Efficacy and safety of transarterial chemoembolization with chemotherapy, PD-1/PD-L1 inhibitors, and tyrosine kinase inhibitors in unresectable intrahepatic cholangiocarcinoma

Abstract

BACKGROUND

Chemotherapy, targeted therapy, and immunotherapy have all been shown to achieve some efficacy in treating intrahepatic cholangiocarcinoma (ICC). However, these systemic treatments have not provided optimal results for some patients. Therefore, the combination of transarterial chemoembolization (TACE) and hepatic artery infusion chemotherapy or other local interventional therapy methods is being considered for the treatment of liver tumors.

AIM

To evaluate the efficacy and safety of combining chemotherapy, targeted therapy, and immunotherapy, with or without TACE, in patients with ICC.

METHODS

We recruited 83 patients with unresectable ICC from July 2021 to December 2023 at the Affiliated Hospital of Xuzhou Medical University. Forty-one patients received TACE combined with chemotherapy, tyrosine kinase inhibitors, and programmed death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors (experimental group), whereas 42 patients were treated with chemotherapy, tyrosine kinase inhibitors, and PD-1/PD-L1 inhibitors (control group). Short-term efficacy was assessed using the modified response evaluation criterion, and the objective response rate, disease control rate, progression-free survival, and incidence of adverse events were compared between groups.

RESULTS

The objective response rate in the experimental group was greater than that in the control group (39.0% vs 19.0%, P < 0.05). The disease control rate in the experimental group was significantly greater than that in the control group (75.6% vs 52.4%, P < 0.05). The median progression-free survival times were 14.3 months in the experimental group and 12.7 months in the control group (P < 0.05). All 41 patients in the experimental group developed postembolization syndrome. Among the symptoms, fever and pain were significantly more common in the experimental group than in the control group (85.4% vs 11.9%, P < 0.001 and 58.5% vs 9.5%, P < 0.001). No grade 4 or 5 treatment-related adverse events were observed in either group.

CONCLUSION

In patients with unresectable ICC, TACE combined with chemotherapy, tyrosine kinase inhibitors, and PD-1/PD-L1 inhibitors has good efficacy and high safety, indicating potential benefits for these patients.

Key Words: Intrahepatic cholangiocarcinoma; Transarterial chemoembolization; Programmed death 1/programmed cell death ligand 1 inhibitors; Tyrosine kinase inhibitors; Efficacy

Core Tip: This study retrospectively evaluated the efficacy and safety of transarterial chemoembolization combined with chemotherapy, tyrosine kinase inhibitors, and programmed death 1/programmed cell death ligand 1 inhibitors in patients with intrahepatic cholangiocarcinoma. In conclusion, the combination of transarterial chemoembolization with chemotherapy, tyrosine kinase inhibitors, and programmed death 1/programmed cell death ligand 1 inhibitors demonstrates good efficacy and a favorable safety profile, offering potential benefits for patients with intrahepatic cholangiocarcinoma.

INTRODUCTION

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer after hepatocellular carcinoma. It is characterized by an insidious onset, as early symptoms are often subtle or absent[1,2]. As a result, many patients are diagnosed at an advanced stage, missing the optimal surgical window. Thus, they must be treated with chemotherapy, immunotherapy, targeted therapy, or local interventional treatments to manage the disease[3-5]. Chemotherapy can effectively control disease progression[6], and given its well-established efficacy, it is widely used in clinical practice.

Transarterial chemoembolization (TACE) is a localized treatment for advanced ICC[5,7-9], that induces tumor ischemia and necrosis through embolization of the tumor-feeding artery while selectively delivering chemotherapeutic agents to the tumor site. For patients whose ICC has a high tumor burden and vascular invasion, complete embolization with TACE can be challenging and often requires repeated treatments. However, repeated TACE may stimulate increased expression of hypoxia-inducible factors in residual tumor tissue, which, in turn, significantly increases the expression of vascular endothelial growth factor, promoting tumor angiogenesis[10]. This process is also associated with increased expression of antigen-presenting molecules, along with programmed death receptor (PD-1) and programmed cell death ligand 1 (PD-L1)[11].

Rapid advancements in molecular biology and the increasing popularity of molecular targeting and immunotherapy have led to the relatively routine implementation of tyrosine kinase inhibitors (TKIs) for increasing treatment efficacy. For example, the TKI lenvatinib has been approved as a first-line treatment for advanced biliary malignant tumors[12-14]. However, few studies have evaluated the effectiveness of combining TACE with different systemic therapies in ICC. This study retrospectively assessed the efficacy and safety of TACE combined with chemotherapy, TKIs, and PD-1/PD-L1 inhibitors in patients with unresectable ICC.

MATERIALS AND METHODS

Study population

We recruited 83 patients with unresectable ICC treated at the Affiliated Hospital of Xuzhou Medical University between July 2021 and December 2023. Among them, 41 patients received TACE combined with chemotherapy, TKIs, and PD-1/PD-L1 inhibitors (experimental group), whereas 42 patients were treated with chemotherapy, TKIs, and PD-1/PD-L1 inhibitors (control group). Baseline data from patients with advanced-stage ICC in both groups were collected for comparative analysis. Follow-up assessments were conducted to evaluate the short-term efficacy, progression-free survival (PFS), and safety profiles of the treatments.

The inclusion criteria for this study were as follows: (1) A clinical diagnosis and/or histopathological confirmation of ICC; (2) Age between 18 and 75 years; (3) Child-Pugh class A or B; (4) Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1; (5) Barcelona Clinic Liver Cancer stage B or C; and (6) Ability to provide informed consent for treatment. The exclusion criteria were as follows: (1) The presence of other malignant tumors; (2) Unmeasurable target lesions; (3) A history of prior surgery, radiotherapy, or organ transplantation; (4) Severe renal insufficiency, coagulation dysfunction, heart failure, myocardial infarction, or stroke; and (5) Serious complications such as hepatic encephalopathy or hepatorenal syndrome.

TACE

After the patient was placed under local anesthesia, the modified Seldinger technique was employed to puncture the right femoral artery. Under digital subtraction angiography guidance, a catheter was advanced into the celiac trunk and superior mesenteric arteries for angiography to identify the tumor’s arterial blood supply. After angiography, a 3F microcatheter was super selectively inserted into the tumor’s feeding artery. In accordance with the size of the tumor, 2-4 mg of raltitrexed, 20-40 mg of epirubicin, and 5-10 mL of ethiodized poppy seed oil were slowly injected. Gelatin sponge particles were used to embolize the tumor vessels, typically by occluding the hepatic artery on the tumor’s feeding side. Four to eight weeks after TACE, follow-up assessments, including enhanced abdominal computed tomography or magnetic resonance imaging, tumor marker measurements, liver and kidney function tests, and complete blood counts, were performed to determine whether additional TACE treatment was needed. If untreatable local progression was observed, TACE was discontinued.

Chemotherapy

Systemic chemotherapy was administered within one month following TACE treatment. The patient received a combination of gemcitabine and oxaliplatin. Gemcitabine was intravenously infused on day 1 and day 8 at a dose of 1000 mg/m², whereas oxaliplatin was administered intravenously on day 1 at a dose of 100 mg/m². Chemotherapy was repeated every 21 days.

TKIs plus PD-1/PD-L1 inhibitors

TKIs: TKIs plus PD-1/PD-L1 inhibitors were administered within one month after TACE. Oral lenvatinib was administered at 8 mg (2 capsules of 4 mg each) once daily for patients with a body weight < 60 kg or at 12 mg (3 capsules of 4 mg each) once daily for patients with a body weight ≥ 60 kg; alternatively, sorafenib (300 mg) was given once daily, or anlotinib (12 mg) was administered once daily from days 1-14 over a 3-week cycle.

PD-1/PD-L1 inhibitors: Patients were intravenously infused with camrelizumab every 3 weeks at a dose of 200 mg per infusion; with pembrolizumab every 3 weeks at a dose of 200 mg per infusion; or with toripalimab every 3 weeks at a dose of 240 mg per infusion. TKIs were suspended 3 days before and 3 days after subsequent TACE procedures. If the patient experienced disease progression or intolerable adverse events, the treating physician determined whether to discontinue or adjust the dosage.

Data collection

Demographic characteristics (age and sex), ECOG PS score, history of hepatitis and liver cirrhosis, Child-Pugh classification, clinical features (number of tumors, maximum tumor size on imaging, major vascular invasion, extrahepatic metastasis), and tumor marker (alpha-fetoprotein and carbohydrate antigen 19-9) levels were obtained from the hospital’s electronic medical records system.

Patients were followed up until December 2024, during which data were collected from outpatient visits, telephone surveys, or in person (for hospitalized patients). Tumor response was evaluated based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) as follows[15-17]: (1) Complete response: Complete disappearance of all target lesions with arterial phase enhancement and a reduction of the short axes of all target lymph nodes to < 10 mm; (2) Partial response: A reduction of ≥ 30% in the sum of the maximum diameters of the target lesions (arterial phase enhancement) with respect to baseline; (3) Progressive disease: A ≥ 20% increase in the sum of the maximum diameters of the target lesions (arterial phase enhancement) with respect to the minimum value during the study, an absolute increase of at least 5 mm, or the appearance of new lesions; and (4) Stable disease: A decrease in the sum of the maximum diameters of the target lesions that does not meet the criteria for partial response or an increase that does not meet the criteria for progressive disease. Follow-up assessments were conducted after treatment to evaluate the short-term efficacy of the two groups on the basis of the above criteria.

The objective response rate (ORR) was calculated as the total effective rate (%) = (complete response + partial response)/total number of patients × 100%. The disease control rate (DCR) was calculated as the percentage of patients who achieved disease control (%), that is, (complete response + partial response + stable disease)/total number of patients × 100%. PFS was defined as the time from treatment initiation to disease progression or death from any cause. Adverse events during the treatment process were assessed using the Common Terminology Criteria for Adverse Events version 5.0 to analyze the safety of the two treatment methods[18,19].

Statistical analysis

Statistical analysis of the data was performed using SPSS software. Categorical data are presented as frequencies (percentages), and comparisons of these data, as well as of adverse events, between the groups were conducted using the χ² test or Fisher’s exact test. Median survival was determined with the Kaplan-Meier method, and the corresponding survival curves were plotted. The log-rank test was used to compare the survival time between treatment groups. A P value < 0.05 was considered to indicate statistical significance.

RESULTS

Baseline data

Among the 83 patients, 41 were in the experimental group, and 42 were in the control group. The baseline data, including age, sex, ECOG PS score, history of hepatitis, previous cirrhosis, Child-Pugh classification, number of tumors, maximum tumor size on imaging, macrovascular invasion, extrahepatic metastasis, and tumor marker levels, did not significantly differ between the groups, as shown in Table 1.

Table 1 Comparison of baseline characteristics between the two groups, n (%).

Baseline data	Experimental group (n = 41)	Control group (n = 42)	P value
Sex
Male	20 (48.8)	27 (64.3)	0.154
Female	21 (51.2)	15 (35.7)
Age
> 60	17 (41.5)	23 (54.8)	0.225
≤ 60	24 (58.5)	19 (45.2)
ECOG PS score
0	24 (58.5)	24 (57.1)	0.898
1	17 (41.5)	18 (42.9)
HBV infection
No	14 (34.1)	12 (28.6)	0.584
Yes	27 (65.9)	30 (71.4)
Cirrhosis
No	14 (34.1)	9 (21.4)	0.196
Yes	27 (65.9)	33 (78.6)
Child-Pugh
A	17 (41.5)	18 (42.9)	0.898
B	24 (58.5)	24 (57.1)
AFP (ng/mL)
< 400	34 (82.9)	30 (71.4)	0.213
≥ 400	7 (17.1)	12 (28.6)
CA19-9 (U/mL)
> 1000	7 (17.1)	10 (23.8)	0.447
≤ 1000	34 (82.9)	32 (76.2)
Max tumor size (mm)
> 50	20 (48.8)	24 (57.1)	0.445
≤ 50	21 (51.2)	18 (42.9)
Tumor number
One	7 (17.1)	6 (14.3)	0.727
More than one	34 (82.9)	36 (85.7)
Large vessel invasion
No	25 (61.0)	32 (76.2)	0.135
Yes	16 (39.0)	10 (23.8)
Extrahepatic metastasis
No	25 (61.0)	21 (50.0)	0.315
Yes	16 (39.0)	21 (50.0)
TKIs
Lenvatinib	26 (63.4)	24 (57.1)	0.121
Anlotinib	11 (26.8)	7 (16.7)
Sofantinib	4 (9.8)	11 (26.2)
PD1/PD-L1 inhibitors
Camrelizumab	19 (46.3)	21 (50.0)	0.815
Toripalimab	14 (34.2)	15 (35.7)
Pembrolizumab	8 (19.5)	6 (14.3)

ECOG PS: Eastern Cooperative Oncology Group performance status; HBV: Hepatitis B virus; AFP: Alpha fetoprotein; CA19-9: Carbohydrate antigen 19-9; TKIs: Tyrosine kinase inhibitors; PD-1: Programmed death 1; PD-L1: Programmed cell death ligand 1.

Treatment efficacy evaluation

According to the mRECIST criteria, the ORR in the experimental group was greater than that in the control group (39.0% vs 19.0%, P < 0.05). The DCR significantly differed between the experimental group (75.6%) and the control group (52.4%) (P < 0.05), as shown in Table 2.

Table 2 Comparison of short-term efficacy between the two groups, n (%).

Efficacy evaluation	Experimental group (n = 41)	Control group (n = 42)	P value
Complete response	2 (4.9)	0
Partial response	14 (34.1)	8 (19.0)
Stable disease	15 (36.6)	14 (33.3)
Progressive disease	10 (24.4)	20 (47.6)
ORR	16 (39.0)	8 (19.0)	0.045
DCR	31 (75.6)	22 (52.4)	0.028

ORR: Objective response rate; DCR: Disease control rate.

Survival analysis

At the end of the follow-up period, a total of 98 TACE procedures were performed on the 41 patients in the experimental group. The median PFS (mPFS) in the experimental group was 14.3 months [95% confidence interval (CI): 13.1-16.0], which significantly differed from the 12.7 months (95%CI: 10.6-15.6) in the control group (P = 0.016), as shown in Figure 1.

Figure 1 Comparison of progression-free survival between the experimental and control groups. The experimental group received transarterial chemoembolization combined with chemotherapy, tyrosine kinase inhibitors, and programmed death 1/programmed cell death ligand 1 inhibitors, while the control group received chemotherapy, tyrosine kinase inhibitors, and programmed death 1/programmed cell death ligand 1 inhibitors without transarterial chemoembolization. The number of patients at risk at different time points is shown below the horizontal axis.

Treatment safety

No treatment-related deaths occurred in either group. A comparison of adverse event rates between the two groups is shown in Table 3. All 41 patients in the experimental group developed postembolization syndrome after TACE, classified as grade 1 or 2. Fever and pain were significantly more common in the experimental group than in the control group (85.4% vs 11.9%, P < 0.001 and 58.5% vs 9.5%, P < 0.001). No grade 4 or 5 treatment-related adverse events were observed in either group.

Table 3 Comparison of adverse event rates between the two groups, n (%).

Treatment-related adverse events	Experimental group (n = 41)	Control group (n = 42)	P value
Nausea and vomiting	20 (48.8)	14 (33.3)	0.152
Fever	35 (85.4)	5 (11.9)	< 0.001a
Pain	24 (58.5)	4 (9.5)	< 0.001a
Weakness	13 (31.7)	18 (42.9)	0.294
Diarrhea	9 (22.0)	8 (19.0)	0.743
Constipation	17 (41.5)	19 (45.2)	0.729
Trachyphonia	4 (9.8)	2 (4.8)	0.326
Gingival hemorrhage	7 (17.1)	3 (7.1)	0.146
Hypertension	5 (12.2)	12 (28.6)	0.065
Hand-foot syndrome	15 (36.6)	17 (40.5)	0.716
Hypothyroidism	8 (19.5)	7 (16.7)	0.736
Rash	6 (14.6)	9 (21.4)	0.421
Proteinuria	7 (17.1)	8 (19.0)	0.815

^aP < 0.001.

The experimental group received transarterial chemoembolization combined with chemotherapy, tyrosine kinase inhibitors, and programmed death 1/programmed cell death ligand 1 inhibitors. The control group received chemotherapy, tyrosine kinase inhibitors, and programmed death 1/programmed cell death ligand 1 inhibitors without transarterial chemoembolization. Adverse events were graded according to the Common Terminology Criteria for Adverse Events version 5.0.

DISCUSSION

Currently, systemic chemotherapy remains the first-line treatment for unresectable ICC. However, the survival benefit of chemotherapy alone is limited. Therefore, combining systemic chemotherapy with other therapeutic approaches is essential for delaying the progression of ICC. Targeted therapy and immunotherapy are currently popular research topics, as they have demonstrated promising potential in the treatment of unresectable, advanced-stage ICC. In a study conducted by Kelley et al[20], the median overall survival (mOS) in the pembrolizumab group was 12.7 months, which was significantly greater than the 10.9 months observed in the chemotherapy group (P < 0.05). In the study by Zhu et al[21], the mPFS (12.13 months vs 6.77 months, P < 0.01) and mOS (25.0 months vs 11.6 months, P = 0.029) were significantly longer in the first-line treatment group receiving lenvatinib plus anti-PD-1 antibody and systemic chemotherapy.

Although chemotherapy, targeted therapy, and immunotherapy have been shown to achieve some efficacy in ICC, systemic treatments have not provided optimal results for some patients. Therefore, the combination of TACE with hepatic artery infusion chemotherapy or other local interventional therapy methods is being considered for use in the treatment of liver tumors, demonstrating therapeutic benefits in certain circumstances[5]. In the study by Xia et al[22], the mOS and mPFS in the TACE plus lenvatinib group were significantly longer than those in the lenvatinib monotherapy group (mOS: 15.9 months vs 8.6 months, P = 0.002; mPFS: 8.6 months vs 4.4 months, P < 0.001), suggesting that TACE was effective in prolonging patient survival over systemic therapy alone.

In this study, we retrospectively analyzed the efficacy and safety of TACE combined with chemotherapy, TKIs, and PD-1/PD-L1 inhibitors in treating unresectable ICC. The results revealed that the mPFS of the experimental group was significantly longer than that of the control group (P < 0.05). Moreover, the ORR (according to the mRECIST criteria) in the experimental group was greater than that in the control group (39.0% vs 19.0%, P < 0.05). Similarly, the DCR in the experimental group (75.6%) was significantly greater than that in the control group (52.4%) (P < 0.05). These findings suggest that the combination of chemotherapy with targeted therapy and immunotherapy, along with TACE as a local treatment, is more effective than systemic therapy alone. Wang et al[23] reported that the combination of TACE, lenvatinib and PD-1 inhibitors significantly improved overall survival, PFS, ORR, and DCR without significantly increasing the risk of adverse events of any grade, which is consistent with the findings of this study.

Previous studies have also demonstrated a synergistic effect among TACE, TKIs and PD-1 inhibitors[24-27]. The tumor cell necrosis generated via TACE induces the release of antigens and proinflammatory cytokines, which increases the efficacy of PD-1 inhibitors[28]. Additionally, the hypoxic microenvironment produced with TACE increases the expression of vascular endothelial growth factor, whereas TKIs inhibit angiogenesis, thereby reducing the risk of recurrence and metastasis after TACE[29-31]. In this study, none of the patients experienced grade 4 or 5 treatment-related adverse events, and no new adverse events were identified. All adverse events, regardless of grade, were manageable.

There were several limitations in this study. First, the sample size for this study was small. Second, the patients included in the study were treated with different types of TKIs and PD-1 inhibitors, leading to some inconsistency in the treatment protocols. Additionally, we employed PFS as the primary endpoint, but sufficient data on overall survival were unavailable, limiting the ability to assess the long-term efficacy and safety of the treatment.

The combination of TACE with chemotherapy, TKIs, and PD-1/PD-L1 inhibitors has good efficacy and a favorable safety profile, offering potential benefits for patients with ICC. However, given the limitations of the current study, large-scale, randomized controlled trials are needed to further validate the efficacy and safety of the combination of TACE with chemotherapy, TKIs, and PD-1/PD-L1 inhibitors in patients with ICC in the future.

CONCLUSION

In patients with unresectable ICC, TACE combined with chemotherapy, TKIs, and PD-1/PD-L1 inhibitors demonstrated good efficacy and high safety, indicating potential benefits for these patients.

ACKNOWLEDGEMENTS

The authors gratefully acknowledge the support and contributions of colleagues and friends who assisted in the preparation of this manuscript. We also extend our heartfelt thanks to all the patients at the Affiliated Hospital of Xuzhou Medical University whose participation was essential to the completion of this study.