Introduction
According to global cancer statistics for 2022, Liver cancer is the sixth most commonly diagnosed cancer worldwide and the third leading cause of cancer-associated mortalities (1). In 2022, ~860,000 new cases and 750,000 mortalities were reported globally (1). The prevalence of liver cancer is higher in regions such as East Asia and South Africa (1). Hepatocellular carcinoma (HCC) accounts for ~75% of all primary liver cancer cases (2), with 70–80% of patients being diagnosed at an advanced stage, often with large size tumors and concomitant poor liver function. Among these cases, the incidence of portal vein tumor thrombus (PVTT) ranges between 13 and 45% (3,4), and these patients face the poorest prognosis, often developing severe complications such as portal hypertension, hepatocellular jaundice and refractory ascites (5). The median survival time for patients with HCC and PVTT who receive only supportive care is 2.7 months (5).
Currently, the optimal treatment strategy for technically resectable HCC with PVTT remains a subject of debate. Both the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases recommend the Barcelona Clinic Liver Cancer (BCLC) staging system for managing and prognosticating HCC (6). According to this system, patients with HCC and PVTT are classified as advanced (BCLC stage C) and are eligible only for palliative systemic treatment (6). However, treatment guidelines have been updated across various regions, including mainland China (7), Hong Kong (8) and Japan (9). Portal vein invasion does not preclude surgical resection, which has been shown to markedly improve the survival of patients with HCC and PVTT (10). Notably, the surgical mortality rate for these cases remains <10% (11). A study from Japan have indicated that the median survival time for patients undergoing surgical removal of PVTT ranges between 8 and 22 months, with 1-year overall survival (OS) rates varying between 21.7 and 69.6% (11).
Neoadjuvant therapies, including radiotherapy (12), chemotherapy (13), immunotherapy (14), targeted therapy (15) and interventional therapy (16), have gained attention for treatment of HCC. Advocates of neoadjuvant therapy argue that it can help manage small metastatic lesions, reduce the preoperative tumor burden, lower recurrence rates and improve OS. Additionally, neoadjuvant therapies for tumor downstaging are often characterized by a relatively short treatment duration and high patient compliance (17). On the other hand, some experts recommend surgical resection as the preferred treatment for HCC with isolated PVTT, due to the fact that surgery typically results in improved preservation of liver function compared with non-surgical approaches (18). In light of the ongoing debate surrounding neoadjuvant therapy, the present study aimed to perform a meta-analysis of the available literature to evaluate the efficacy and safety of neoadjuvant therapy for the treatment of resectable HCC with PVTT.
Discussion
HCC is classified using various staging systems, with the BCLC staging system (32) being the most widely adopted. Under this system, patients with HCC and PVTT are categorized as stage C (33). In a number of Western medical systems, including the United States, any degree of vascular invasion has traditionally been considered a contraindication for surgical intervention (34). However, the 2022 updated BCLC guidelines recommend atezolizumab-bevacizumab as the first-line treatment for these patients (35).
In contrast to Western practices, vascular invasion, whether in the portal vein, hepatic vein or with extrahepatic metastasis, does not universally preclude surgical resection in HCC management (36). Several surgical centers in Asia have reported favorable clinical outcomes for patients with technically resectable BCLC stage C HCC (36,37). For instance, a national multicenter study in Japan conducted by Kokudo et al (38) revealed that hepatectomy in patients with PVTT confined to the primary or peripheral branches markedly extended the median survival by 1.77 years compared with non-surgical management. These findings suggest that hepatectomy may be a viable option for treating HCC with PVTT in carefully selected cases.
While surgical resection offers a potentially curative approach for HCC with PVTT, its effectiveness is limited by several critical factors. Surgical resection is primarily feasible for patients with type I/II PVTT, where prognosis is comparatively more favorable, with 5-year OS rates ranging between 10 and 59% (39). By contrast, for patients with type III/IV PVTT, the prognosis is worse, with survival rates dropping to 0–26% (39). Additionally, hepatic resection is only possible under specific conditions, such as a performance status grade of 0–2, Child-Pugh grade A or sufficient liver reserve, which restricts the number of eligible patients (40,41). Furthermore, hepatectomy is associated with considerable trauma and carries the risk of severe complications, particularly in cases of advanced HCC with metastasis. In such cases, resecting the primary tumor often does little to improve survival due to the high likelihood of recurrence (42). A clinical trial involving 47 patients with advanced HCC underscored this issue, reporting 40 fatalities, 37 of which were due to tumor recurrence (43). Furthermore, when PVTT extends to the main, left or right branches of the portal vein, the complexity of the surgery increases substantially, leading to worse postoperative survival outcomes (44).
Due to these limitations, there is a growing emphasis on multimodal combination therapies to improve long-term survival in these patients, including neoadjuvant/adjuvant/downstaging therapy for surgery and the combined modality of non-operative therapies (45). The present literature analysis aimed to evaluate whether combining neoadjuvant therapy with hepatectomy is associated with improved prognostic outcomes compared with priority surgery. Data from Eastern countries indicated that integrating neoadjuvant therapy with surgery offers a survival advantage over prioritizing surgery as the sole treatment.
Neoadjuvant therapy, including radiotherapy and interventional therapy, improves the prognosis of patients with HCC and PVTT when combined with hepatectomy. Neoadjuvant radiotherapy can effectively downstage PVTT, expanding the pool of patients eligible for surgical intervention and increasing the success rate of surgeries (25–30). A pivotal study (46) reported a 5-year survival rate of 57% for patients who underwent salvage surgery following the downstaging of initially unresectable HCC, which compares favorably to that in patients who underwent liver resection when they first presented with resectable tumors, demonstrating notable improvement in long-term outcomes.
By alleviating the adverse effects of PVTT on the blood supply of the hepatic portal vein, which is crucial for maintaining liver function, neoadjuvant radiotherapy prevents tumor cell dissemination into surrounding liver tissues, thereby reducing the risk of intrahepatic and extrahepatic metastases (47–51). This approach utilizes a targeted radiation dose that is markedly lower than that used in adjuvant therapies, minimizing damage to the liver while focusing primarily on the tumor thrombus (52). Furthermore, the use of low-dose radiation, critical for ensuring both surgical safety and efficacy, is effective in lowering HCC-related mortality and recurrence rates, while concurrently preserving liver function and capacity (25).
By reducing the size and extent of PVTT, neoadjuvant therapy decreases the risk of tumor dissemination during hepatectomy (25). This is especially crucial when the thrombus extends into major portal branches, facilitating a more comprehensive resection of cancerous tissue and lowering the risk of postoperative recurrence (12). Neoadjuvant radiotherapy can markedly increase surgical margins. For instance, one study demonstrated that the median surgical margin increased from 0 to 1 cm, with the addition of neoadjuvant intensity modulated radiation therapy (IMRT), making nearly half of previously unresectable lesions suitable for surgery (53). This suggests neoadjuvant IMRT may be associated with improved OS by increasing the R0 resection rate. This improvement not only enhances the likelihood of achieving a complete resection but also reduces the incidence of positive surgical margins, thereby improving OS outcomes for patients (12).
In addition to neoadjuvant radiotherapy, interventional therapies such as transcatheter arterial chemoembolization (TACE) serve a pivotal role in the management of liver cancer, particularly in intermediate to advanced stages of HCC (54). TACE, including its variants conventional TACE and drug-eluting beads TACE, targets the hepatic artery, the primary vascular supply for both HCC and PVTT.TACE refers to injection of selective vascular embolization with chemotherapy drugs into the tumor-feeding arteries to prevent its nutrition and blood supplying, thereby leading to ischemic necrosis of the targeted tumor (55). TACE improves survival rates in patients with all types of PVTT compared with those of patients receiving conservative treatment (56).
Another advanced interventional option, hepatic arterial infusion chemotherapy (HAIC), offers a more consistent and targeted delivery of chemotherapeutic agents directly to the tumor. HAIC is particularly beneficial for patients with significant arterial-portal shunts or complete portal vein obstruction, maximizing therapeutic efficacy while minimizing systemic side effects (57). A study performed by Hatooka et al (58) demonstrated that HAIC achieved notable disease control and objective response rates of 79.9 and 25.4%, respectively. These interventional strategies underscore the evolving landscape of neoadjuvant therapies, affirming their role in improving the long-term prognosis of patients with advanced HCC.
In the present study, compared with the control group (priority hepatectomy group), neoadjuvant therapy was associated with a survival advantage across the Chinese, Japanese and Korean subgroups; however, the survival benefits did not reach statistical significance in the Japanese and Korean groups. The pronounced effects observed in the Chinese subgroup can be attributed to the substantial representation of Chinese cases, reflecting the broader epidemiological reality, as China accounts for ~50% of the global HCC incidence (59), with PVTT prevalence rates between 44 and 62% (5). Since 1995, Chinese medical institutions have increasingly adopted the associating liver partition and portal vein ligation for staged hepatectomy procedure for managing large HCCs, leading to improvements in 1-, 3- and 5-year OS rates compared with earlier decades (60). This surgical approach has transitioned numerous patients from being considered inoperable to operable, enhancing treatment outcomes beyond palliative care (46,60). Additionally, experienced surgical teams in China have managed to reduce 30-day mortality rates to 2.7%, notably below the global average of 5–10% (61), highlighting the critical role of surgical expertise in improving these outcomes. In the present study, the efficacy of interventional therapies, particularly regarding RFS, remains inconclusive, potentially due to the limited sample size.
Another concern is the impact of neoadjuvant therapy on liver function and the associated risks. Preoperative interventions, including TACE, have been scrutinized for potential adverse effects, including hepatic artery injury, on-target embolization, fever and decreased immune function, all of which could compromise postoperative recovery (62). For example, an RCT by Zhou et al (63) indicated that while preoperative TACE did not improve mortality or tumor recurrence rates, it increased the complexity and duration of surgical procedures and elevated the risk of postoperative liver failure. Similarly, another study highlighted that preoperative targeted immunotherapy raised the risk of severe biliary complications (64). However, data from other studies, including those by Hu et al (26) and Zhang et al (29), suggest that neoadjuvant TACE did not exacerbate postoperative complications, affirming its safety when performed in experienced clinical settings. The present comprehensive statistical analysis supports these findings, showing no significant increase in complications such as bile leakage or ascites, thereby confirming the overall safety profile of neoadjuvant therapy in the surgical management of HCC with PVTT.
The present meta-analysis systematically and comprehensively evaluated the efficacy and safety of neoadjuvant therapy in patients with HCC complicated by PVTT, suggesting that neoadjuvant therapy represents a viable alternative treatment modality. A total of four previous meta-analyses (65–68) have assessed the efficacy of adjuvant therapies (in single or combined modalities) in patients with HCC and PVTT. A key distinction between these studies and the present study lies in the inclusion criteria. In three network meta-analyses (65–67), the experimental groups consisted of patients receiving adjuvant therapy (single or combined), and these studies comprehensively compared the benefits and safety of various treatment methods for patients with HCC and PVTT. In another study (68), only seven of the included articles focused on comparative studies of adjuvant therapy, which was administered either before or after surgery.
By contrast, the present study strictly limited the experimental and control groups to neoadjuvant therapy plus surgery vs. priority surgery, providing novel insights into the comparative prognosis and safety of these two approaches, an aspect not addressed in previous studies. For patients with HCC and PVTT, only a select few undergo radical surgery; however, the findings of the present study suggested that surgery following neoadjuvant therapy yielded superior outcomes compared with priority surgery. This expands the candidate pool for radical surgery, representing a significant and core contribution of the present research. Neoadjuvant therapy combined with surgery not only improved patient survival rates and reduced recurrence but was also safe. Additionally, the present study conducted a subgroup analysis based on the type of neoadjuvant therapy, which has not been performed in similar studies.
The classification of PVTT influences the outcomes of neoadjuvant therapy (69), and future studies should take this into consideration. However, several limitations of the present study warrant emphasis. Firstly, the number of included studies was limited, which may affect the robustness of the conclusions and precluded the use of a suitable network meta-analysis. Secondly, while the classification of PVTT is crucial in determining treatment strategies and outcomes, the lack of original data hindered the ability to perform subgroup analyses based on PVTT classifications. Thirdly, most of the included studies were observational, and there were substantial differences in treatment methods, contributing to the heterogeneity in statistical results and potentially weakening the reliability of the findings. Beyond treatment heterogeneity, variations in patient populations also introduce unavoidable heterogeneity. The disease characteristics of HCC differ between patients in Asia and Western regions (70), and since the present study population predominantly comprised East Asian individuals, the generalizability of these findings to a global context is limited. The development of neoadjuvant therapies in HCC is progressing rapidly, and the present study will be updated as new relevant literature is published.
The present meta-analysis evaluated the long-term prognosis and safety of neoadjuvant therapy in patients with HCC complicated by PVTT. The findings suggested that neoadjuvant therapy not only offered superior efficacy compared with priority surgery, but also demonstrated a favorable safety profile. However, these preliminary conclusions require further validation through larger, multicenter RCTs to improve their reliability and generalizability across diverse patient populations.