Risk Predictors of Post-Embolization Syndrome after Transarterial Chemoembolization by Sex: A Retrospective Study

Hepatocellular carcinoma is the second leading cause of death from malignant neoplasms and significantly contributes to mortality among individuals in their 40s and 50s [1]. While surgical resection is the most effective treatment, it is only suitable for approximately 30% of patients and carries a substantial risk of complications and recurrence. As a result, Transarterial Chemoembolization (TACE) has emerged as a widely adopted non-surgical therapeutic alternative [2]. TACE has demonstrated a promising prognosis for single tumors smaller than 5 cm in diameter [3]. However, a common complication of this procedure is Post-Embolization Syndrome (PES), which is characterized by symptoms such as abdominal pain, nausea, vomiting, and fever [4]. The PES incidence is estimated as 36.1% and 72.5% among TACE recipients [4, 5, 6]. TACE-induced symptoms can vary across different studies, but they most frequently appear in the sequence of pain, nausea, vomiting, and fever [7]. PES not only impacts the patient's prognosis and mortality rate [4], but it also diminishes their quality of life. From a social perspective, it results in extended hospital stays and increased healthcare costs [8]. Therefore, early detection and intervention in PES after TACE is vital in nursing care to alleviate patient discomfort [9].

Previous studies on PES following TACE have categorized risk factors into three groups: clinical characteristics, laboratory data, and radiological findings [10, 11, 12, 13]. Among the clinical characteristics, amount of doxorubicin and lipiodol [14], as well as the number of TACE procedures [10], significantly influence the probability of PES. Doxorubicin (also known as adriamycin) is a chemotherapy drug used to treat a variety of cancers, including those of the breast, bladder, stomach, liver, ovaries, and thyroid. It is frequently administered alongside cyclophosphamide [15]. A study found that a group given 100 mg/m² of doxorubicin had fever durations roughly twice as long as those given 50 mg/m², suggesting that higher dosages increase the risk of PES [13, 16]. The side effects of nausea and vomiting, which are associated with cytotoxic agents like doxorubicin, result from the release of neurotransmitters, the activation of chemoreceptor trigger zones in the medulla oblongata, and the stimulation of receptors connected to the gastrointestinal tract and the vomiting center [16, 17]. TACE employs lipiodol as a radio-opaque contrast agent and a carrier of chemotherapeutic agents, and higher dosages are associated with increased nausea and vomiting [14]. The risk of these symptoms escalates as the quantity of lipiodol used enlarges the emboli, exacerbating tissue ischemia and hypoxia [14]. Moreover, patients undergoing TACE for the first time are more prone to PES because patients develop an increased tolerance to pain with each subsequent TACE treatment [10]. Therefore, the number of TACE procedures should also be carefully considered.

Laboratory data also help predict the incidence of PES following TACE. For example, patients with lower serum levels of albumin have a higher likelihood of developing PES [11]. Total bilirubin levels that exceed 19.0 mol/L are associated with a lower risk of nausea and vomiting, while Alanine aminotransferase (ALT) levels above 40.0 U/L, a marker of liver cell damage, are linked to a higher severity of these symptoms [18]. Other potential risk factors, such as the International Normalized Ratio (INR) and α-Fetoprotein (AFP) [19], are still under discussion and necessitate further investigation.

The radiological features of hepatocellular carcinoma have been recognized as risk factors, however evidence for the relationship between them is still lacking [6]. In the advanced stages of the disease, tumor cells frequently invade the liver veins. Hepatocellular carcinoma often manifests with large tumors and multiple lesions, leading to more significant tumor necrosis and inflammatory responses during TACE [20]. Assessments using the Liver Imaging Reporting and Data System (LI-RADS) Treatment Response Algorithm (TRA) [21] to evaluate the effects of radiation therapy revealed that 62.2% of tumors classified as nonviable (Liver Imaging Reporting and Data System-Treatment Response [LR-TR] nonviable) after TACE had incomplete necrosis while 33.3% of tumors classified as LR-TR equivocal had incomplete necrosis [22]. These results suggest that the tumor response could influence the incidence of PES after TACE. Furthermore, factors such as the tumor's anatomical location within the liver, the presence of three or more tumors, or a tumor size greater than 5 cm have been associated with an increased risk of abdominal pain after TACE [10].

The role of demographic factors such as sex and age in the incidence of PES following TACE remains unclear [6, 10]. Some studies have reported that female patients were 2.76 times more likely to experience this syndrome than male patients, reflecting a significant difference [5, 13]. These findings suggest that being female is a risk factor. However, no significant differences have been observed in the rates of nausea and vomiting between men and postmenopausal women [23]. This raises questions about the potential influence of other factors, such as estradiol hormone levels or body mass index [13]. Much of the existing research has concentrated on the prevalence of PES after TACE by sex, but there is scant data on how risk factors vary between male and female patients. Some studies have found that female patients are more likely to be affected [5, 13], while others have found that male patients are also at risk [18]. The specific risk factors associated with sex remain unidentified, underscoring the need for further research. Thus, the aim of this study was to identify sex-specific risk factors for PES following TACE, in order to provide valuable data that could improve the quality of nursing care.

The aim of this study was to identify risk predictors for PES following TACE, with a particular focus on sex differences in its onset. Post-TACE, the most common symptoms experienced by female patients were fever, pain, and nausea/vomiting, in descending order. Male patients, meanwhile, most frequently reported pain, fever, and nausea/vomiting. The overall incidence of these symptoms was 43.9% in female patients and 37.3% in male patients, which falls within the previously reported range of 36.1% to 72.5% for PES incidence after TACE [4, 5, 6]. In female patients, ALT levels were the only significant variable identified. For male patients, however, several factors presented significant relationships, including the presence of a tumor larger than 5 cm in diameter, the amount of lipiodol, CRP and ALT levels, lymphocyte levels, and the presence of a tumor in the right posterior segments (S6, S7).

Seven variables showed statistically significant correlations with PES after TACE in female patients. The multivariate logistic regression analysis of these variables revealed that an increase in ALT levels following TACE contributed to the development of PES. However, the risk increase was marginal (1.01 times), meaning that this variable could not be deemed decisive for predicting PES after TACE. This finding aligns with a study that reported nearly double AST and ALT levels in over 40% of patients following TACE [26], and another study that identified ALT levels as an independent risk factor for fever post-TACE [12]. Liver enzymes, including alkaline phosphatase, gamma-glutamyl transferase, AST, and ALT, are important markers. Increases in AST and ALT levels signify liver cell damage [27], indicating ongoing liver damage. This study also identified ALT levels as a risk factor in male patients. Consequently, an increase in ALT levels can predict liver cell damage and may lead to fever or pain, underscoring the need for preventive nursing intervention based on these findings. However, another study found a negative correlation between ALT levels and the incidence of nausea and vomiting [23], suggesting that further investigation is warranted.

Eleven variables presented statistically significant correlations with PES after TACE in male patients. The multivariate logistic regression analysis of these variables identified six significant risk factors: a tumor size exceeding 5 cm in diameter, the amount of lipiodol, CRP levels, ALT levels, lymphocyte levels, and the presence of tumors in the right posterior segments (S6, S7). Importantly, the risk of PES following TACE was 2.51 times higher for tumors larger than 5 cm in diameter. This observation is consistent with a study by Dai et al. [28], which found that a tumor size larger than 5 cm significantly predicted mortality within five years and early recurrence within two years in patients with hepatocellular carcinoma. Another study identified tumor size as an independent risk factor for fever following TACE [10]. The typical cut-off size for tumor dimensions in predicting PES after TACE varies, but 5 cm is a commonly accepted standard [7]. These findings suggest that the embolization area expands after chemoembolization for larger tumors, leading to increased tumor necrosis and inflammatory responses [6]. As a result, extra precautions are necessary, as male patients with tumors larger than 5 cm are at a higher risk of developing PES.

The amount of lipiodol was identified as a risk factor, with increased usage leading to a 1.27-fold rise in the incidence of PES. This finding aligns with previous research [14] that explored the relationship between the amount of lipiodol and PES following TACE. The expanded embolization area resulting from increased amount of lipiodol [15] can cause ischemia, hypoxia, and some hepatocyte necrosis, potentially leading to PES [29]. Although tumor size may also contribute to the syndrome, its impact is less direct than that of lipiodol usage. Doxorubicin, the most frequently used cytotoxic chemotherapy agent in TACE, is emulsified with lipiodol and injected into the tumor's blood vessels [30]. By cleaving the double strands of DNA in rapidly dividing cells, such as malignant tumors, doxorubicin induces cytotoxicity, which can lead to symptoms like abdominal pain, nausea, and vomiting [31]. Conventional TACE can induce systemic side effects as doxorubicin, once separated from the unstable lipiodol emulsion, is introduced systemically. In contrast, drug-eluting bead TACE employs anticancer agents that are slowly released from microspheres infused into the tumor's blood vessels. This approach maintains a high concentration of anticancer agents within the tumor while minimizing their presence in systemic plasma, thereby reducing systemic side effects [32]. As a result, patients who underwent drug-eluting bead TACE experienced PES for a shorter duration than those who received conventional TACE [7]. It would be beneficial for nurses to be aware of the type of TACE a patient has received, especially when caring for those at risk for PES following TACE.

Levels of CRP, an acute-phase reactant produced by the liver, are modulated by inflammatory cytokines in response to acute inflammation, infection, tissue damage, and cancer [33]. This study's findings align with those of Jun et al. [12], which pinpointed CRP levels as a risk factor for fever following TACE. In a similar vein, a one-unit increase in CRP was associated with a 1.11-fold increase in the incidence of PES. CRP levels also show a significant correlation with tumor size and type. The exact mechanism that connects elevated CRP levels to a poor prognosis in cancer remains unclear. However, this association is likely due to the proinflammatory cytokines produced by tumor necrosis or local tissue damage, which stimulate tumor growth and trigger a systemic inflammatory response [12].

If the tumor is situated in the right posterior segments, the risk of PES following TACE decreases by a factor of 0.71. Predicting the incidence of PES after TACE based solely on tumor location is challenging, given that most patients had multiple tumors and this study included overlapping data. However, considering the limited research on the relationship between tumor location and TACE, this study is of considerable importance. The effectiveness of TACE is influenced by its dual blood supply-both artery and portal vein-and by the collateral arterial circulation that develops post-procedure. This suggests that the rate of PES after TACE can vary depending on the tumor's location. When lipiodol is extensively absorbed into tissues, it can cause almost total necrosis of the tumor. However, this process can stimulate an overproduction of vascular endothelial growth hormone, promoting the regeneration of tumor vessels. This effect may lead to tumor recurrence and subsequently diminish the effectiveness of TACE [34]. Moreover, the peripheral region's fewer blood vessels, compared to the central part, result in inadequate collateral circulation and anastomotic flow, which could potentially affect liver function enhancement [35]. Therefore, tumors located in right posterior segment seems to be somewhat more effective for TACE and presents a lower risk of PES following TACE. Nevertheless, these findings require further research for confirmation.

In female patients, only one significant risk factor was identified and the magnitude of the increased risk associated with that factor was relatively small, making it difficult to explain. However, this study did not consider the socio-psychological factors of the patient or the quality of comfort care they received as independent variables, which could mean that some significant factors were missed. Patient anxiety or depression can directly or indirectly influence sleep patterns and the onset of pain. Furthermore, nursing comfort care involves managing the patient's pain and ensuring suitable environmental care [9]. As a result, these factors could directly or indirectly contribute to the incidence of PES following TACE. Notably, these elements seem to impact female patients more than male patients, suggesting that clinical characteristics, laboratory data, and radiological findings were not considered as significant in this study. Therefore, further research is needed on the factors influencing the incidence of PES after TACE in female patients.

This study is significant because it identified sex-specific risk factors for PES following TACE, thereby establishing a foundation for future nursing interventions. Additionally, the risk model developed can be utilized in the creation of a clinical decision support system. However, there are certain inherent limitations to consider. First, due to the retrospective nature of this study, which relied on record reviews rather than direct patient input, the incidence of PES post-TACE may not have been accurately recorded due to potential underreporting of patient symptoms. Second, while there are likely additional variables associated with PES post-TACE, many variables were omitted due to inadequate documentation in the medical records, which restricts our understanding of the influencing factors. Consequently, prospective studies are necessary to accurately document the incidence of PES post-TACE in patients and to gather more comprehensive data.

This retrospective study was conducted to determine whether the risk factors for the incidence of PES after TACE differ by sex. In female patients, elevated ALT levels were identified as a contributing factor to the syndrome, although the increase in risk associated with ALT changes was not substantial. In male patients, significant risk factors included the presence of a tumor larger than 5 cm in diameter, amount of lipiodol, CRP levels, ALT levels, lymphocyte levels, and the presence of a tumor in the right posterior segments (S6, S7). Therefore, nurses caring for male patients undergoing TACE should closely monitor laboratory data such as CRP levels, ALT levels, and lymphocyte levels, as well as radiological features like tumor size and location, and the amount of lipiodol, to predict the potential incidence of PES. This study will also provide foundational data for the development of a clinical decision support system that utilizes these risk factors.

The following recommendations are proposed: First, the study was limited in its generalizability as it only utilized samples from a single medical institution. Consequently, future studies should aim to expand their scope by incorporating samples from various medical institutions. Second, although the study identified clear sex differences in risk factors for PES following TACE, it did not identify the underlying causes. Further research is required to identify the specific characteristics of each sex that contribute to these disparities.