Systemic complications and management strategies in liver cancer patients undergoing interventional therapy

Abstract

Liver cancer presents unique challenges due to its systemic impact and complex treatment modalities. Patients often experience a range of complications, including cardiovascular, renal, hematological, and metabolic abnormalities, which can significantly affect treatment outcomes and quality of life. This article emphasizes the integration of multidisciplinary strategies and artificial intelligence-driven diagnostics, which have the potential to improve patient outcomes by optimizing early detection and targeted management of these complications. A recent study on 60 liver cancer patients undergoing interventional therapy highlighted the importance of recognizing and managing these complications. This article offers an overview of systemic complications in liver cancer, focusing on pathophysiological mechanisms, risk factors, and strategies to improve care. By addressing gaps in the existing literature and proposing future research directions, it underscores the importance of comprehensive, patient-centered approaches to refine therapeutic strategies.

Key Words: Liver cancer; Interventional therapy; Systemic complications; Risk factors; Multidisciplinary care

Core Tip: Liver cancer management demands a comprehensive approach to address systemic complications arising from interventional and systemic therapies. These complications, spanning cardiovascular, renal, hematological, and metabolic domains, significantly affect patient outcomes and quality of life. Advances in interventional techniques, combination therapies, and supportive technologies such as artificial intelligence provide innovative solutions for optimizing care. Multidisciplinary collaboration remains pivotal in tailoring interventions to individual patient needs. Future research should emphasize refining therapeutic strategies, improving patient selection, and leveraging biomarkers for early detection to ensure holistic and effective management of liver cancer.

INTRODUCTION

Liver cancer poses unique challenges due to its systemic impact and the complexity of its treatment modalities. Patients often experience complications affecting multiple organ systems, arising from both the disease itself and therapeutic interventions such as transarterial chemoembolization (TACE) and radiofrequency ablation (RFA). Complications associated with TACE include renal dysfunction, with incidence rates reported between 10%-25%, and cardiovascular issues such as arrhythmias and ischemic events. RFA, although less invasive, is also associated with complications like hepatic bleeding and bile duct injury, with varying incidence rates depending on the tumor size and location. Recent studies, including a report on 60 patients undergoing interventional surgery for liver cancer diagnoses, have highlighted the impact of various parameters and influencing factors on treatment outcomes[1]. These complications, ranging from cardiovascular to metabolic abnormalities, significantly influence treatment outcomes and patients’ quality of life. Addressing these issues is essential for optimizing care and improving prognoses. The systemic management of these complications is critically important due to the complex nature of the disease and the multifaceted treatment approaches required. Liver cancer, particularly hepatocellular carcinoma (HCC), is a leading cause of cancer-related mortality globally, necessitating comprehensive treatment strategies that integrate both systemic and interventional therapies. While combination therapies enhance efficacy by improving tumor response rates and extending survival periods, they also increase the risk of complications, such as autoimmune-related adverse events[2]. Systemic management is necessary to monitor and mitigate these effects, ensuring that they remain controllable and optimizing patient outcomes.

SYSTEMIC COMPLICATIONS ASSOCIATED WITH LIVER CANCER AND INTERVENTIONAL THERAPIES

Cardiovascular complications

Cardiovascular complications are common in liver cancer patients undergoing interventional therapy. They include arrhythmias, myocardial ischemia, and hypertension. Electrocardiographic abnormalities, such as QT prolongation, are frequently observed. These complications result from a combination of procedural stress, systemic inflammation, and pre-existing cardiac conditions. Patients with liver cancer have a significantly higher risk of cardiovascular mortality compared to the general population, influenced by factors such as age, sex, and cancer stage[3]. Liver disease, particularly cirrhosis, exacerbates cardiovascular issues by altering hemodynamics, increasing cardiac output, and affecting vascular reactivity[4]. Sorafenib, a common treatment for HCC, is associated with major adverse cardiovascular events, including heart failure, acute coronary syndrome, and cerebrovascular accidents. Predictive tools like the CARDIOSOR scale help assess the risk of these events in patients undergoing treatment[5]. Additionally, therapies targeting vascular endothelial growth factor (VEGF) or VEGF receptor, such as sorafenib, increase the risk of thromboembolic and bleeding events, especially in patients with pre-existing cardiovascular risks[6].

Despite being a minimally invasive option, TACE can lead to cardiovascular complications such as ischemic events due to embolization. Awareness of these risks and appropriate management strategies are essential to balance its benefits[7]. The emerging field of interventional onco-cardiology provides a framework for managing cardiovascular complications arising from cancer treatments, including safer alternatives like transcatheter valve replacement for cancer patients[8]. Comprehensive cardiovascular care through regular monitoring and multidisciplinary approaches is vital to improving outcomes in this patient population. While cardiovascular complications are a major concern, kidney function is also significantly affected in liver cancer patients, particularly due to disease progression and treatment-related effects. The next section explores these renal complications in more detail.

Renal complications

Renal dysfunction is a significant concern in liver cancer patients, arising both as a direct consequence of the disease and as a result of its treatments. Hepatorenal syndrome is a frequent complication characterized by renal vasoconstriction and reduced glomerular filtration rate without structural kidney damage, often seen in advanced liver cancer[9]. Direct tumor effects, including renal invasion or urinary tract obstruction, and tumor metabolites can also contribute to renal dysfunction[10]. Interventional treatments such as TACE can exacerbate renal complications due to embolization and chemotherapeutic toxicity. Careful monitoring and management are required to mitigate these risks[7]. Additionally, post-liver transplantation renal dysfunction is often related to nephrotoxic immunosuppressive drugs like calcineurin inhibitors. Strategies such as delayed introduction of these drugs and the use of alternative medications can help minimize renal damage[11,12]. Systemic therapies, including chemotherapy and targeted treatments, may lead to renal damage through mechanisms such as acute tubular necrosis and thrombotic microangiopathy, necessitating dose adjustments and close monitoring for patients with pre-existing renal impairment[13]. Renal complications not only limit treatment options but also significantly impact the prognosis and quality of life of liver cancer patients, emphasizing the need for a multidisciplinary approach to balance effective cancer treatment with the preservation of renal function[14,15]. Alongside renal complications, abnormalities in blood cell production and coagulation present further challenges in liver cancer patients. The next section delves into these hematological issues and their clinical implications.

Hematological abnormalities

Hematological issues, including coagulopathy, thrombocytopenia, and an increased risk of thromboembolic events, are prevalent in liver cancer patients. Liver dysfunction exacerbates these conditions by impairing coagulation factor synthesis and platelet production, increasing the risk of bleeding or thrombosis. Anemia is a common complication in liver cancer, often resulting from mechanisms such as chronic disease anemia, nutritional deficiencies, and bleeding. Disruption of the liver’s role in iron metabolism and erythropoiesis further contributes to decreased red blood cell production and increased destruction[16]. Thrombocytopenia, frequently observed in liver cancer patients, arises due to hypersplenism and impaired thrombopoietin production by the liver, leading to an elevated bleeding risk that complicates both disease progression and treatment[16]. Coagulation disorders, including impaired synthesis of coagulation factors, vitamin K metabolism dysfunction, and increased fibrinolysis, further exacerbate bleeding tendencies, resulting in severe episodes[16].

Interventional treatments such as systemic chemotherapy can aggravate hematological complications, including anemia, thrombocytopenia, and neutropenia, increasing infection risks and limiting treatment options[17]. TACE, though minimally invasive, can cause post-embolization syndrome characterized by fever, pain, and leukocytosis, mimicking infection and complicating management[7]. Radiotherapy may also lead to hepatic dysfunction, manifesting as ascites, jaundice, and variceal bleeding, further compounding hematological abnormalities[18]. These hematological abnormalities significantly contribute to morbidity and mortality in liver cancer patients by limiting aggressive cancer therapies and reducing quality of life. Management strategies often include supportive care such as blood transfusions, growth factor support, and monitoring of coagulation parameters to mitigate their impact[16,17]. Beyond hematological challenges, metabolic and nutritional disturbances also play a critical role in shaping patient outcomes. The following section discusses these issues, with a focus on their impact on treatment tolerance and overall prognosis.

Metabolic and nutritional issues

Electrolyte imbalances, such as hypokalemia and hyponatremia, are common metabolic disturbances in liver cancer patients. Malnutrition and sarcopenia are prevalent due to impaired dietary intake, altered metabolism, and increased energy expenditure, leading to protein-energy malnutrition and muscle wasting[19,20]. Liver cancer disrupts macronutrient metabolism, often compounded by anorexia, malabsorption, and hypermetabolism, further complicating nutritional management[21,22]. Micronutrient deficiencies, resulting from impaired liver function and malabsorption, exacerbate these challenges and necessitate careful nutritional planning[23]. These nutritional disturbances significantly impact clinical outcomes, as malnutrition and sarcopenia are associated with poorer treatment tolerance, increased therapy-related side effects, and reduced quality of life[20,24]. Nutritional therapy should include dietary modifications to provide adequate energy and protein, alongside supplementation strategies such as branched-chain amino acids to improve treatment response and survival[25]. A multidisciplinary approach is critical to addressing these complex needs and supporting the overall health and recovery of liver cancer patients[25]. Considering these systemic complications, it is important to explore the various patient-related, therapy-related, and disease-related risk factors that contribute to these challenges. The next section provides a comprehensive analysis of these factors and their role in clinical decision-making.

RISK FACTORS FOR SYSTEMIC COMPLICATIONS

Patient-related factors

Age, comorbidities, and the severity of liver dysfunction play critical roles in determining the risk of systemic complications. Older patients, particularly those with pre-existing conditions such as diabetes mellitus, cardiovascular diseases, or chronic kidney disease, are at an increased risk of complications[26,27]. Lifestyle factors such as smoking further exacerbate risks by contributing to systemic inflammation and impaired immune response, increasing vulnerability to infections and delayed recovery[28]. Patients with immunocompromised status, such as those undergoing chemotherapy or with HIV infection/AIDS, also face higher risks of systemic complications due to infections and poor wound healing[26].

Therapy-related factors

The type of interventional therapy, procedural techniques, and contrast agent dosage significantly influence the likelihood of complications. TACE, for example, carries a higher risk of renal dysfunction due to chemotherapeutic toxicity and embolization effects compared to RFA[7]. Surgical interventions also pose risks of postoperative complications, including cardiovascular events and infections, particularly in patients with pre-existing comorbidities[27]. Moreover, the side effects of systemic therapies, such as dyslipidemia and hyperglycemia associated with antiretroviral treatments, contribute to systemic complications requiring close monitoring[28].

Disease-related factors

Tumor burden, vascular invasion, and underlying portal hypertension contribute to the systemic impact of liver cancer and the associated risks during treatment. Additionally, systemic inflammatory processes seen in autoimmune diseases or infectious conditions like coronavirus disease 2019 exacerbate systemic complications through mechanisms such as cytokine storms and coagulopathies[29,30]. Chronic conditions like muscular dystrophies also increase systemic complication risks due to the involvement of multiple organ systems, further complicating patient management[31].

PATHOPHYSIOLOGICAL MECHANISMS UNDERLYING COMPLICATIONS

Liver cancer and its treatments disrupt systemic homeostasis through multiple mechanisms.

Systemic inflammation

Chronic inflammation, often exacerbated by bacterial translocation, contributes to both portal hypertension and systemic complications, including cardiovascular and renal issues, as the liver’s role in maintaining immune and endocrine homeostasis is disrupted[32].

Portal hypertension and angiogenesis

Portal hypertension, characterized by increased intrahepatic vascular resistance and VEGF-induced neovessel formation, is common in HCC. VEGF plays a critical role in tumor angiogenesis by stimulating the formation of new blood vessels, which supply the growing tumor with oxygen and nutrients, promoting tumor growth and metastasis. This condition leads to complications such as significant ascites and variceal bleeding, complicating both disease management and treatment[33]. Anti-VEGF therapies, such as bevacizumab, have shown promise in targeting tumor angiogenesis, reducing vascular permeability, and inhibiting metastatic spread. However, resistance to VEGF inhibitors can develop due to compensatory mechanisms like the upregulation of alternative angiogenic pathways, including fibroblast growth factors and platelet-derived growth factors, which can bypass the blockade of VEGF. These limitations highlight the need for more comprehensive strategies, including combination therapies, to overcome resistance and improve the efficacy of anti-VEGF treatments in HCC.

Therapy-induced stress

Systemic therapies, including tyrosine kinase inhibitors and immune checkpoint inhibitors, can lead to hepatotoxicity, steatohepatitis, and immune-mediated hepatitis. TACE-induced renal dysfunction occurs through several mechanisms, including ischemia caused by embolization, contrast-induced nephropathy from the use of iodine-based contrast agents, and nephrotoxic effects of chemotherapy agents such as doxorubicin. These treatments not only affect liver function but also compromise other organ systems, making the management of these complications critical for improving patient outcomes[34]. The choice of interventional therapy depends on various factors, including tumor characteristics and patient comorbidities. The risks and benefits of different treatment methods, such as TACE, RFA, and systemic therapies, are summarized in Table 1. This table provides an overview of the key therapeutic options, their indications, contraindications, and potential risks, helping clinicians make informed decisions about the best approach for each individual patient.

Table 1 Risks and benefits of liver cancer treatments.

Treatment	Benefits	Risks	Indications	Contraindications
TACE	Minimally invasive, effective for large or unresectable tumors, improves survival rates	Renal dysfunction, ischemic events, bleeding, thrombosis, embolization-related complications	Unresectable HCC, large tumors, portal vein thrombosis	Severe hepatic dysfunction, portal vein thrombosis, poor renal function
Radiofrequency ablation	Less invasive, useful for small tumors, quick recovery, fewer complications	Hepatic bleeding, bile duct injury, less effective for larger tumors or tumors near vital structures	Small, localized tumors, tumors in safe areas for ablation	Large tumors, tumors near critical structures (bile duct, major vessels)
Systemic chemotherapy	Targets cancer cells directly, reduces tumor size, can be combined with other therapies	Hematological toxicity, nausea, infection risk, limited efficacy for advanced-stage cancers	Advanced HCC, patients with distant metastasis, combination with other therapies	Severe hepatic impairment, poor general health, bone marrow suppression
Sorafenib	Targets VEGF, inhibits tumor angiogenesis, reduces tumor growth and metastasis	Cardiovascular complications (hypertension, heart failure), gastrointestinal bleeding, thrombosis	Advanced HCC with vascular invasion, combination therapy with TACE	Pre-existing cardiovascular disease, gastrointestinal disorders, severe bleeding risks
Immunotherapy	Stimulates immune system to target cancer cells, effective for advanced cancers	Autoimmune-related adverse events, organ-specific toxicity, cytokine release syndrome	Advanced HCC, patients unresponsive to traditional therapies	Autoimmune conditions, severe organ dysfunction, immunosuppressive therapy contraindications

TACE: Transarterial chemoembolization; HCC: Hepatocellular carcinoma; VEGF: Vascular endothelial growth factor.

Cardiovascular and circulatory complications

Oxidative stress, inflammation, and endothelial dysfunction in liver cancer can promote arrhythmias, cardiomyopathy, pulmonary hypertension, and renal failure, complicating patient management and increasing morbidity[32].

Drug resistance and combination therapies

Resistance to systemic therapies limits treatment effectiveness and can exacerbate complications. While combination therapies, including chemotherapy and immunotherapy, improve efficacy by targeting multiple tumor pathways, they also increase the risk of adverse events[35,36]. For example, the combination of TACE and sorafenib is commonly used, but this can lead to an increased risk of gastrointestinal bleeding, thromboembolic events, and liver dysfunction. Each treatment modality has specific indications and contraindications that must be carefully considered to minimize risks and optimize therapeutic outcomes. TACE is generally indicated for patients with unresectable HCC or those with large tumors, while contraindications include patients with severe hepatic dysfunction or portal vein thrombosis. RFA is an alternative for smaller, localized tumors but should be avoided in cases with tumors near vital structures, such as the bile ducts or major blood vessels.

MANAGEMENT STRATEGIES FOR SYSTEMIC COMPLICATIONS

Cardiovascular complications

Pre-procedure cardiac assessments are essential to identify high-risk patients. Beta-blockers and anticoagulants may be used judiciously, while continuous electrocardiogram monitoring can help detect and manage arrhythmias early.

Renal complications

Hydration protocols and the use of nephroprotective agents like N-acetylcysteine can mitigate contrast-induced nephropathy. Monitoring renal function post-procedure ensures early detection of dysfunction. For patients with hepatorenal syndrome, vasoconstrictors and albumin therapy are often employed to improve renal perfusion[9]. In cases of post-transplantation renal dysfunction, adjusting immunosuppressive regimens and employing alternative medications may reduce nephrotoxicity[11].

Hematological management

Careful management of anticoagulants, platelet transfusions, and prophylactic measures can reduce bleeding risks while addressing coagulopathy effectively. Supportive care strategies such as blood transfusions and growth factor support are critical in managing anemia and thrombocytopenia[16,17].

Nutritional and metabolic support

Nutritional supplementation and correction of electrolyte imbalances play critical roles in supporting recovery and minimizing systemic complications. Dietary interventions that include adequate protein and energy intake, along with the use of branched-chain amino acids, are essential to mitigate malnutrition and support treatment tolerance[25]. A multidisciplinary approach ensures comprehensive care for addressing the complex nutritional and metabolic needs of liver cancer patients.

MULTIDISCIPLINARY AND INTEGRATED CARE APPROACHES

A multidisciplinary approach involving hepatologists, interventional radiologists, oncologists, nutritionists, and nurses is vital for comprehensive care. Nurses play a critical role in early detection and management of complications, while patient education fosters self-management and adherence to therapy. Multidisciplinary rounds, which involve patients and their families in care decisions, have been shown to improve patient satisfaction and foster collaborative relationships[37]. For patients awaiting liver transplants, systemic management of complications like portal hypertension and portal vein thrombosis is crucial to maintaining transplant candidacy. Interventional radiology plays a key role in addressing these issues, emphasizing the need for an integrated approach.

Moreover, interdisciplinary collaboration enhances operational efficiency and patient safety. In surgical settings, structured collaboration among team members reduces postoperative complications and increases patient satisfaction[38]. Addressing communication barriers and hierarchical dynamics within multidisciplinary teams is essential. Effective communication protocols, supported by technologies like electronic health records and telemedicine, can facilitate real-time coordination and care delivery[39]. Empowering nursing roles through interdisciplinary training and policy reforms further strengthens the ability of multidisciplinary teams to provide holistic patient care[40].

FUTURE PERSPECTIVES AND RESEARCH OPPORTUNITIES

Future research should focus on refining interventional techniques such as TACE and transarterial radioembolization to minimize complications while improving therapeutic efficacy. However, despite these advancements, limitations persist, including suboptimal patient selection criteria, treatment resistance, and a lack of standardized protocols for combination therapies. Advances in combination therapies, including immunotherapy and targeted treatments, offer significant promise but require robust clinical trials to determine optimal patient stratification methods and validate emerging therapeutic approaches. Furthermore, leveraging artificial intelligence and advanced imaging technologies can enhance precision in diagnosis and intervention, reducing risks and improving outcomes. For instance, artificial intelligence (AI)-driven automated imaging analysis has been used for early detection of liver tumors, significantly improving diagnostic accuracy. Additionally, AI-guided preoperative planning tools are helping clinicians to better assess tumor characteristics and vascular involvement, enabling more precise interventions. AI-driven predictive models are particularly promising for refining risk assessment and personalizing treatment regimens. Multidisciplinary approaches, integrating supportive care and enhanced recovery protocols, are essential for optimizing patient outcomes and maintaining quality of life. Addressing these areas through a combination of innovation, clinical rigor, and personalized patient care holds the key to advancing liver cancer interventional therapy.

CONCLUSION

The effective management of systemic complications in liver cancer requires a multidisciplinary and patient-centered approach. Addressing cardiovascular, renal, hematological, metabolic, and nutritional complications demands tailored interventions and vigilance. Advances in interventional techniques and combination therapies, supported by technologies like AI and advanced imaging, offer promising solutions. Collaborative care involving hepatologists, oncologists, and nutritionists is essential for optimizing outcomes and improving quality of life. Future research should focus on refining therapies, patient selection, and biomarkers for early detection, ensuring that innovations translate to holistic and effective care strategies for this challenging disease.