Treatment of Gastrointestinal Tumor Liver Metastases with the Combination of Apatinib and Transarterial Chemoembolization

Background There are no exact treatments been recommended for gastrointestinal tumor liver metastasis patients. This study intends to assess the safety and ecacy of transarterial chemoembolization (TACE) plus apatinib as a combination treatment for gastrointestinal tumor liver metastasis patients. Methods From to 53 patients with gastrointestinal liver metastases were included in the analysis. Results were and 17 respectively. The of sites was 12 The control rate (DCR) and objective response rate (ORR) values were 86.8% (46/53) and 49.1% (26/53), respectively. The multivariate regression analysis showed that Child-Pugh and Eastern Cooperative Oncology Group (ECOG) were independent predictors for OS. The independent predictors for overall PFS include carbohydrate antigen 724 (CA 724), CA 199, TACE session, Child-Pugh, and ECOG; while for liver tumor PFS, the independent predictors are TACE session and ECOG scores. There were no changes of leukocyte, lymphocyte, carcinoemnryonicantigen (CEA), CA 724, CA 199, CA 125 of patients before receiving the treatments and one after receiving the (all P>0.05). Common adverse events at any were poor (64.2%), hypertension (56.6%), and hand-foot syndrome (50.9%). Some patients had III or IV-grade adverse events after receiving the TACE-apatinib combination treatment. However, these adverse events alleviated after reducing apatinib administration or receiving symptomatic treatments. the TACE-apatinib combination in treating metastatic liver cancer.


Introduction
Gastrointestinal tumor (GIT) is one of the most highly morbid malignant tumors with one of the greatest mortality rates. The 2018 global cancer statistics state that 18 million new cancer cases emerged across the world, and 9.6 million died from cancer-associated conditions. Besides, the incidences of gastrointestinal cancers (e.g. gastric, colon, and rectal cancers) were some of the highest. [1] Despite signi cant improvements in gastrointestinal tumor management, such as widespread screening programs, effective systemic therapies, and enhanced surgical and locoregional control, many patients still develop incurable metastatic gastrointestinal tumors. [2] The liver is an organ that is susceptible to GIT metastasis, and secondary hepatic malignancies are 18-40 times more prevalent than primary ones. [3][4][5] About half of the liver metastasis patients have primary colorectal cancer (CRC), followed by gastric cancer (about 5-9%).
[6] Besides, liver metastasis is a primary reason for morbidity, organ failure, and eventually mortality for gastrointestinal cancer patients [6,7]. For these patients, there were no treatments recommended as the rst-line choice. Thus, more treatments for these patients still needed to be explored.
Apatinib is an oral inhibitor of vascular endothelial growth factor (VEGF) receptor-2 [8] developed by Adrenchen Laboratories. It has been approved as a second-line novel agent to treat metastatic or advanced gastric cancer by FDA. [9] The literature has suggested that apatinib has promising antitumor activity against lung and colorectal cancers with tolerable toxicity. [10,11] Besides, in a Phase III study, apatinib has been proved to improve PFS and OS of gastric cancer patients who have endured heavy pretreatments [9]. A pilot study also indicated that apatinib has the potential to be a third-line treatment agent for refractory metastatic colorectal cancer. [11] Transarterial chemoembolization (TACE) is the rst-line treatment option for medium-term liver cancer. [12] Recent studies have shown that TACE is also effective in the metastasis of liver cancer [13][14][15]. Studies showed that TACE is capable of bringing satisfactory tumor control and being used in palliative treatments for patients with either colorectal cancer liver metastases (CCLM) or gastric cancer liver metastases (GCLM) conditions.[16-18] The literature has suggested that TACE plus apatinib is potent to treat advanced liver cancer [19,20], but in metastatic liver cancer, few studies have focused on the therapeutic e cacy of such combination. As the combination of TACE and apatinib has shown great therapeutic potential for GCLM and CCLM in previous research, this single-arm study aims to explore the safety and e cacy of the TACE-apatinib combination in treating metastatic liver cancer.

Patient Selection
The review board of the Union Hospital, Tongji Medical College, Huazhong University of Science and Technology approved this retrospective study. Informed consent was waived since the study was retrospective. The principles of the Declaration of Helsinki were followed throughout the study. In this study, we selected 53 GCLM and CCLM patients who underwent consecutive TACE treatment in our medical center from January 2015 to December 2019. Before the initial TACE session, all patients were noti ed of all treatment options by the multidisciplinary tumor treatment board. TACE, a treatment capable to reduce tumor burden, was the last approach we could give to control disease progression.
Inclusion criteria were as follows: (1) Before TACE, the patients had their primary tumor(s) removed, and the chemoembolization indications were unresectable GCLM and CCLM with no disease progression, no response, and no toxicity after the administration of two systemic chemotherapy lines. (2) liver metastases as diagnosed by biopsy or imaging; (3) age > 18 years; (4) Child-Pugh A or B; (5) an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 or 2; (6) patients did not receive TACE or apatinib. (7) patents with platelet count >50*109/L Patients falling in either one of the following exclusion criteria were removed from the study: (1) main portal vein obstruction; (2) serious medical comorbidities, such as hepatic dysfunction (serum albumin level < 2.0 mg/dL, INR > 1.5, serum total bilirubin level > 3 mg/dL) and renal impairment (serum creatinine level >2 mg/dL) and ; (3) diffuse liver tumors which can not be evaluated; TACE Procedure TACE was performed following our previously-reported standard protocol. All operators had prior experience in performing TACE (≥5 years). At rst, tumor-feeding arteries and tumor staining were observed and determined via angiography. Subsequently, a 2.6-Fr microcatheter (Terumo™, Japan) was inserted into the tumor-feeding arteries, through which an emulsion of 20-60 mg doxorubicin hydrochloride (Hisun Pharmaceutical Co., Ltd., Zhejiang, China) and 2-20 mL iodized oil (Lipiodol Ultra-Fluid; Laboratoire Andre Guerbet, Aulnay-sous-Bois, France) were administered inside the target blood vessels. The dosage of doxorubicin hydrochloride and lipiodol was decided based on the tumor vascularity/size and the patient's baseline liver function. Speci cally, iodized oil was applied on a dosage of 1-3 mL per cm of tumor diameter, which varied based on the blood supply. For patients with poor liver function (Child-Pugh score ≥ 8) or a large tumor burden (tumor diameter > 10 cm), the initial TACE treatment was conducted with a smaller emulsion amount or via fractional embolization to avoid liver failure. Finally, the mixture of gelatine sponge particles (300-500 µm, Cook™, Bloomington, Indiana, USA) and a contrast material was administered into the tumor-feeding arteries until the arterial ow became stable.

Apatinib Administration
Patients in the TACE-apatinib group took 500 mg apatinib (Hengrui Pharmaceutical Co. Ltd, Jiangsu, China) orally at 3-5 days following TACE. Adjustment of apatinib doses was based on the patients' drug tolerance. Grading of apatinib-associated adverse events was given according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). If an apatinib-related adverse event was graded ≥3, then the apatinib dose would decrease to 250 mg. If the event continued to be ≥3 grade even after the dose reduction, the drug administration would be temporarily interrupted. Following the alleviation or elimination of the adverse event, the patient with temporary drug interruption would resume an apatinib dose of 250 mg/day.

Follow-up
All patients in this study were followed by CT or MRI and laboratory tests. The interval of follow-up was 1 month for the rst three months after the initial TACE, and 2-3 months afterward. All treatment responses (based on the CT or MRI imaging) were evaluated by a diagnostic radiologist (experience >15 years) and an interventional radiologist (experience >10 years). Meanwhile, the patients were not blinded to their treatment information because iodine could be found in the imaging. The decision of another TACE for patients was based on the tumor burden evaluated by the mRECIST criteria. When the tumor progressed during the follow-up or residual tumors were observed, the patients were recommended to undergo another TACE session on the condition of good liver function or physical condition. The end time of follow up for the study was June 2021.

Assessments
The study took PFS, OS, DCR, and ORR as the parameters for assessment. PFS, ORR, and DCR were evaluated according to the modi ed Response Evaluation Criteria for Solid Tumors (mRECIST) [21]. ORR was de ned as the portion of patients whose liver tumor showed either partial response (PR) or complete response (CR). DCR was de ned as ORR plus the portion of patients with stable disease (SD) in all patients, OS was de ned as the time interval from the rst TACE session to the last follow-up or death. Overall PFS was de ned as the time interval from the rst TACE session to any tumor progression or death. PFS of liver tumors was de ned as the time interval from the rst TACE session to liver tumor progression or death.
Statistical Analysis SPSS 26.0 software (IBM, Armonk, New York) was used to perform all statistical analyses. Non-normally distributed data, categorical variables, and normally distributed data,were expressed as median (quartile range), frequency (percentage), and mean±standard deviation, respectively. OS and PFS of the study cohort were described by the Kaplan-Meier method. The survival and tumor progression of patients receiving TACE plus apatinib were predicted with the Cox regression risk model. Variables with P<0.05 in the univariable regression analysis were included in a multivariate regression analysis, and P<0.05 (twotailed) was considered statistically signi cant.

Patient demographic characteristics
In this study, 53 patients were included from January 2015 to December 2019. Patient selection was executed as described in Figure 1, and Table 1 (Table 3).

The Changes Of Blood Examinations And Tumor Markers
The leukocyte, lymphocyte, neutrophils, CEA, CA 724, CA 199, CA 125 of patients before receiving the treatment and after receiving the treatment were reported. There was no signi cant statistically difference of the factors in patients before the treatment and after the treatment (all P>0.05) (Figure 3).

Complications
Adverse event evaluations for patients after receiving the combination treatment are shown in   [20,23] The reason behind such a phenomenon is that the microenvironment is ischemic and hypoxic after TACE, which is favored for tumor angiogenesis, recurrence, and progression mediated by various factors, such as MMP-9 and VEGF. [24,25] On the other hand, apatinib is a strong inhibitor of VEGFR-2 and a promising anti-angiogenic agent with great anti-tumor activity. [26,27] Speci cally, it has been used to treat advanced gastrointestinal tumors and achieved good results. [9,28] For primary liver tumors, such as hepatocellular carcinoma, a recent retrospective study [29] revealed that the TACE-apatinib combination could result in a signi cant increase of the median TTP and OS compared to TACE treatment alone. Therefore, TACE plus apatinib may be a favorable and effective treatment combination as a part of interdisciplinary palliative therapy management. In the study, the multivariable regression analysis presented that ECOG and Child-Pugh scores were independent predictors for OS and overall PFS, while only ECOG scores were independent predictors for PFS of liver tumors. The result showed that the patients' physical conditions and liver function might in uence the prognosis and tumor progression. Thus, boosting the liver function and physical health of the patients before receiving TACE plus apatinib might improve the patients' survival. In the study, the changes of blood examinations and tumor markers of patients before receiving the treatment and after receiving the treatment. There was no signi cant statistically difference of these factors, which might mean that the treatment did not in uence blood test indicators and tumor markers. Even with 58 severe adverse events reported. The adverse events were relieved after symptomatic treatments, suggesting that TACE plus apatinib could still be a relatively safe treatment.
As a retrospective study, this study has certain limitations. The most critical limitation of this report is the small sample size. Secondly, no other treatments were involved as a reference for TACE plus apatinib to compare with. Therefore, further prospective studies in which other treatments are discussed are necessary to verify the therapeutic effects of the TACE-apatinib combination.

Conclusions
Patients with gastrointestinal liver metastases might get survival bene ts from transarterial chemoembolization combined with apatinib. The results might provide new evidence for clinics to choose suitable treatment for these patients.

Declarations
Competing interests: All authors declared that there were no competing interests existing. Guidelines for Methods: This study was carried out in compliance with the Helsinki Declaration.
Consent for publication: All authors approve it for publication.
Data Availability: The data used in the study can be available from the correspondence authors upon reasonable request.
Competing interests: All authors declared that there were no con icts of interest existing.