnosis (9.1%, 2/22), control of liver tumor bleeding (4.5%, 1/22) and patients with cerebral infarction (4.5%,1/22). A total of 6 complete response (CR) cases (27.3%) and 2 pathological CR (PCR) cases (9.1%) were noted. The ORR was 63.6% (14 / 22) and the DCR 90.9 % (20/22). The success rate of downstaging was 50.0% (6/12) in the patients not aiming at downstaging and 10% (1 /10) in the patients aiming at downstaging. The incidences of abdominal adhesion and arterial injury were 90.9% (20/22) and 45.5% (5/11). Conclusion TACE can be used in preoperative conversion therapy for patients who are temporarily unsuitable for surgery and is more suitable for bridging therapy in liver transplantation patients compared with downstaging due to the high DCR. Surgery should be carried out following TACE even in patients with CR.


Introduction
Hepatocellular carcinoma (HCC) is one of the most common and lethal malignancies in the world that exhibits a poor prognosis [1]. Surgical treatment, including hepatectomy and liver transplantation (LT)is still the preferred method for the treatment oflivercancer [2]. However, unfortunately, not all HCC patients are treated with surgery. At present, the majority of the studies attribute the loss of surgical opportunity to tumor stage, which exceeds the standard of resection or transplantation [3][4][5][6]. However, we have previously found that several other reasons in clinical practice, such as insu cient residual liver function, patients with myocardial infarction, cerebral infarction, poor lung function and other surgical practices, as well as patients themselves may prevent the process of surgery.
The overall ve-year survival rate of liver cancer is approximately 5-30% [7], while surgical treatment can signi cantly improve this situation. The ve-year survival rate of liver resection and liver transplantation can reach 60-70% and 72-78% respectively [8,9]. In order to improve the therapeutic effect of HCC, transcatheter arterial embolization (TACE) sequential surgery was applied for HCC patients and the present study was conducted to investigate the reasons, treatment effects of preoperative TACE and its in uence on the surgery outcome.

Patients
The present study was approved by the Ethics Committee on Scienti c Research of Qilu hospital of Shan Dong University (approval number: KYLL-2020-207). A total of 22 consecutive HCC patients who underwent TACE sequential surgery between January 2018 and August 2020 were included in the study.
A total of 17 males and 5 females were present, aged 36-68 years. All patients were diagnosed as HCC cases according to the University of California, San Francisco criteria [10]. A total of 7 cases exhibited BCLC stage A, whereas 15 cases presented with BCLC stage B. The preoperative liver function was child A/B grade, including 8 cases of A grade and 14 cases of B grade. The number of TACE ranged from 1 to 3 times and the time between the last TACE and surgery ranged from 1 to 6 months. A total of 11 cases underwent hepatectomy and 11 cases received liver transplantation (LT) following TACE. The causes of preoperative TACE included patient selection, downstaging, de nite diagnosis and control of liver cancer bleeding and bridging therapy during the waiting period for the donor liver. The details of this information are shown in Table1 and the statistical data in Table 2.
TACE and surgical operation protocol TACE was performed by transcatheter superselective catheterization of hepatic artery. 100-300 μm doxorubin-eluting beads (DEB) were injected at a xed dose of 50 mg/vial. The embolizing endpoint was achieved when the contrast agent could not be emptied within the time period required for 3-5 cardiac cycles. When the tumor volume was too large to reach the embolizing endpoint by one vial DEB, lipiodol was used for supplementary embolization and the dosage depended on the tumor size. CT was performed in one month following TACE and the response of the tumor to TACE was evaluated, which was divided into four following grades according to the mRECIST guidelines (11): complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). TACE was performed again in patients with PR or SD and the total TACE times was no more than 3. Considering that TACE Failure/Refractoriness existed in PD patients [12], sorafenib or lenvastinib was used instead of TACE in the subsequent treatment plan. Moreover, In view of the higher diagnostic rate of lipiodol CT compared to that of TACE CT and/or MRI [13], TACE was also used for de nite diagnosis when the size and number of lesions could not be accurately determined preoperatively.
Surgical operation was performed at any stage of treatment when the factors hindering the operation were eliminated or suitable liver donors were found. Anatomic resection was the preferred operation for hepatectomy and non-anatomic resection was only performed when the tumor was at the edge of the liver. All liver transplantations were performed by classic orthotopic liver transplantation. TACE, hepatectomy and liver transplantation were conducted by the same senior surgeon.

Assessment of outcome
Enhanced CT follow-up was performed one month following TACE until surgical resection or transplantation. The last CT results collected preoperatively were used to evaluate the response of the tumor to TACE and the effects of downstaging and pathological CR (PCR) were de ned when the tumor tissue was completely necrotic in the resected specimen. In addition, objective remission rate (ORR, including CR+PR) and disease control rate (DCR, including CR+PR+SD) were calculated. Downstaging was successful when the tumor reached CR or met the Milan criteria following TACE [14.15].

Statistical analysis
The data were collected and analyzed with the SPSS statistical software (SPSS version 17.0, Chicago, IL, USA). P values less than 0.05 were considered for signi cant differences.

Results
Reasons and effect evaluation of preoperative TACE Among the reasons of preoperative TACE, the downstaging effect accounted for the highest proportion (45.5%), whereas bridging therapy ranked second (22.7%), followed by individual choice (13.7%) and de nite diagnosis (9.1%). The control of liver tumor bleeding and the number of patients with cerebral infarction who were not suitable for operation accounted for 4.5% each (Table 3).

The impact of TACE on surgical operation
The impact of TACE on surgical operation is mainly re ected in abdominal adhesion and arterial intima injury. Among 22 patients, 20 cases (90.9%, 20/22) exhibited abdominal adhesion and the adhesion was mainly noted between the liver and diaphragm. According to pelvic adhesion standards (16), all adhesions are mild adhesions and easy to separate without increasing the di culty of operation. A total of 5 liver transplantation patients (45.5%, 5/11) suffered from intimal injury of hepatic artery, which resulted in the separation of the internal and external membrane of the hepatic artery. However, this injury did not affect the anastomosis of the hepatic artery (Table 4). No arterial complications occurred in all patients following liver transplantation.

Discussion
The purpose of TACE preoperation is to increase the chance of surgery in HCC patients, which is the socalled "conversion therapy". In a narrow sense, conversion therapy refers to the downstaging of unresectable HCC [17,18]. However, during the clinical application of this method, various reasons may exist in addition to tumor stage that may explain why patients cannot be treated with surgery temporarily. Therefore, it is believed that compared with "unresectable", the concept of "temporarily unsuitable for surgery" is more suitable. The present study nally carried out surgical treatment for such patients successfully, which all can be termed "conversion therapy" cases. It is believed that this is a broad concept of conversion therapy, which can re ect the current clinical situation more accurately. In the present study, to the temporary lack of suitable surgery for patients may be attributed to several reasons, among which the individual choice of patients is worth mentioning. We often choose the best treatment for patients from the perspective of medical practice. However, after informing the patients of the advantages and disadvantages of various treatment methods, they have the right not to choose the best treatment measure in medicine. In this case, the treatment measure can be accepted by the patients to control the progression of the disease. The patients can wait patiently and communicate fully, so as to ensure the optimal selection of the best treatment measure. In the present study, 3 patients refused surgery at the beginning and selected TACE. Finally, the operation was performed successfully following full communication with the patients.
The ORR is a pivotal factor for downstaging [19]. TACE has been considered as a means of downstaging [20,21] for some intermediate stage HCC patients in the last several years and performs better in ORR than both tyrosine kinase inhibitors (TKI) and the immune checkpoint inhibitor PD-1. The ORR of TACE for intermediate-stage HCC is estimated to 52.5% [22] and 63.3%. In the present study, the ORR of sorafenib (SHARP study) and lenvatinib (REFLECT study) was estimated to 2 and 24.1% respectively [23]. Pembrolizumab demonstrated 18.4% ORR in the phase 3 KEYNOTE-240 trial, which was similar to that noted for lenvatinib [24]. However, although higher ORR was noted, the success rate of downstaging was still low by TACE alone, notably in the intermediate stage HCC and was estimated to approximately 20% [25]. In the present study, the downstaging rate in the NDS group was higher than that of the DS group (50% vs. 10%) although no statistical signi cance was noted. It is believed that the reason for the lack of statistical signi cance may be due to the small sample, which shows that the expected downstaging effect could not be achieved by TACE alone for the intermediate stage HCC. The combination of other therapeutic methods, such as TKI and PD-1 inhibitor, may be a better choice.
Bridging therapy is another important application of TACE noted in liver transplantation [26]. TACE achieved higher DCR in the present study (90.9%), which ensured that it could be widely used in bridging therapy of liver transplantation compared with downstaging. Other studies have also con rmed this conclusion. The LT reported for the bridging group was 66% while the downstaging was 34% [27].
Not all patients with CR can reach PCR and the proportion of PCR in CR is approximately 54.2-76% [28,29]. This percentage was estimated to 33.3% in the present study and therefore the surgery was still recommended for CR patients. However, the question still remains of whether surgery is necessary for patients with PCR. It is di cult to nd a de nite answer due to the lack of the sensitive and speci c standard for PCR diagnosis following TACE. That is to say, we cannot accurately judge whether the patient experiences PCR or not prior to removal of the tumor. In addition, even if there is a standard for accurate diagnosis of PCR, long-term follow-up and further comparative studies are still required to address this question. TACE may increase the di culty of operation by causing abdominal adhesion and arterial injury [30].
However, this in uence is acceptable. In the present study, all abdominal adhesion cases were mild adhesions and easy to separate. Based on the successful application of arterial anastomosis technology, no arterial complications occurred even in liver transplantation patients with hepatic artery injury.

Conclusion
In conclusion, the present study indicated that TACE could be used in preoperative conversion therapy for patients who are temporarily unsuitable for surgery due to various reasons in addition to downstaging. Preoperative TACE did not increase the di culty of operation and the incidence of complications.
However, the success rate of single downstaging TACE was limited, whereas the combination with TKI and PD-I were recommended for a better downstaging effect. In view of the low rate of PCR and the lack of diagnostic criteria, it is suggested that surgery should be carried out at speci c time points even in patients with CR following TACE. Due to the different nature of surgical methods and preoperative staging of HCC, survival analysis was not performed in the present study. Moreover, the small number of cases limited the validity of the results and additional studies involving larger cohorts of patients are required for further validation.

Availability of data and materials
All data generated or analyzed during this study are included in this manuscript.

Ethics approval and consent to participate
This study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee on Scienti c Research of Qilu hospital of Shan Dong University (approval number: KYLL-2020-207).

Consent for publication
Not applicable.

Con ict of interest
The authors declare that they have no con ict of interests.  Abdominal adhesion 20 90.9 Arterial intima injury 5 22.7 The success rate of downstaging of NDS group 6/12 50 The success rate of downstaging of DS group 1/10 10 0.074