Multidisciplinary treatment strategies for the assessment of immune, coagulation, and biomarker responses after transarterial chemoembolization for hepatocellular carcinoma

Abstract

BACKGROUND

Currently, there is a notable lack of reliable studies evaluating the impact of multidisciplinary treatment strategies following transarterial chemoembolization (TACE) on patients with hepatocellular carcinoma (HCC), underscoring the urgent need for higher-level research in this area.

AIM

To investigate the association of multidisciplinary treatment strategies with the immunological, coagulation, and tumor biomarker responses after post-TACE in HCC.

METHODS

This retrospective analysis included 100 patients with HCC who were categorized based on the treatment approach into the control (patients treated with TACE alone) and experimental groups (patients receiving multidisciplinary treatment strategies post-TACE). Participant characteristics, short-term efficacy, and safety assessment as well as immunological, coagulation, and tumor biomarker responses between the two groups were collected and compared.

RESULTS

Compared with the control group, the experimental group demonstrated a superior overall response rate, along with an increased fibrinogen, markedly improved immunological biomarker, lower prothrombin time, thrombin time, alpha-fetoprotein, carcinoembryonic antigen, and carbohydrate antigen 199 levels, as well as a decreased abnormal prothrombin incidence, and a lower overall rate of adverse reactions. Notably, no significant difference in the activated partial thromboplastin time and D-dimer levels was observed between the two groups.

CONCLUSION

Multidisciplinary treatment strategies post-TACE have improved the treatment outcome, the immunological response, and the coagulation function, lowered the tumor biomarker response levels, and reduced the risk of adverse reactions in patients with HCC.

Key Words: Hepatocellular carcinoma; Transarterial chemoembolization; Multidisciplinary treatment strategies; Coagulation; Tumor biomarker

Core Tip: Given the suboptimal efficacy of single-treatment modalities for hepatocellular carcinoma (HCC) patients, this study proposes comprehensive multidisciplinary treatment strategies for HCC patients post-transarterial chemoembolization (TACE). Through multidimensional assessments including patient characteristics, short-term efficacy and safety evaluations, as well as immune, coagulation, and tumor biomarker responses, the study demonstrates that the multidisciplinary approach enhances treatment outcomes, improves immune responses and coagulation functions, reduces tumor biomarker levels, and decreases the risk of adverse reactions in post-TACE HCC patients. These findings contribute to the development of more favorable treatment strategies for improving survival outcomes in HCC patients post-TACE and may offer more effective clinical guidance for implementing multidisciplinary treatment or nursing strategies.

INTRODUCTION

In China, hepatocellular carcinoma (HCC) is the fourth most prevalent malignant tumor and the second leading cause of cancer-related deaths, which seriously threatens the lives and health of individuals[1]. Statistics reported approximately 841000 new HCC cases globally in 2018, with China accounting for 46.7% of the global cases[2,3]. The incidence of HCC is constantly increasing with lifestyle and dietary habit changes. The disease has a strong concealment at its onset, and detecting it in the early stages is usually challenging. When generally diagnosed, HCC has already entered the middle to advanced stages, thereby seriously affecting the safety of the lives of patients[4].

Liver resection is currently the preferred treatment for early HCC, and early resection significantly extended the survival of patients with HCC[5]. Liver transplantation is considered one of the curative treatment options for patients with advanced HCC and is particularly suitable for patients with HCC having liver dysfunction. However, surgical treatment has disadvantages of postoperative recurrence, high costs, a relatively limited supply of liver donors, controversial clinical application, and a longer waiting time for patients who will undergo transplant[6]. Statistics indicated that the median survival time of conventional treatment methods was only approximately 10 months[7]. The 5-year overall survival rate of patients with HCC in China is < 15%[8]. Transarterial chemoembolization (TACE) is an interventional procedure that involves catheter and guidewire placement into the vascular supply of tumors under the guidance of a digital subtraction angiography machine[9]. The procedure injects drugs into the blood vessels through embolization to kill tumor cells and cut off the corresponding blood supply[4]. This technique caused the tumor to shrink due to the lack of blood supply, and it is one of the preferred treatment options for patients with advanced HCC who are not candidates for surgery[10]. Further, it is the most prevalent treatment for advanced HCC that cannot be surgically removed. TACE has been predominantly used in clinical treatment with continuous medical technology improvement[11]. Related data indicated the 5-year survival rate of patients with HCC after treatment at < 60%, whereas the recurrence rate was > 43%[12]. Targeted therapy directly attacks cancer cells through drugs or other treatment methods while minimizing normal cell damage, but it has the issues of drug resistance, high costs, and limited research target selectivity. Some studies have revealed that the complex etiology, atypical clinical features, highly malignant biological behavior, chronic liver damage and cirrhosis, and numerous prognostic factors of HCC make achieving satisfactory outcomes with a single treatment modality frequently challenging[13], resulting in some patients being unable to undergo single treatment modality[14]. Consequently, adopting novel therapeutic approaches to improve treatment efficacy is imperative.

Multidisciplinary treatment strategies, grounded in HCC staging, are designed to optimize patient survival and improve the quality of life through a comprehensive and collaborative approach[15]. This paradigm seamlessly integrates surgical intervention, radiotherapy, chemotherapy, and targeted therapies, thereby establishing a combination of localized and systemic treatments for the unique needs of each patient. Developing a personalized treatment plan that considers the specific characteristics and conditions of the individual harnesses the collective expertise of various medical disciplines[15]. Effectively bridging the gap between different treatment modalities fosters a cohesive and interconnected approach across all therapy stages. It provides patients with the most suitable treatment options, thereby reducing the time spent on treatment and hastening the therapeutic process, thereby improving outcomes, reflecting the commitment to advancing patient care through innovation and collaboration[16,17]. Studies have revealed that only approximately 30% of patients received curative treatments during diagnosis due to the subtle onset of HCC. Systemic therapy was of paramount importance for patients with advanced HCC who could not receive curative treatments. Systemic therapy needs to be integrated throughout the treatment process for China liver cancer staging stage IIIb HCC. Hence, local treatments, such as ablation therapy, TACE/hepatic artery infusion chemotherapy, and radiotherapy, could be combined[18]. Additionally, studies have demonstrated that multidisciplinary treatment strategies include interventional therapy combined with systemic drugs (targeted and immunotherapy), interventional therapy combined with radiotherapy, and interventional therapy combined with surgical resection or local ablation therapy[19]. These treatment strategies could be considered the first choice among patients with China liver cancer staging stages IIb and IIIa HCC who were not suitable for surgical resection[20]. Each treatment has demonstrated commendable efficacy, coupled with a favorable safety profile and a notably low incidence of severe adverse reactions, despite the diversity in treatment combinations[21].

Currently, multidisciplinary treatment strategies are primarily centered around three primary areas. The first pertains to patients with HCC who were eligible for orthotopic liver transplantation, which is a procedure that frequently represents a definitive treatment option for selected cases. The second focuses on those with advanced-stage HCC who are undergoing immunological checkpoint inhibitor therapy, which is a rapidly evolving area of oncology treatment. The third involves the application of these strategies merely as an adjunct for auxiliary management within treatment modalities across all stages of patients with HCC, functioning as an integral part of a comprehensive multidisciplinary care paradigm[22-24]. A dearth of robust studies assesses the effect of multidisciplinary treatment strategies post-TACE on patients with HCC, thereby emphasizing an urgent need for higher caliber research in this domain. More practical studies are warranted to support the results of the study. Therefore, this study aimed to investigate the association of multidisciplinary treatment strategies post-TACE with the immunological, coagulation, and tumor biomarker responses in patients with HCC, to improve treatment effectiveness and safety. This study aimed to provide data that support the clinical selection of suitable treatment plans and prognostic evaluation.

MATERIALS AND METHODS

Sample size calculation

A sample size calculation was conducted to estimate the number of participants needed for the final study analysis. The sample size for our study was meticulously identified to account for two distinct groups, drawing upon our hospital’s extensive clinical experience. We anticipated a 7% incidence of adverse reactions in the experimental group and a comparatively higher rate of 25% in the control group. To achieve this, a minimum of 41 cases per group was considered necessary. This calculation was based on a two-sided significance level of 0.05, which is conventionally utilized to minimize the risk of type I errors. Additionally, we incorporated a constant parameter of 1, representing a direct comparison between the two groups. The study was designed with a power of 80%, which ensures a robust ability to detect a true effect if one exists, thereby minimizing the risk of type II errors. An estimated of approximately 41 patients would be required per group. A total of 100 participants were considered adequate, considering a 20% drop-out rate.

Screening

This study retrospectively analyzed the clinical files of 100 patients with HCC treated at the Fudan University Affiliated Hua Dong Hospital from January 1, 2021, to December 31, 2023. After screening based on the inclusion and exclusion criteria, the final analysis included 89 patients. Patients were categorized according to the treatment approach into experimental (patients treated with multidisciplinary treatment strategies post-TACE, n = 45) and control groups (patients treated with TACE, n = 44). This ensures that the study maintained a robust sample size for meaningful statistical analysis. Diagnostic criteria were as followed: (1) The patient met the diagnostic and staging criteria for HCC in the “Guidelines for the Diagnosis and Treatment of Primary Hepatoc Carcinoma” (2019 edition)[22]; (2) Lesions with typical imaging features of HCC, such as X-ray-computed tomography, magnetic resonance imaging, and positron emission tomography/computed tomography; or (3) Lesions without typical imaging features of HCC but with a pathological diagnosis of primary HCC through liver biopsy.

Inclusion criteria were patients who met the above diagnostic criteria; diagnosed with primary HCC for the first time by histopathology; aged ≥ 18 years; reported no liver surgery history; received no previous anti-tumor treatment; did not meet the surgical indications for primary HCC or refused surgery; who underwent TACE and had completed for > 3 months; and with complete clinical and imaging data. Exclusion criteria were patients with TACE treatment contraindications; liver function classified as Child-Pugh grade C; severe coagulopathy; complete main portal vein obstruction with portal hypertension and reverse flow; a tumor volume of ≥ 70% occupying the total liver area; the presence of systemic widespread metastasis; other malignancies or hepatitis C post-liver cirrhosis; infectious disease, multi-organ functional failure, and cachexia; psychiatric diseases and poor treatment compliance; pregnant or lactating women; previously underwent surgical resection or radiochemotherapy for primary HCC; and with incomplete clinical and imaging data.

Multidisciplinary treatment strategies

First, all the patients were treated with TACE, which was performed using the Seldinger technique for femoral artery puncture and catheterization, and administered with embolization therapy after mixing the reteplase injection (Nanjing Zhengda Tianqin Pharmaceutical Co., Ltd., China Drug Approval Number H20090325), oxaliplatin injection (Sino-Foreign, Hangzhou Pharmaceutical Co., Ltd., China Drug Approval Number H20113457), and iodized oil (Jiangsu Hengrui Medicine Co., Ltd., China Drug Approval Number H20163348) in proportion. Multidisciplinary treatment strategies post-TACE were performed as follows: (1) Establishing a multidisciplinary team: In our study, a selected group of 13 healthcare professionals, spearheaded by the chief physician of the interventional unit, was gathered to form the core of the multidisciplinary treatment strategies team. This team included 10 nurse practitioners, 1 dietitian, and 1 pain therapist, each bringing their unique expertise to the collaborative effort. The multidisciplinary approach was developed to address the individual requirements of each patient. Personalized dietary plans were created to support nutritional requirements, whereas strategies for preventing and managing complications were developed to mitigate risks and improve patient outcomes. Further, rehabilitation training was provided to help in the recovery process and enhance the quality of life of patients. All treatments and interventions were conducted within the Fudan University Affiliated Hua Dong Hospital setting, which ensure a controlled and supportive environment for patients. The treatment observation period was set at 3 months, enabling a comprehensive assessment of the effectiveness of the multidisciplinary treatment strategy; (2) Liver resection and perfusion chemotherapy: A guidewire was inserted through the mesenteric vein after opening the abdomen, and the guidewire was guided using angiography until it entered the tumor lesion. The superficial tissue structure of the tumor underwent clamping and crushing or electrocoagulation and cutting to dissect the liver parenchyma. An ultrasonic knife could be used for the operation during the dissection process. The site of the lesion was stained with daunorubicin (Hengrui Pharmaceutical Co., Ltd., China Drug Approval Number H33021981) and mitomycin (Hengrui Pharmaceutical Co., Ltd., China Drug Approval Number H19999025) before precise resection; and (3) Targeted therapy: Tosylfenib mesylate tablets (Bayer HealthCare Pharmaceuticals Inc., China Drug Approval Number HJ20160201) were orally taken at 0.4 g/time for 2 times/day. The dosage was adjusted following the disease progression and adverse reactions of the patients.

Data collection

We reviewed the clinical electronic medical records, laboratory results, and radiological findings of all the participants. Clinical data, including gender, age, body mass index (BMI), Nutritional Risk Score 2002 (NRS2002) score, maximum tumor diameter, Barcelona Clinic Liver Cancer (BCLC) staging, liver function Child-Pugh grading, smoking history, alcohol history, tumor family history, and chronic underlying disease, as well as adverse reactions, were collected. Laboratory results included immunological, coagulation, and tumor biomarkers. All patients underwent imaging assessment to evaluate efficacy.

Participants characteristics

This study compared the preoperative gender, age, BMI, NRS2002 score, maximum tumor diameter, BCLC staging, liver function Child-Pugh grading, smoking history, alcohol history, tumor family history, and chronic underlying disease between the two groups of participants.

Short-term efficacy

The short-term efficacy of the two groups of patients was judged and compared using the new standard for solid tumor assessment three months after treatment (response evaluation criteria for solid tumors 1.1). Lesions that did not increase in size after treatment indicated a complete response (CR), whereas partial response (PR) is when the diameter of the lesions decreased by > 30% after treatment, stable disease (SD) is when the diameter of the lesions did not increase after treatment, and progression of disease is when the diameter of the lesions increased or new lesions appeared after treatment. The formula was: Overall response rate (%) = (CR + PR + SD)/total cases × 100%[23].

Immunological biomarker responses

Blood (3 mL) was obtained from the peripheral vein of patients in the morning on an empty stomach and stored in a heparin anticoagulant tube. The XL/XL-MCL flow cytometer (American Beckman Colter company) was used to analyze the whole blood immunological fluorescence of patients. The flow cytometry counting method was utilized to measure and compare the T lymphocyte subsets of the two groups of patients (CD3⁺, CD4⁺, CD8⁺, and CD4⁺/CD8⁺ T cells). The normal values were a CD3⁺ positive rate of 61%-85%, a CD4⁺ positive rate of 28%-58%, and a CD4⁺/CD8⁺ ratio of 0.9-2.0.

Coagulation biomarker responses

Blood (not < 5 mL each time) was collected from the veins of the patients, and the activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen (Fbg), and D-dimer (D-D) were detected and compared using the ACL 3000 automated hematology analyzer.

Tumor biomarker responses

Patients were instructed to fast for 6-8 hours before blood collection and to collect 4 mL of fasting blood from the cubital vein the next morning. After standing at room temperature for 30 minutes, the blood was centrifuged at a speed of 3800 rpm, with a radius of 10 cm, for 10 minutes. The serum was collected. Serum tumor biomarker response levels, including carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), abnormal prothrombin (PIVKA-II), and carbohydrate antigen 199 (CA199), were detected and compared using chemiluminescence. Abbott supplied the reagents used in the detection.

Safety assessment

The incidence of adverse reactions was observed and compared in the two groups of patients during the three months of treatment, including decreased appetite, diarrhea, headache, lethargy, liver function damage, rash (rash is the eruptions or spots that appear on the skin, which is caused by various reasons, including infections, allergies, skin diseases, etc.), abnormal blood pressure (a diagnosis of hypertension can be made if the systolic/diastolic blood pressure is higher than 140/90 mmHg, and a diagnosis of hypotension can be made if the systolic/diastolic blood pressure is lower than 90/60 mmHg), heart function abnormalities, and reactive telangiectasia (symptoms, such as redness, swelling, heat, and joint pain, including the knee, ankle, and shoulder, is further diagnosed through blood tests, joint fluid checks, and laboratory tests, among others). The formula is as followed: Total incidence of adverse reactions = (total number of adverse reaction cases/total number of cases) × 100%.

Statistical analysis

Statistical analysis was conducted using Statistical Package for the Social Sciences IBM Statistics Version 27.0.1 (SPSS Inc, Beijing, China). Categorical variables should be presented as n (%). Further, comparisons between groups were performed using Pearson’s χ²-test if data met the criteria of theoretical frequencies of > 5 and a total sample size of at least 40. Initially, we performed normality tests for continuous data (histograms and one-sample Shapiro-Wilk test). In this study, continuous variables following a normal distribution are represented as mean ± SD. Inter-group comparisons were conducted using two independent sample t-tests if the data met the assumption of homogeneity of variance. The Welch’s t-test was used for the group comparison if the assumption was not met. Quantitative data with a skewed distribution are presented as median (interquartile range), and the comparison between the two groups is done using the Mann-Whitney U test for independent samples. The data before the intervention were utilized as covariance and a one-way analysis of variance was used for intragroup comparison. P values of < 0.05 in the comparison indicated significant differences.

RESULTS

Participant characteristics in patients with post-TACE HCC

The preoperative gender, age, BMI, NRS2002 score, maximum tumor diameter, BCLC staging, liver function Child-Pugh grading, smoking history, alcohol history, tumor family history, and chronic underlying disease were not statistically significant between the two groups (P > 0.05, Table 1).

Table 1 Comparative analysis of participant characteristics between the two groups.

	Experimental group (n = 45)	Control group (n = 44)	χ2/t	P value
Gender, male/female	35 (77.78)/10 (22.22)	37 (84.09)/7 (15.91)	0.574	0.449
Age, years	61.55 ± 9.53	62.34 ± 10.34	0.375	0.709
BMI, kg/m2	24.03 ± 1.37	24.12 ± 1.65	0.280	0.780
NRS2002 score	2.86 ± 0.87	2.79 ± 1.03	0.347	0.730
Maximum tumor diameter, cm	5.79 ± 1.54	6.03 ± 1.48	0.749	0.456
BCLC staging, A/B/C	8 (17.78)/32(71.11)/ 5 (11.11)	7 (15.91)/35 (79.55)/2(4.55)	1.437	0.541
Liver function Child-Pugh grading, A/B	39 (86.67)/6 (13.33)	41 (93.18)/3 (6.82)		0.485
Smoking history, yes/no	29 (64.44)/16 (35.56)	33 (75.00)/11 (25.00)	1.173	0.279
Alcohol history, yes/no	27 (60.00)/18 (40.00)	32 (72.73)/12 (17.27)	1.613	0.204
Tumor family history, yes no	13 (28.89)/32 (71.11)	14 (31.82)/30 (68.18)	0.090	0.764
Chronic underlying disease, yes/no	26 (57.78)/19 (42.22)	23 (52.27)/11 (47.73)	0.801	0.371

Results expressed as means ± SD, or n (%). BMI: Body mass index; NRS2002: Nutritional Risk Score 2002; BCLC: Barcelona Clinic Liver Cancer.

Short-term efficacy in patients with post-TACE HCC

Three months after treatment, 17 (19.10%), 42 (47.19%), 19 (21.35%), and 11 (12.36%) patients achieved CR, PR, SD, and progression of disease, respectively. The overall response rate was 87.64% (78/89). Compared with the control group, the experimental group demonstrated a higher overall response rate, which was statistically significant (P < 0.05, Table 2).

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

	Experimental group (n = 45)	Control group (n = 44)	P value
Overall response rate	43 (95.56)	35 (79.55)	0.027
CR	11 (24.44)	6 (13.64)
PR	25 (55.56)	17 (38.64)
SD	7 (15.56)	12 (27.27)
PD	2 (4.44)	9 (20.45)

CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progression of disease.

Immunological biomarker responses in patients with post-TACE HCC

Before treatment, no statistically significant difference was observed in the immunological markers between the two groups (P > 0.05). Three months after treatment, CD3⁺, CD4^+, and CD4⁺/CD8⁺ levels in the two groups were higher than before treatment, with the CD8⁺ levels lower than before treatment. Three months after treatment, CD3⁺, CD4⁺, and CD4⁺/CD8⁺ levels in the experimental group were higher than those in the control group, with the CD8⁺ levels lower than those in the control group (P < 0.05, Table 3).

Table 3 Comparative analysis of immunological biomarker responses between the two groups, mean ± SD.

	Experimental group (n = 45)	Control group (n = 44)	F value	P value
CD3+, %			43.869	< 0.001
Before treatment	54.09 ± 5.33	53.93 ± 5.21	0.011	0.918
3 months after treatment	69.18 ± 7.03	59.46 ± 6.72
CD4+, %			39.005	< 0.001
Before treatment	32.64 ± 3.84	33.03 ± 3.79	1.223	0.272
3 months after treatment	45.18 ± 4.91	39.06 ± 4.23
CD8+, %			84.859	< 0.001
Before treatment	30.55 ± 4.52	31.13 ± 4.78	0.158	0.692
3 months after treatment	21.76 ± 2.15	26.35 ± 2.52
CD4+/CD8+			103.782	< 0.001
Before treatment	1.10 ± 0.24	1.09 ± 0.22	0.643	0.425
3 months after treatment	2.10 ± 0.33	1.50 ± 0.22

Coagulation biomarker responses in patients with post-TACE HCC

Before treatment, no statistically significant difference was found in APTT, D-D, Fbg, PT, and TT levels between the two groups (P > 0.05). Meanwhile, APTT, D-D, PT, and TT levels in the two groups were lower 3 months after treatment than before treatment, with the Fbg levels higher than before treatment. No statistically significant difference was observed in APTT and D-D levels between the two groups after 3 months of treatment (P > 0.05). Further, PT and TT levels 3 months after treatment were lower in the experimental group than in the control group, with the Fbg levels higher than in the control group (P < 0.05, Table 4).

Table 4 Comparative analysis of coagulation biomarker responses between the two groups, mean ± SD.

	Experimental group (n = 45)	Control group (n = 44)	F value	P value
APTT, second			3.105	0.082
Before treatment	36.52 ± 3.06	37.45 ± 3.34	0.024	0.878
3 months after treatment	31.27 ± 2.94	32.42 ± 3.15
D-D, μg/mL			0.686	0.105
Before treatment	1.68 ± 0.37	1.75 ± 0.33	0.048	0.826
3 months after treatment	1.51 ± 0.35	1.62 ± 0.25
Fbg, g/L			28.943	< 0.001
Before treatment	2.06 ± 0.56	1.89 ± 0.52	0.167	0.684
3 months after treatment	2.87 ± 0.59	2.15 ± 0.68
PT, second			14.511	< 0.001
Before treatment	12.26 ± 2.18	11.97 ± 2.42	1.250	0.267
3 months after treatment	9.25 ± 2.13	10.92 ± 2.10
TT, second			19.431	< 0.001
Before treatment	16.72 ± 2.08	16.53 ± 2.26	1.910	0.170
3 months after treatment	13.25 ± 2.17	15.42 ± 2.42

APTT: Activated partial thromboplastin time; D-D: D-dimer; Fbg: Fibrinogen; PT: Prothrombin time; TT: Thrombin time.

Tumor biomarker responses in patients with post-TACE HCC

Before treatment, no statistically significant difference was found in the serum tumor biomarker levels between the two groups (all P > 0.05). AFP, CEA, CA199, and PIVKA-II levels in the two groups were lower 3 months after treatment than before treatment, with their levels in the experimental group lower than in the control group (all P < 0.05, Table 5).

Table 5 Comparative analysis of tumor biomarker responses between the two groups, mean ± SD.

	Experimental group (n = 45)	Control group (n = 44)	F value	P value
CEA, ng/mL			164.563	< 0.001
Before treatment	34.57 ± 2.35	34.62 ± 2.32	0.017	0.897
3 months after treatment	18.14 ± 1.27	22.59 ± 1.92
AFP, ng/mL			1019.687	< 0.001
Before treatment	434.52 ± 12.05	433.59 ± 12.16	0.831	0.364
3 months after treatment	251.25 ± 16.58	362.91 ± 16.38
PIVKA-II, mAU/mL			6.165	0.015
Before treatment	723.14 ± 201.20	724.34 ± 202.54	0.226	0.636
3 months after treatment	559.25 ± 157.45	643.82 ± 162.25
CA199, U/mL			257.831	< 0.001
Before treatment	254.81 ± 10.56	255.85 ± 10.06	2.111	0.150
3 months after treatment	179.58 ± 5.62	201.49 ± 7.28

CEA: Carcinoembryonic antigen; AFP: Alpha-fetoprotein; PIVKA-II: Abnormal prothrombin; CA199: Carbohydrate antigen 199.

Safety assessment in patients with post-TACE HCC

The overall incidence of adverse reactions in the experimental group was lower than that in the control group during the 3-month treatment period (P = 0.030, Table 6).

Table 6 Comparative analysis of safety assessment between the two groups, n (%).

	Experimental group (n = 45)	Control group (n = 44)	χ2	P value
Adverse reaction	5 (11.11)	13 (29.55)	4.686	0.030
Decreased appetite	1 (2.22)	2 (4.55)
Diarrhea	1 (2.22)	1 (2.27)
Headache	0 (0.00)	1 (2.27)
Lethargy	1 (2.22)	3 (6.82)
Liver function damage	0 (0.00)	1 (2.27)
Rash	1 (2.22)	1 (2.27)
Abnormal blood pressure	0 (0.00)	1 (2.27)
Heart function abnormalities	0 (0.00)	1 (2.27)
Reactive telangiectasia	1 (2.22)	2 (4.55)

DISCUSSION

Patients with HCC are characterized by a complex interplay of etiological factors, subtle clinical features, highly malignant biological behavior, chronic liver damage, cirrhosis, and numerous prognostic factors, frequently causing the poor efficacy of single treatment methods and low patient satisfaction[23]. In this study, we adopted multidisciplinary treatment strategies to treat patients with post-TACE HCC, which not only improved outcomes and immunological response, but also optimized coagulation, diminished tumor biomarker response levels, and demonstrated a superior safety profile. In this study, a team of distinguished healthcare professionals was convened to collaboratively establish personalized treatment plans tailored to the unique needs of each patient. To improve patient outcomes, a nutritionist-led approach was used in the multidisciplinary treatment strategies, which involved reducing preoperative fasting periods and expediting the introduction of postoperative dietary interventions. This strategy was tailored to individual patient needs, which ensured a reasonable and personalized nutritional care plan. We not only augmented the patients’ nutritional intake but also stimulated gastrointestinal motility by incorporating high-calorie, easily digestible foods into the early postoperative diet. These interventions resulted in a significant reduction in the incidence of postoperative gastrointestinal adverse reactions, including nausea, vomiting, anorexia, and diarrhea. Ultimately, this approach improved patients’ postoperative comfort and overall quality of life, which contributed to a more favorable clinical trajectory[24]. Further, it effectively promoted gastrointestinal motility, reduced the risk of gastrointestinal adverse reactions such as nausea, vomiting, loss of appetite, and diarrhea, improved patient comfort, and improved the quality of life of patients. Moreover, the multidisciplinary treatment strategies model included pharmacological treatment by pain therapists and psychological intervention by counselors, which alleviated headaches, depression, and other adverse effects while relieving pain[25,26]. The liver has a dual blood supply system; thus, simple TACE treatment could not eliminate cancer cells, greatly increase vascular endothelial growth factor secretion, and promote tumor angiogenesis, thereby promoting recurrence or metastasis of the lesion[27]. Therefore, multidisciplinary treatment strategies post-TACE need to be implemented.

In our study, the application of multidisciplinary treatment strategies post-TACE in patients with HCC yielded a notably higher overall response rate, indicating that the multidisciplinary treatment strategies could significantly improve the clinical outcomes of patients with post-TACE HCC. The success of this mode was related to its ability to transcend the inherent limitations of single-discipline treatments, particularly for challenging and intricate cases[28-30]. In particular, Ali et al[28] conducted a retrospective review of 28 patients presenting with blunt liver injury, and all those who were conservatively treated achieved poor clinical outcomes, whereas those who were managed by a multidisciplinary team achieved relatively better outcomes. Abe et al[29] revealed that multidisciplinary treatment significantly slowed the decline in estimated glomerular filtration rate in patients with chronic kidney disease and was effective regardless of the primary disease, including in its early disease stage, and recommended multidisciplinary treatment for patients with chronic kidney disease stages 3-5. Stergioula et al[30] demonstrated that multidisciplinary treatment, including surgery and radiotherapy, provided the greatest survival benefit for patients with primary cardiac angiosarcoma. The results of these studies were consistent with the findings of the present study, all indicating that the multidisciplinary treatment strategies were effective in improving the outcome and quality of life of patients.

In this study, CD3⁺, CD4⁺, and CD4⁺/CD8⁺ levels were increased and CD8⁺ levels were decreased in patients after using multidisciplinary treatment strategies. It indicates that multidisciplinary treatment strategies can improve the immunological biomarker responses in HCC patients post-TACE, consistent with the findings of Lee[31]. Furthermore, nutritional food application and chemotherapy drug administration based on the actual condition of the patient promotes cytokine production and stimulates CD3⁺ and CD4⁺ cell proliferation and activation, thereby enhancing T cell maturation and improving cellular immunological function[32]. Concurrently, within multidisciplinary teams, a psychotherapist provides immediate evaluations and support, helping patients manage disease-related anxieties and depression, which improves their treatment efficacy and quality of life[33]. Additionally, the pain therapist in multidisciplinary teams provided personalized pain management plans for patients that effectively alleviated the degree of pain they experienced during their treatment process, thereby further helping in improving the treatment effect of patients with post-TACE HCC and doubling immunological function improvement, reducing liver damage, and enhancing the quality of life of patients[34]. Finally, within the multidisciplinary treatment strategies, the combination of systemic and local treatments further improved anti-tumor immunology without generating overlapping toxicity, which was beneficial for reducing tumor burden, enhancing immunological response, slowing tumor progression, and alleviating symptoms in patients[19].

In this study, no significant change in the APTT and D-D levels was observed in patients after adopting multidisciplinary treatment strategies, the PT and TT levels were reduced, and the Fbg level was increased, indicating that the multidisciplinary treatment strategies improved coagulation in patients with post-TACE HCC. Additionally, AFP, CEA, CA199, and PIVKA-II levels were reduced in patients after the multidisciplinary treatment strategies used in this study, indicating that the multidisciplinary treatment strategies reduced the tumor biomarker response level in patients with post-TACE HCC. This may be because sorafenib, as a tyrosine kinase inhibitor in multidisciplinary combination therapy, not only exerts a rapid onset of action[35] but also hinders tumor cell proliferation through serine/threonine kinase inhibition in the receptor tyrosine kinase KIT and FIJT-3 and Raf/MEK/ERK pathways, which in turn improve the effect of inhibiting serum molecules of the tumor and enhanced the coagulation function of the patients, thereby prolonging tumor progression and prolonging the survival time of patients[36,37]. It not only directly acts on the abnormal expression pathway of the tumor foci but also inhibits the VECF target, blocks the vascular synthesis pathway of the tumor foci, inhibits the growth of the tumor cells, and promotes their apoptosis, which helps slow down tumor development and improve the survival rate in patients with HCC[38].

The study results revealed a lower overall incidence of adverse reactions in patients after using multidisciplinary treatment strategies, indicating that multidisciplinary treatment strategies reduced the risk of adverse reactions in patients with post-TACE HCC. This may be because the multidisciplinary treatment strategies model of care provides quality care to patients through the collaboration of multidisciplinary healthcare professionals[18,24,28,30]. However, after adopting multidisciplinary treatment strategies post-TACE, adverse reactions remain in five patients, including decreased appetite, headache, lethargy, liver function damage, and heart function abnormalities, respectively. This may be due to the addition of systemic combined local therapy to the multidisciplinary treatment strategy, the relative increase in side effects with the elevated concentration of the administered drug, and the inevitability of adverse effects in certain patients with poorer body conditions, as well as the exact mechanism of adverse effects warranted to be confirmed by further studies[19]. Some studies have demonstrated that the gastrointestinal tract of patients with HCC was in a state of prolonged emptying post-TACE, which was more likely to occur or even aggravate the gastrointestinal adverse reactions under chemotherapeutic drug stimulation and may further induce ulceration or hemorrhage[25]. Gastrointestinal reactions occurred in three cases receiving no multidisciplinary treatment strategies, whereas only one case of gastrointestinal reaction was observed in patients who had adopted dietary management as part of the multidisciplinary treatment strategies, which markedly improved gastrointestinal functioning and the quality of survival of patients[32,33]. Further, the patient who was not managed with the multidisciplinary treatment strategies developed a rash during the treatment course. The side effects of the treatment medication or an allergic reaction to certain drugs may have caused this condition[39]. Multidisciplinary treatment strategies reduce the risk of rash in patients, which may be because a multidisciplinary team could regularly monitor the adverse reactions of the patient and adjust the treatment plan based on the response of patients, including changes in medication dosage and intervals, to reduce rash occurrences[40]. The results of this study revealed that in patients who received no multidisciplinary treatment strategies, one case of heart function abnormalities and two cases of reactive telangiectasia were reported, both of which were higher than the incidence of adverse effects in patients who received the multidisciplinary treatment strategies (no cases of heart function abnormalities and only one case of reactive telangiectasia). This may be because multidisciplinary treatment strategies also reduce the risk of cardiac dysfunction in patients, possibly because a multidisciplinary team regularly monitors the heart function of patients and adjusts the treatment plan based on the treatment effect and changes in heart function, ensuring that the heart function is effectively protected[41]. To reduce the risk of cardiac toxicity, cardiac protection measures were taken promptly, such as the use of cardiac protection drugs or adjustments to the treatment plan, when the patient shows any discomfort[42]. Reactive telangiectasia is a vascular abnormality that is typically associated with the tumor microenvironment, including hypoxia, inflammation, and tumor-related factor production[41]. Multidisciplinary treatment strategies reduce the risk of reactive telangiectasia in patients, possibly because multidisciplinary treatment decreases the negative effect of tumors on blood vessels through surgical removal of tumors or the administration of drugs to inhibit tumor cell proliferation, thereby alleviating reactive telangiectasia[37].

This study has numerous limitations. The results of this study may be prone to bias because of its retrospective analysis, single-center design, small sample size, short follow-up period, and potential confounding factors. Further, only the near-term efficacy was investigated due to the short observation time of the treatment in this study, and the observation time of the prognosis of patients had to be prolonged thereafter to study the effect of multidisciplinary treatment strategies modality on the long-term efficacy and survival time of patients with post-TACE HCC to corroborate the results of the study. These limitations may introduce bias to our results and warrant further multi-center, large-sample, prospective, and long-term follow-up studies to confirm the findings.

CONCLUSION

Multidisciplinary treatment strategies could improve the treatment outcome, the immunological response, and the coagulation function, lower the tumor biomarker response levels, and reduce the risk of adverse reactions in patients with post-TACE HCC. Therefore, we recommend the use of multidisciplinary treatment strategies for patients with post-TACE HCC, to improve patient outcomes and prognosis. The results are instrumental in providing treatment strategies that are demonstrably more beneficial in terms of survival outcomes for patients after TACE. Our study not only contributes substantial and reliable clinical management evidence for this particular patient population but also holds the potential to provide more effective clinical guidance on the implementation of multidisciplinary treatment or care strategies in patients post-TACE. Additionally, due to the heterogeneous nature of HCC, individualized multidisciplinary treatment strategies according to the differences in tumor heterogeneity should be formulated in the future by studying the individualized biological characteristics of patients with HCC.