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Efficacy of hepatic arterial infusion chemotherapy in patients with primary liver cancer with portal vein tumor thrombosis: a comparative analysis of different perfusion chemotherapeutic regimens

European Journal of Medical Research volume 29, Article number: 465 (2024) Cite this article

Abstract

Background

Portal vein tumor thrombosis (PVTT) commonly occurs in patients with primary liver cancer (PLC). Transarterial chemoembolization (TACE) is a treatment for patients with PLC and PVTT. Some studies have shown that combining TACE therapy with hepatic arterial infusion chemotherapy (HAIC) might improve the survival rate of PLC patients with PVTT. However, few studies have compared the different regimens of PLC with PVTT. We aimed to compare the differences between the oxaliplatin + raltetrexed regimen and FOLFOX regimen.

Methods

We divided the 248 patients into two groups. There were 60 patients in the oxaliplatin + ratitetrexed group and 74 patients in the FOLFOX group. The primary endpoints were OS and PFS. The secondary endpoints were ORR and adverse events. We used SPSS software, the Kaplan–Meier method, the t test, and the rank sum test to compare the differences between the two groups.

Results

The median OS was 10.82 months in the oxaliplatin + raltitrexed group and 8.67 months in the FOLFOX group. The median PFS time was greater in the oxaliplatin + raltitrexed group (10.0 months) than that in the FOLFOX group (7.1 months). The ORR was greater in the oxaliplatin + raltitrexed group than that in the FOLFOX group (18.3% vs. 13.5%; P = 0.445). The DCR in the oxaliplatin + raltitrexed group was higher than that in the FOLFOX group (70.0% vs. 64.8%; P = 0.529). However, in the subgroup analysis, the difference between them was more significant in the type II PVTT subgroup. The OS was 12.08 months in the oxaliplatin + raltitrexed group and 7.26 months in the FOLFOX group (P = 0.008). The PFS was 11.68 months in the oxaliplatin + raltitrexed group and 6.26 months in the FOLFOX group (P = 0.014). In the right branch of type II PVTT, the OS was 13.54 months in the oxaliplatin + raltitrexed group and 6.89 months in the FOLFOX group (P = 0.015), and the PFS was 13.35 months in the oxaliplatin + raltitrexed group and 6.27 months in the FOLFOX group (P = 0.030). The incidence of adverse reactions was similar between the two groups.

Conclusions

Compared with the FOLFOX regimen, the oxaliplatin + raltitrexed chemoembolization regimen had longer OS, PFS time and ORR and DCR and it was safe and tolerable.

Background

Primary liver cancer (PLC) is a common malignancy and the fourth leading cause of cancer-related death worldwide [1]. There are two types of hepatic vascular invasion: macroscopic and microscopic. Portal vein tumor thrombosis (PVTT) is the most common form of macrovascular invasion of the PLC [2]. Patients with PVTT usually lose the opportunity for surgery and have an aggressive disease course, decreased liver function reserve, limited treatment options, higher recurrence rates after treatment, and, therefore, worse overall survival [3,4,5]. Clinically, PVTT is related to tumor size, tumor number, tumor stage, Child–Pugh score, and serum alpha-fetoprotein (AFP) levels [6]. Some studies have shown that combining transarterial chemoembolization (TACE) therapy with hepatic arterial infusion chemotherapy (HAIC) might improve the survival rate of patients with PLC with PVTT [7].

TACE is a treatment in which embolic agents and chemotherapy drugs are mixed together and injected from the hepatic artery to the tumor site, serving to embolize the tumor-feeding arteries and induce ischemic necrosis in the tumor tissue and it is one of the most commonly recommended first-line treatments for PLC, especially combined with PVTT [8,9,10]. Many studies have shown that TACE combined with HAIC is superior to TACE alone in terms of overall survival (OS) and progression-free survival (PFS), and the treatment-associated toxicities are generally well tolerated [7, 11, 12]. Other studies have shown that in the unresectable and advanced PLC, compared with those in patients treated with two chemoembolization regimens [oxaliplatin + raltetrexed and oxaliplatin + fluorouracil + leucovorin calcium regimen (FOLFOX)], the disease control rates (DCRs) of patients treated with oxaliplatin and realtitrexed were greater than those in patients in the FOLFOX group, and the incidence of adverse reactions was similar [13, 14]. However, the clinical data on the use of raltitrexed in TACE for treating PLC are compared with those on specific chemotherapeutic drug regimens and related effectiveness comparisons [15]. To date, there are still arguments about the effectiveness of different drug regimens for HAIC combined with TACE in patients with PLC with PVTT.

Methods

Aim

Therefore, we designed this retrospective study to compare the effectiveness and safety of different drug regimens for patients with PLC with PVTT treated with HAIC combined with TACE.

Section of patients

Patients were recruited from the Second Affiliated Hospital of Chongqing Medical University. The inclusion criteria were as follows: (1) patients aged > 18 years with PLC who were unsuitable for resection or percutaneous ablation, (2) the Barcelona Clinic Liver Cancer (BCLC) stage is the B–C, or Chinese liver cancer (CNLC) stage is Ib, IIa and llb, (3) Eastern Cooperative Oncology Group (ECOG) performance status is less than or equal to 2, (4) preserved liver function (Child–Pugh) class A or B, (5) a life expectancy greater 12 weeks, (6) a leukocyte count of > 3.0 × 109/L, platelet count ≥ 80 × 109/L, hemoglobin (Hb) ≥ 80 g/L; creatinine (Cr) ≤ 2.0 × UNL (upper normal limits), bilirubin (BIL) ≤ 2.0 × UNL, alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 7.0 × UNL and (7) treatment with programmed cell death protein 1 (PD1) or programmed cell death-ligand 1 (PD-L1) before.

All patients were excluded if they had any other primary tumors, severe liver dysfunction, Child–Pugh class C disease, including severe jaundice, hepatic encephalopathy, refractory intraperitoneal effusion, or hepatorenal syndrome. Patients were also excluded if they had coagulation dysfunction that could not be corrected, if the main portal vein was completely embolized by cancer thrombolysis, if the portal vein collateral compensation was insufficient, if the portal vein could not flow back through the portal vein, if it was combined with severe infection and could not be effectively controlled, or if other serious illnesses or medical conditions occurred. In addition to TACE and HAIC, patients receiving other invasive therapies [radiofrequency, liver resection, high-intensity focused ultrasound (HIFU), etc.] were also excluded.

A total of 248 patients with PLC and PVTT were selected from the Department of Hepatobiliary Surgery, Gastroenterology and Hepatic Disease Center from January 2019 to October 2022. All patients underwent contrast-enhanced ultrasound (CEUS) imaging. It represents an important tool for the identification of PVTT, particularly for identifying differentiating neoplastic and nonneoplastic thrombosis through the analysis of the ultrasound enhancement characteristics of the thrombosis (malignant findings are characterized by intraluminal arterial hyperenhancement during the arterial phase and washout in the portal or late phase, while benign thrombosis lacks contrast enhancement in any phase) [16]. The 248 patients were divided into the oxaliplatin + raltitrexed group and FOLFOX groups. After excluding 26 patients with metastatic tumors from other sites and 88 patients who were lost to follow-up after one treatment session, there were 60 patients in the oxaliplatin + ratitetrexed regimen group and 74 patients in the FOLFOX regimen group were included (Fig. 1). The primary endpoints were OS and PFS. The secondary endpoints were ORR and adverse events.

Fig. 1
figure 1

Flow diagram showing patient selection. Abbreviations PLC, primary liver cancer; PVTT, portal vein tumor thrombosis; TACE, transarterial chemoembolization; HAIC, hepatic arterial infusion chemotherapy

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Treatment plan

Using the Seldinger technique, we punctured the 5Fr micropuncture into the right femoral artery of patients and placed the 5F vascular sheath. The tumor nourishing arteries were hyperselectively intubated with a microcatheter and a superslip wire. Then, we injected chemicals (3 mg of realtitrexed, 50 mg of loplatin, 20 mg of pyrorubicin mixed with 5–20 ml of iodized oil or loplatin combined with pyrorubicin mixed with iodized oil) into the tumor nourishing arteries. The actual dose was determined based on the size and number of target tumors and the patients’ liver function. Polyvinyl alcohol (PVA) particles were used after embolization of the iodooil emulsions, and digital subtraction angiography (DSA) was performed 5 min after embolization to confirm stagnant blood flow in the feeding artery. We placed an arterial catheter after TACE and performed perfusion chemotherapy in the general ward. We intravenously administered dexamethasone (5 mg i. v) and micropumped oxaliplatin (85 mg/m2) through the catheter sheath artery for 3 h and raltetrexed (3 mg/m2) for 5 h in the oxaliplatin + raltitrexed group. We intravenously administered dexamethasone (5 mg i. v) and micropumped oxaliplatin (85 mg/m2) through the catheter sheath artery for 3 h, calcium folinate (200 mg/m2) for 2 h and fluorouracil (2500 mg/m2) for 46 h in the FOLFOX group. All patients were followed up every 4–6 weeks after the last TACE and then every 1–3 months if there was no significant recurrence or metastasis. If new lesions or residual tumors were identified, TACE was repeated until untreatable progression occurred.

Statement of ethics

This retrospective study was conducted in accordance with the Declaration of Helsinki. This study was approved by the Chongqing Medical University, the Second Affiliated Hospital of Chongqing Medical University. All patients provided written informed consent form.

Statistics

The data were statistically analyzed using the SPSS 26.0 software. The measurement data were expressed as the mean ± standard deviation (x ± s), with groups compared utilizing the t test and χ2 test for count data, OS and PFS were analyzed via Kaplan–Meier curves, with statistically significant indicated by P < 0.05.

Results

Study subject

Between January 2019 and October 2022, 248 patients were received HAIC combined with TACE treatment. After excluding 26 patients with metastatic tumors from other sites and 88 patients who were lost to follow-up after one treatment session, there were 60 patients in the oxaliplatin + ratitetrexed regimen group and 74 patients in the FOLFOX regimen group (Fig. 1). The median tumor size was 9.4 cm (range 3.0–18.7 cm). The baseline characteristics of the two groups are summarized in Table 1; none of these characteristics differed significantly between the two groups. Most patients were diagnosed with hepatitis B virus (HBV) related PLC, and most of them were male (Table 1).

Table 1 Baseline characteristics of all recruited patients
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Safety and toxicity

Toxic and adverse reactions were evaluated according to the standards for toxicity and side reactions of World Health Organization (WHO) anticancer drugs [17]. There were no cases of procedure-related mortality or 30-day mortality. The complications are listed in Table 2. The most common complications were postembolization syndrome and liver dysfunction. Six of the 60 patients in the oxaliplatin + raltitrexed group and ten of the 74 patients in the FOLFOX group experienced grade 3–4 adverse events. Pain adverse effects occurred in 24 (40.0%) patients in the oxaliplatin + raltitrexed group and 42 (56.7%) patients in the FOLFOX group (P = 0.034). The other adverse reactions were similar between the two groups (Table 2).

Table 2 Number of complications in the two groups
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Tumor response

We evaluated the therapeutic efficacy of PLC according to the WHO modified Response Evaluation Criteria in Solid Tumors (mRECEIST) [18] divided into complete remission (CR) (no enhancement of the intratumoral artery), partial remission (PR) (the tumor was reduced by 30%), stable disease (SD), and progressive disease (PD) (tumor diameter increase of 20% or new tumors). CR + PR was the objective response rate (ORR) and CR + PR + SD was the disease control rate (DCR). Efficacy was evaluated by review after 2 cycles of chemotherapy. A physical examination was performed before the start of each cycle of chemotherapy and routine blood routine, liver and kidney function, AFP, electrocardiogram, computed tomography (CT) or magnetic resonance imaging (MRI), and color ultrasound examinations were performed. Follow-up visits were used to assessed the median survival time. Tumor response was assessed at 4–6 weeks. The results for the two groups are shown in Table 3. The ORR and DCR were higher in the oxaliplatin + raltitrexed group than that in the FOLFOX group (ORR: 18.3% vs. 13.5%; P = 0.445; DCR: 70.0% vs. 64.8%; P = 0.529).

Table 3 Tumor response in the two groups
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Survival analysis

At the end of the study period, 12 (20.0%) patients in the oxaliplatin + raltitrexed group and 6 (8.1%) patients in the FOLFOX group were still alive. The median follow-up time was 6 months, and the total follow-up time was 20 months. The median OS was 10.82 months in the oxaliplatin + raltitrexed group [95% confidence interval (CI) 8.80, 12.85] and 8.67 months in the FOLFOX group (95% CI 7.11, 10.22; P = 0.066) (Fig. 2a). The median PFS time was slightly longer in the oxaliplatin + raltitrexed group (10.02 months, 95% CI 7.69, 12.36) than in the FOLFOX group (7.07 months, 95% CI 5.28, 8.85; P = 0.102) (Fig. 2b). The ORR was greater in the oxaliplatin + raltitrexed group than that in the FOLFOX group (18.3% vs. 13.5%; P = 0.445). The DCR of the oxaliplatin + raltitrexed group was also greater thanthat of the FOLFOX group (70.0% vs. 64.8%; P = 0.529).

Fig. 2
figure 2

Survival analysis function of the two groups. The median follow-up time was 6 months, and the total follow-up time was 20 months. A Kaplan–Meier curves of OS in patients with unresectable primary liver cancer who underwent TACE in the two groups. B Kaplan–Meier curves of PFS in patients with unresectable primary liver cancer who underwent TACE in the two groups

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Univariate and multivariate logistic regression analyses

We used univariate and multivariate logistic regression analyses to assess risk factors for each variable (Table 4). We found that age, the type of PVTT, tumor size and extrahepatic metastasis were independent risk factors affecting the prognosis of patients with PLC.

Table 4 Univariable and multivariable logistic regression analysis
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Table 5 Subgroup analysis by age
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Subgroup analysis

Subgroup analysis by age

Previous studies have indicated a better protective effect of ralterexed on myocardial function [19], so our study divided patients into four subgroups by age (< 36 years, 36–50 years, 51–65 years and > 65 years). In the 1st subgroup, the OS was 4.00 months in the oxaliplatin + raltitrexed group (95% CI 2.04, 5.96) and 4.50 months in the FOLFOX group (95% CI 3.90, 5.10; P = 0.695); the PFS was 1.50 months in the oxaliplatin + raltitrexed group (95% CI 0.00, 4.44) and 3.75 months in the FOLFOX group (95% CI 1.78, 5.72; P = 0.107). In the 2nd subgroup, the OS was 13.80 months in the oxaliplatin + raltitrexed group (95% CI 10.01, 17.58) and 8.44 months in the FOLFOX group (95% CI 6.65, 10.43; P = 0.080); the PFS was 13.23 months in the oxaliplatin + raltitrexed group (95% CI 8.98, 17.48) and 6.47 months in the FOLFOX group (95% CI 4.52, 8.41; P = 0.072). In the 3rd subgroup, the OS was 12.95 months in the oxaliplatin + raltitrexed group (95% CI 10.06, 15.83) and 9.17 months in the FOLFOX group (95% CI 6.12, 12.21; P = 0.128); the PFS was 12.32 months in the oxaliplatin + raltitrexed group (95% CI 8.93, 15.72) and 7.71 months in the FOLFOX group (95% CI 4.35, 11.07; P = 0.095). In the 4th subgroup, the OS was 10.03 months in the oxaliplatin + raltitrexed group (95% CI 6.42, 13.64) and 8.27 months in the FOLFOX group (95% CI 5.36, 11.19; P = 0.951); the PFS was 9.68 months in the oxaliplatin + raltitrexed group (95% CI 5.66, 13.70) and 8.28 months in the FOLFOX group (95% CI 5.36, 11.19; P = 0.728) (Table 5). Overall, the OS and PFS of the oxaliplatin + raltitrexed group were longer than those of the FOLFOX group, but there were no significant differences between the two groups, and the examination indices of myocardial enzyme levels, cardiac color ultrasound results and other indicators did not appear significantly differ among the age groups. Therefore, the cardioprotective effect of raltetrexed needs to be further verified.

Subgroup analysis by PVTT classification

The more conventional and better-known classification of PVTT was proposed by the Liver Cancer Study Group of Japan (LCSGJ) [20, 21]. Chen et al. proposed Cheng's classification type: Type I0: microscopic tumor thrombosis formation; Type I: tumor thrombosis involving secondary level and above portal vein branch (type Ia: tumor thrombosis involving portal vein grade i and j level and above branch; type Ib: tumor thrombosis involving portal vein secondary branch); Type II: tumor thrombosis involving primary portal branch [type IIa: primary portal branch (such as left or right portal stem); type IIb: secondary primary portal branch (involving left and right portal stem)]; Type III: tumor thrombolysis involving the main portal vein (type IIIa: tumor thrombolysis involving the main portal vein, portal vein trunk confluence below no more than 2 cm; type IIIb: tumor thrombolysis involving the main portal vein, portal vein trunk trunk confluence below more than 2 cm); Type IV: tumor thrombolysis involving superior mesenteric vein or inferior vena cava (type IVa: tumor thrombolysis involving superior mesenteric vein; type IVb: cancer thrombolysis involving inferior vena cava) [22].

We subjected all patients to PVTT subgroup analysis by Cheng's classification type. In the type II PVTT subgroup, the OS was 12.08 months in the oxaliplatin + raltitrexed group (95% CI 9.18, 14.98) and 7.26 months in the FOLFOX group (95% CI 5.79, 8.72; P = 0.008) (Fig. 3a); the PFS was 11.68 months in the oxaliplatin + raltitrexed group (95% CI 8.46, 14.90) and 6.26 months in the FOLFOX group (95% CI 4.80, 7.73; P = 0.014) (Fig. 3b). The ORR and DCR were greater in the oxaliplatin + raltitrexed group than in the FOLFOX group (ORR: 24.1% vs. 15.2%; P = 0.357; DCR: 75.8% vs. 60.9%; P = 0.221) (Table 6).

Fig. 3
figure 3

Survival analysis function of patients in the type II PVTT subgroup. A Kaplan–Meier curves of OS in patients with type II PVTT who underwent TACE in the two groups. B Kaplan–Meier curves of PFS in patients with type II PVTT who underwent TACE in the two groups

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Table 6 Subgroup analysis by PVTT classification
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Subgroup analysis by tumor number

In the baseline comparison, there were significant differences between the number of tumors in the two groups, so we performed Cox multivariate regression analysis. All patients were divided into two subgroups: a single-tumor subgroup and a multiple-tumor subgroup. In the single-tumor subgroup, the OS was 11.25 months in the oxaliplatin + raltitrexed group (95% CI 8.58, 13.91) and 7.81 months in the FOLFOX group (95% CI 5.27, 10.35; P = 0.044) (Fig. 4a); the PFS was 10.66 months in the oxaliplatin + raltitrexed group (95% CI 7.53, 13.80) and 5.95 months in the FOLFOX group (95% CI 3.34, 8.56; P = 0.041) (Fig. 4b). In the multiple-tumor subgroup, the OS was 12.96 months in the oxaliplatin + raltitrexed group (95% CI 9.83, 16.08) and 9.10 months in the FOLFOX group (95% CI 7.10, 11.09; P = 0.046) (Fig. 4c); the PFS was 12.54 months in the oxaliplatin + raltitrexed group (95% CI 9.10, 15.87) and 8.24 months in the FOLFOX group (95% CI 5.90, 10.57; P = 0.047) (Fig. 4d) (Table 7).

Fig. 4
figure 4

Survival analysis function of subgroups by tumor numbers. A Kaplan–Meier curves of OS in patients with a single tumor who underwent TACE in the two groups. B Kaplan–Meier curves of PFS in patients with a single tumor who underwent TACE in the two groups. C Kaplan–Meier curves of OS in patients with a multiple tumor who underwent TACE in the two groups. D Kaplan–Meier curves of OS in patients with a multiple tumor who underwent TACE in the two groups

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Table 7 Subgroup analysis by tumor number
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Subgroup analysis by the position of type II PVTT

In the type II PVTT subgroup, the oxaliplatin + raltitrexed regimen showed better efficacy than FOLFOX, and we again divided all patients into left, right and bilateral type II PVTT groups according to the location of the PVTT.In the right group, the OS was 13.54 months in the oxaliplatin + raltitrexed group (95% CI 9.52, 17.56) and 6.89 months in the FOLFOX group (95% CI 5.17, 8.60; P = 0.015) (Fig. 5a); the PFS was 13.35 months in the oxaliplatin + raltitrexed group (95% CI 9.08, 17.63) and 6.27 months in the FOLFOX group (95% CI 4.48, 8.07; P = 0.030) (Fig. 5b). These two drug treatment modalities were significant different (Table 8).

Fig. 5
figure 5

Survival analysis of subgroups stratified by the location of type II PVTT. A Kaplan–Meier curves of OS in patients with type II PVTT in the right branch who underwent TACE in the two groups. B Kaplan–Meier curves of PFSS in patients with type II PVTT in the right branch who underwent TACE in the two groups

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Table 8 Subgroup analysis by the position of type II PVTT
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Discussion

In our study, after a 20-month follow-up time, the OS and PFS in the oxaliplatin + raltitrexed group were slightly longer than those in the FOLFOX group. However, neither of the two groups exhibited statistically significant differences. The ORR was 18.3% in the oxaliplatin + raltitrexed group and 13.5% in the FOLFOX group (P = 0.445). The DCR was 70.0% in the oxaliplatin + raltitrexed group and 64.8% in the FOLFOX group (P = 0.529). Pain adverse effects occurred in 24 (40.0%) patients in the oxaliplatin + raltitrexed group and 42 (56.7%) patients in the FOLFOX group (P = 0.034). However, the other adverse reactions were almost the same between the two groups.

The FOLFOX treatment modality was previously used to treat gastrointestinal tumors (including primary and metastatic liver cancer, biliary tract system tumors, pancreatic tumors, and colorectal tumors.) [23, 24]. According to previous reports, FOLFOX-HAIC significantly improved OS compared with TACE in patients with unresectable large hepatocellular carcinoma [25, 26]. However, fluorouracil should be administered intra-arterially for approximately 44 h, and a higher incidence of pain, catheter thrombosis and catheter-associated infection has been reported [27]. The oxaliplatin + raltitrexed regimen had been gradually used for HAIC treatment after TACE due to its advantages of less cardiotoxicity and shorter perfusion time in recent years [28]. The OS and PFS were longer than those of the FOLFOX group in previous studies not only for HCC but also for colorectal cancer (CRC) liver metastasis (CRCLM) [29, 30]. There are few studies on perfusion chemotherapy for liver cancer combined with PVTT. Cui et al. proposed that the PFS of patients treated with raltitrexed was longer in unresectable hepatocellular carcinoma complicated with PVTT, but no significant statistical difference was observed between the two groups [13]. However, this finding did not further explain the reason for the longer PFS of the oxaliplatin + raltitrexed regimen. OS and PFS were also longer in the oxaliplatin + raltitrexed group than those in the FOLFOX group, but there was no significant difference between the two groups in our study. Unlike previous studies, our drug dose was calculated by body weight in order to obtain the best results for each patient and decrease toxic side effects. In addition, we also conducted subgroup analysis through age, type of PVTT, and the number of tumors and still concluded that oxaliplatin + raltitrexed was superior to FOLFOX, and there were significant differences in the subgroups of type II PVTT and the number of tumors. Moreover, the sample size was somewhat larger than that in previous studies. It can be seen that oxaliplatin + raltitrexed regimen has beneficial advantages and safety for PLC in combination with PVTT.

According to our subgroup analysis by PVTT classification, oxaliplatin + raltitrexed showed better efficacy than FOLFOX in the type II PVTT subgroup. The OS was 12.08 months in the oxaliplatin + raltitrexed group (95% CI 9.18, 14.98) and 7.26 months in the FOLFOX group (95% CI 5.79, 8.72; P = 0.008); the PFS was 11.68 months in the oxaliplatin + raltitrexed group (95% CI 8.46, 14.90) and 6.26 months in the FOLFOX group (95% CI 4.80, 7.73; P = 0.014). Moreover, oxaliplatin + raltitrexed was more effective for type II PVTT located in the right branch in our study. Theoretically speaking, there may be two reasons for this. First, the efficacy of chemotherapy drugs may be related to the location of the PVTT. When the PVTT is located in the right branch of the portal vein and the tumor is located on the same side, the drug can be better transported to the target vessel through the right hepatic artery, while when the PVTT is located in the left or bilateral or even the main portal vein (MPV), the perfusion effect of the drug through the arteriae hepatica propria (AHP) may be slightly attenuated. On the other hand, this is due to the pharmacokinetic difference between ratitetrexed and fluorouracil. Raltitrexed can directly or specifically cause DNA chain breakage and apoptosis by inhibiting thymidylate synthase (TS), a key enzyme in the synthesis of deoxythymidine 5-triphosphate (TTP). However, fluorouracil was first converted to a 5-fluorine-deoxyuracil nucleotide at first in vivo after which TS was inhibited to inhibit DNA. Nevertheless, further prospective studies are needed to determine the possible advantages of the right-branch type II PVTT will in the oxaliplatin + raltitrexed group.

Previous studies reported that fluorouracil has some cardiotoxic effects, such us fluoropyrimidine-induced cardiotoxicity (FIC), including coronary artery vasospasm, endothelial or cardiomyocyte damage, toxic metabolites, and dihydropyrimidine dehydrogenase deficiency and so on [31]. Compared with fluorouracil, raltitrexed is less cardiotoxic [32]. According to our subgroup analysis by age, the OS and PFS of the oxaliplatin + raltitrexed group were longer than those of the FOLFOX group in every subgroup, but neither the OS nor PFS of the two groups in the subgroups were significantly different. All patients in our study underwent accessory examinations including myocardial enzyme spectrum, type B natriuretic peptide precursor (BNP), cardiac color ultrasound and electrocardiogram before and after TACE, and none of the findings showed significant cardiac damage. Therefore, the cardioprotective effect of raltetrexed needs to be further verified. According to the subgroup analysis by tumor number, the OS and PFS in the oxaliplatin + raltitrexed group were grater than those in the FOLFOX group and there were significant differences regardless of the number of tumors. The study of Rong et al. noted that as the number of tumors increased, the OS decreased [33], while the OS of our study was slightly longer in multiple tumor groups than in a single tumor group. Therefore, further studies on the impact of tumor number on patient prognosis are needed, but these studies did not reveal an obvious prognostic benefit of raltitrexed.

Our study also evaluated the safety and tolerability of these two treatments. We found that the incidence of major complications was not significantly different between the two groups. Only a greater proportion of pain response in the FOLFOX group may be associated with a longer drug perfusion time, but all complications were reversible and adequately controlled by medical treatment. These results indicate that the combination of raltitrexed and oxaliplatin in TACE in patients with unresectable PLC is safe and tolerable.

Our study also had some limitations. First, because it was retrospective, some selection biases were unavoidable. Second, this study was conducted at a single center with a relatively small number of patients, a large number of whom carried hepatitis B (82.8%), and the proportion of males was high (89.5%). Third, the included subjects in this study had no type IV PVTT. Currently, the treatment of type IV PVTT for TACE + HAIC is still being explored currently, and further studies on this topic may be needed. Finally, the sample size of the oxaliplatin + raltitrexed group was small. If we increase the sample size, reduce the loss to follow-up and extend the follow-up time, we can obtain better results. Moreover, the number of TACE procedures differed among individuals, which may also have affected the results of our study. Larger prospective trials are needed to confirm this conclusion.

Conclusion

Despite no significant difference between the oxaliplatin + raltitrexed group and the FOLFOX group, the oxaliplatin + raltitrexed chemoembolization regimen had a longer OS, PFS, ORR and DCR than the FOLFOX regimen. This regimen was safe and tolerable, especially for PLCs with type II PVTT. Our findings suggest that the combination therapy of TACE and HAIC bvia oxaliplatin plus raltitrexed regimen confers more benefits to patients with unresectable PLC than other regimens.

Availability of data and materials

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

PVTT:

Portal vein tumor thrombosis

PLC:

Primary liver cancer

TACE:

Transarterial chemoembolization

HAIC:

Hepatic arterial infusion chemotherapy

OS:

Overall survival

PFS:

Progression-free survival

FOLFOX:

Oxaliplatin + fluorouracil + leucovorin calcium

ORR:

Objective remission rate

DCR:

Disease control rate

cTACE-HAIC:

Transarterial chemoembolization plus hepatic arterial infusion chemotherapy

CI:

Confidence interval

AFP:

Alpha-fetoprotein

BCLC:

Barcelona clinic liver cancer

ECOG:

Eastern Cooperative Oncology Group

Hb:

Hemoglobin

Cr:

Creatinine

UNL:

Upper normal limits

BIL:

Bilirubin

ALT:

Aminotransferase

AST:

Aspartate

PD1:

Programmed cell death protein 1

PD-L1:

Programmed cell death-ligand 1

HIFU:

High intensity focused ultrasound

PVA particles:

Polyvinyl alcohol particles

DSA:

Digital subtraction angiography

HBsAg:

Hepatitis B surface antigen

CA125:

Carbohydrate antigen 125

CA199:

Carbohydrate antigen 199

CA242:

Carbohydrate antigen 242

CA50:

Carbohydrate antigen 50

CA724:

Carbohydrate antigen 724

INR:

International normalized ratio

WBC:

White blood cell

PLT:

Platelet

ALP:

Alkaline phosphatase

GGT:

γ-Glutamyl transferase

WHO:

World Health Organization

mRECIST:

Modified response evaluation criteria in solid tumors

CR:

Complete remission

PR:

Partial remission

SD:

Stable disease

PD:

Progressive disease

ORR:

Objective response rate

DCR:

Disease control rate

CT:

Computed tomography

MRI:

Magnetic resonance imaging

LCSGJ:

Liver Cancer Study Group of Japan

CI:

Confidence interval

CRC:

Colorectal cancer

CRCLM:

Colorectal cancer liver metastasis

MPV:

Main portal vein

AHP:

Arteriae Hepatica Propria

TS:

Thymidylate synthase

TTP:

Deoxythymidine 5-triphosphate

FIC:

Fluoropyrimidine-induced cardiotoxicity

BNP:

B naturetic peptide precursor

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Acknowledgements

We are grateful to the Department of Hepatobiliary Surgery at the Second Affiliated Hospital of Chongqing Medical University. This study was supported by the National Natural Science Foundation of China (No. 82173117), Natural Science Foundation of Chongqing (No. CSTB2023NSCQ-MSX0214) and Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University (NO. kryc-yq-2209).

Funding

This study was supported by the National Natural Science Foundation of China (No. 82173117), Natural Science Foundation of Chongqing (No. CSTB2023NSCQ-MSX0214) and Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University (NO. kryc-yq-2209).

Author information

Author notes

  1. Xinxin Tu and Wenfeng Zhang have contributed equally to this work.

Authors and Affiliations

  1. Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, No. 74, Linjiang Road, Yuzhong District, Chongqing Municipality, 400010, People’s Republic of China

    Xinxin Tu, Wenfeng Zhang, Qi He & Yue Li

  2. Department of Hepatobiliary Pancreatic Tumor Center, Chongqing University Cancer Hospital, Chongqing, No. 181, Hanyu Road, Shapingba District, Chongqing Municipality, 400010, People’s Republic of China

    Sipeng Li

Authors
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Contributions

Study conception and experimental design, collection and analysis of data, and manuscript writing, Xinxin Tu; collection and analysis of data, Xinxin Tu, Wenfeng Zhang, Sipeng Li, Qi He; study conception, design, and supervision, Wenfeng Zhang, Yue Li; supervision, manuscript writing, and final approval of the manuscript; Yue Li. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yue Li.

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Ethics approval and consent to participate

This retrospective study was conducted in accordance with the Declaration of Helsinki. This study was approved by Chongqing Medical University, the Second Affiliated Hospital of Chongqing Medical University. All patients provided written informed consent.

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Not applicable.

Competing interests

The authors declare no competing interests.

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Tu, X., Zhang, W., Li, S. et al. Efficacy of hepatic arterial infusion chemotherapy in patients with primary liver cancer with portal vein tumor thrombosis: a comparative analysis of different perfusion chemotherapeutic regimens. Eur J Med Res 29, 465 (2024). https://doi.org/10.1186/s40001-024-02053-6

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Keywords

European Journal of Medical Research

ISSN: 2047-783X

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