In the 21st century, the global incidence and mortality of cancer are rapidly increasing. According to the latest data from GLOBOCAN 2020 on primary liver cancer, there are approximately 905,677 new cases and 830,180 deaths annually worldwide. This makes primary liver cancer the sixth most common malignancy (4.7%) and the third-highest cause of cancer-related mortality (8.3%) (1). Primary liver cancer comprises hepatocellular carcinoma (HCC) in 75%-85% of cases, intrahepatic cholangiocarcinoma (ICC) in 10%-15% of cases, and other rare types (1). Therefore, HCC is the most prevalent form of liver cancer (2). Surgical curative resection is the standard treatment for achieving long-term survival in HCC patients, with a 5-year survival rate as high as 80% (3–5). However, the overall survival (OS) of patients with advanced HCC is notably poor, with a 3-year survival rate falling below 42.4% (6).

In certain situations, advanced HCC can lead to the formation of tumor thrombus (TT) in the portal vein and hepatic vein. Although TT rarely extends into the inferior vena cava (IVC) or right atrium (RA), when it occurs, the incidence rates are approximately 3.8% and 2.0%, respectively (7–9). TT extension into the IVC or RA may result in systemic metastasis and sudden death, attributed to pulmonary embolism or tricuspid valve embolism with TT. Reports indicate that the median survival times (MST) for untreated patients range from 2 to 5 months (9–14). Currently, there is no established treatment strategy for this type of patient. Advances in surgical techniques and perioperative management have made liver resection a relatively safe treatment option (15). However, the technical demands, associated high surgical risks, and a significantly elevated rate of postoperative complications greatly limit the implementation of this surgery.

With the gradual development of targeted therapies and the exploration of immune checkpoint inhibitors, particularly in the form of combination therapies, the treatment approach for HCC has entered a new stage (16, 17). For advanced HCC patients who are not suitable for surgery, systemic treatments like sorafenib and lenvatinib are recommended as first-line therapies (18). Innovative immunotherapies, encompassing immune checkpoint inhibitors targeting programmed cell death protein-1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4), or its ligand programmed cell death-ligand 1 (PD-L1), have been integrated into the treatment regimens for advanced HCC (19). These advancements play a pivotal role in elevating survival rates and reshaping the overall therapeutic landscape for HCC. Importantly, they instill newfound optimism for patients with HCC and accompanying TT in the IVC/RA.

However, the effectiveness of surgical treatment in conjunction with targeted and immunologic drugs remains uncertain. In this context, we present four cases of HCC and TT in the IVC/RA who underwent surgical resection. These individuals underwent targeted therapy and immunotherapy after the surgical procedure. The primary objective of this study is to assess the impact of the combination of surgical resection with targeted and immune therapies on the prognosis for this specific tumor subtype.

In our center, a total of four patients underwent surgery under these circumstances, demonstrating the following characteristics: 1) diagnosis of HCC; 2) presence of IVC tumor thrombus; 3) no extrahepatic metastasis; 4) no other primary tumor lesions; 5) intact tumor without rupture; 6) child-Pugh classification and residual liver volume suitable for surgical resection. They underwent surgical resection of TT combined with hepatectomy. These patients were all male with an average age of 57 years. Among them, 2 patients presented with type III, 1 with type II, and 1 with type I. For a comprehensive overview of patient characteristics, please refer to Table 1 .

HCC is a highly malignant tumor known for its aggressive nature. It commonly metastasizes to regional lymph nodes, lungs, or bones and exhibits invasion into vasculature (20). As previously mentioned, the occurrence of HCC with TT in the IVC or RA is approximately 3.8% and 2.0%, respectively. Globally, the incidence of IVC and RA involvement ranges from 1.4% to 4.9% (21). Anatomically, TT is clinically categorized into three types based on its location relative to the heart: type I, where the TT is located below the diaphragm in the IVC (referred to as the inferior hepatic type); type II, where the TT is located above the diaphragm in the IVC, but still outside the RA (known as the superior hepatic type); and type III, where the TT is located above the diaphragm and has entered the RA (referred to as the intracardiac type) (15).

According to the Barcelona Clinic Liver Cancer (BCLC) staging system, HCC with TT in the IVC/RA is classified as stage C, representing an extremely poor prognosis in the advanced stage (7, 8). The recommended treatment approach by the European Association for the Study of the Liver (EASL) clinical practice guidelines is “systemic therapy” (18). Studies have reported the MST of 17.8 months for surgical patients, compared to 10.1 months for non-surgical patients (22). Radical resection has demonstrated MSTs of up to 19.0 months, with higher 5-year survival rates than non-surgical approaches (13).

The observed benefits in surgical outcomes may be attributed to the gradual advancements in surgical techniques. At our center, we conduct these surgeries based on the ongoing progress in liver transplantation and extracorporeal circulation technology. However, it is essential to emphasize the associated risks linked with such surgical operations, as patients may face potential complications, such as pulmonary embolism or perioperative bleeding. Drawing from our experience, we employ a combined thoracoabdominal incision, and the extracorporeal circulation device is meticulously prepared in advance. The procedure involves complete resection of the hepatic tumor and embolus causing IVC blockage. Circulation is subsequently re-established using either autologous vessels or DCD vessels.

Li et al. have outlined a surgical guide for the treatment of HCC with TT in the IVC/RA (15). To ensure surgical safety, they emphasized performing surgery exclusively on patients with Child-Pugh A classification and good hepatic reserve for HCC (8). For type I, in cases involving complete hepatic blood flow blockage, a longitudinal incision is made in the IVC, enabling the complete removal of both the primary intrahepatic lesion and TT. In type II, an incision can be made in the diaphragm anterior to the IVC TT through a median sternotomy and thoracotomy, exposing the TT above the diaphragm. Subsequently, the tumor and TT are removed, and the IVC wall, pericardium, and diaphragm are sutured. Type III cases necessitate a combination of cardiothoracic and hepatobiliary surgery under extracorporeal circulation. Blood flow is bypassed to the ascending aorta after ex vivo oxygenation. The RA is incised, and the entire TT is excised.

Two of our cases underwent combined thoracoabdominal surgery under extracorporeal circulation, involving the complete resection of TT and liver masses. However, due to severe invasion of the IVC, all four cases underwent IVC reconstruction, with three cases utilizing DCD vessels for reconstruction. It is noteworthy that, in the literature we reviewed, there were no reports on the use of DCD vessels for IVC reconstruction. This approach contrasts with the use of artificial vessels, which are costly and anticoagulant-dependent. The use of DCD vessels is both cost-effective and of high quality, making it a promising option for patients undergoing this procedure at qualified transplant centers.

The guidelines from the European Association for the Study of the Liver (EASL), the American Association for the Study of Liver Diseases (AASLD), and the Japan Society of Hepatology (JSH) all emphasize that, for advanced HCC patients with well-preserved liver function (Child-Pugh class A), first-line therapeutic options commonly include lenvatinib, sorafenib, atezolizumab plus bevacizumab combination therapy, and camrelizumab plus apatinib (23–25). Additionally, Chinese guidelines also advocate the use of sintilimab in combination with IBI305 (a bevacizumab biosimilar) as a first-line treatment for unresectable or metastatic HCC (26).

Historical literature reports that, for unresectable HCC patients, the MST with sorafenib ranges from 10.3 to 13.6 months, with a median progression-free survival (PFS) of 3.6 to 4.3 months (27–29). Lenvatinib, on the other hand, demonstrates a MST between 12.3 to 12.8 months, with a median PFS of 6 to 7 months (28, 30). A study indicated that patients receiving lenvatinib had improved OS, PFS, objective response rate, and disease control rate (DCR) compared to those treated with sorafenib (31). A randomized phase III study also demonstrated superior efficacy of lenvatinib over sorafenib (OS 15.2 months vs. 10.5 months, PFS 7.0 months vs. 4.5 months). Patients receiving lenvatinib showed a 36% reduction in the risk of death, a 29% reduction in the risk of progression, higher response rates and higher disease control rates (32).

In recent years, there has been rapid development in systemic therapy for advanced HCC, with promising outcomes achieved by novel systemic treatments. Literature reports indicate that monotherapy with pembrolizumab in previously untreated advanced HCC results in a median PFS of 4 months and the MST of 17 months (33). In the analysis of the IMbrave150 study, the MST in the atezolizumab plus bevacizumab group was superior to sorafenib (19.2 months vs. 13.4 months, and the median PFS (6.9 months vs. 4.3 months) (34). Additionally, in the analysis of the ORIENT-32 study, the combination of sintilimab and IBI305 (a bevacizumab biosimilar) significantly improved the MST (not reached vs. 10.4 months) and extended the median PFS (4.6 months vs. 2.8 months) (35). A phase 1b study of pembrolizumab in combination with lenvatinib also yielded positive results: with an overall response rate of 36.0%, disease progression rate of 7.0%, PFS of 8.6 months, and OS of 22.0 months (36). Furthermore, the latest data from the phase 3 LEAP-002 trial (NCT03713593) suggests that the combination of lenvatinib and pembrolizumab provides a survival advantage for patients with advanced HCC (median PFS 8.2 months vs. 8.0 months; MST 21.1 months vs. 19.0 months) (37). These studies collectively underscore the importance of immunotherapy in the management of advanced liver cancer patients.

Moreover, postoperative adjuvant therapy is particularly crucial for patients with a high risk of recurrence in liver cancer. A study demonstrated that postoperative immune checkpoint inhibitors (ICIs) combined with targeted therapy showed significantly higher RFS in univariate analysis. This suggests that postoperative adjuvant ICI combined with targeted therapy may reduce the recurrence of HCC in patients with most risk factors (38). Results from a phase III randomized controlled trial (IMbrave 050) indicated that atezolizumab combined with bevacizumab significantly improved postoperative RFS in patients (39). Another study suggested that postoperative anti-PD-1 antibody treatment in high-risk recurrent HCC patients demonstrated better postoperative 1-year, 2-year, 3-year, and 4-year OS rates (93.1% vs. 85.3%, 86.8% vs. 70.2%, 78.2% vs. 47.7%, 51.1% vs. 30.0%) and postoperative 1-year, 2-year, 3-year RFS rates (81.7% vs. 68.4%, 77.0% vs. 47.7%, 52.3% vs. 25.8%) compared to the non-anti-PD-1 antibody group (40). Additionally, postoperative adjuvant therapy (PAT) with tyrosine kinase inhibitors (TKI) and anti-PD-1 antibodies can improve surgical outcomes for HCC patients at high risk of recurrence. The PAT group showed 1-year and 2-year RFS rates of 82.1% and 40.0%, respectively, and 54.2% and 25.1%. The corresponding 1-year and 2-year OS rates were 95.4% and 69.8% and 84.3% and 55.5% (40). Liver resection surgery combined with postoperative lenvatinib treatment can provide additional survival benefits for patients (28). Taking into consideration the guidance from comprehensive guidelines and the reported patient benefits in previous research literature, we have administered postoperative treatment to patients, including targeted therapy, immunotherapy, or a combination of targeted and immunotherapeutic agents.

The therapeutic outcomes of various treatment strategies for HCC patients with TT in IVC/RA were reviewed in the literature. The median time to recurrence (TTR) after radical resection is 3 to 9.8 months, and the MST ranges from 16.7 to 30.8 months (9, 13, 14). Patients undergoing radiotherapy have an MST of 17.4 months, while TACE results in an MST of 10.9 months (41, 42). Systemic or hepatic arterial infusion chemotherapy achieves an MST of 15.4 months, whereas chemotherapy combined with radiotherapy results in an MST of 7.9 months (22, 42). Best supportive care yields an MST of 5.9 months (22).Combination therapies, including TACE with chemotherapy, TACE plus external beam radiotherapy (EBRT), and TACE with sorafenib, show superior efficacy compared with TACE alone (43–45). Survival rates for patients undergoing liver resection are higher than those receiving TACE, and the MST for surgical resection is superior to that of the EBRT group (15.3 months vs 11.7 months) (46, 47). Patients treated with TACE combined with lenvatinib and sintilimab achieve a median MST of 17.3 months and a median PFS of 13.0 months (48). Radiotherapy combined with targeted therapy provides an MST of 15.8 months and a median PFS of 4.2 months (49).

Overall, aggressive treatments—including surgery, radiotherapy, interventional therapy, systemic therapy, and multimodal approaches—demonstrate improved survival outcomes (21). Among these, surgical resection offers the greatest survival benefit (50).The median RFS and MST of the cases at our center were 32.5 months and 48 months, respectively. Compared to the survival benefit reported in the literature, our case showed a significant survival benefit.

With the advancement of targeted and immunotherapy research, the role of the tumor microenvironment in tumor progression has gained increasing attention. The tumor microenvironment (TME) is composed of immune cells, fibroblasts, cytokines, and extracellular matrix, which dynamically interact with tumor cells to create an immune-suppressive environment (51). This environment promotes the expression of angiogenic factors such as VEGF and immunosuppressive cytokines like TGF-β, accelerating vascular infiltration while weakening antitumor immune responses (52). These processes play a critical role in the initiation and progression of HCC. Recent advances in targeted therapies, including the combination of TKIs and ICIs, have shown significant progress in modulating the TME. For instance, the combination of lenvatinib and pembrolizumab normalizes blood vessels and reawakens exhausted T cells, thereby enhancing antitumor efficacy through TME modulation (51). It is noteworthy that Case 4 showed significant shrinkage of TT, and postoperative pathology indicated severe cancer cell necrosis within the lesion. This further confirms the effectiveness of the combination of targeted and immunological drugs for unresectable advanced HCC and the modulation of TME.

For late-stage HCC patients with TT in the IVC/RA who are not suitable for surgery, a combination of targeted and immunological drugs may successfully convert such cases into operable patients. The amalgamation of aggressive surgical resection and combination of targeted and immunological drugs may confer benefits to HCC patients with TT in IVC/RA. Our clinical cases emphasize the importance of involving relevant experts in a multidisciplinary team and ensuring timely treatment intervention to develop the optimal treatment plan for such patients.

In general, the survival benefits obtained in the four cases at our center exceeded those reported in previous literature. Cases 3 and 4 had a relatively short postoperative period, emphasizing the importance of continuous close follow-up for ongoing assessment. It is essential to emphasize that our center has treated only four patients in this manner, with only one patient receiving preoperative conversion therapy with a combination of targeted and immune therapies. Therefore, further relevant case studies are necessary to strengthen our understanding of the treatment approaches for patients in such conditions.