Hepatocellular carcinoma (HCC) is the most common type of hepatic malignant tumor in the world, with a high mortality rate. Approximately 10% to 40% of HCC patients show macrovascular invasion at the time of initial diagnosis (1). There are two distinct types of macrovascular invasion: portal vein tumor thrombosis (PVTT) and hepatic vein tumor thrombosis (HVTT) (2). It has been reported that the incidence of macrovascular invasion is more than doubled in patients with hepatocellular carcinoma compared with cirrhotic patients without malignancy(24.4% vs 11.4%; p = 0.05) (3). HCC with macrovascular invasion is listed in advanced stage by the American Association for the Study of Liver Diseases/Barcelona-Clinic Liver Cancer (AASLD/BCLC) staging system and treatment recommendations. However, there is no consensus on the diagnosis and treatment criteria for hepatocellular carcinoma combined with PVTT/HVTT, which brings great difficulties to the selection of treatment regimens and the prediction of treatment effects.

In recent years, hepatectomy, local interventional therapy, radiotherapy, molecular targeted therapy and immunotherapy have been widely used, which is of great significance for the quality of life and prolonging survival time of some patients. Currently, Sorafenib or Lenvatinib are recommended as first-line TKI treatment for HCC combined with PVTT (4). Several studies have shown that the combination of TKI and ICI can significantly improve the survival benefits of patients with advanced HCC (5–7), so combination therapy has become the latest trend in the treatment of advanced HCC. These studies have also shown that not all HCC patients can benefit from the combination therapy, one of the reasons is likely to be some patients with primary immune resistance.

Transarterial chemoembolization (TACE) and hepatic artery infusion chemotherapy (HAIC) have become the most commonly used palliative treatments for patients with unresectable HCC and are no longer considered an absolute contraindication for patients with PVTT/HVTT- HCC (8). Moreover, advanced radiotherapy techniques have yielded encouraging results in HCC patients with PVTT/HVTT (9, 10). For all that, current studies on chemotherapy or radiotherapy in patients with concomitant PVTT/HVTT-HCC are limited to single-center, small studies, so our study aimed to use the national-scale SEER database for a retrospective analysis to investigate the effects of chemotherapy and radiotherapy regimens on the survival of patients with PVTT/HVTT- HCC.

Macrovascular invasion has been recognized as one of the most important adverse prognostic factors affecting the long-term survival of patients with HCC (11). And most patients have already lost the chance of radical surgery by the time of diagnosis. Chemotherapy and radiotherapy techniques are now increasingly used for patients with unresectable PVTT/HVTT-HCC. However, there is a lack of multicenter, large-scale studies on the optimal choice of chemotherapy combined with radiotherapy versus mono-therapy, which makes it difficult to make clinical treatment decisions.

Traditionally, HVTT-HCC and PVTT-HCC have been treated with approximately the same strategy. Untreated patients with concomitant macrovascular invasion have a survival rate of just 2-4 months (12). In this study, when analysing all patients, both before and after PSM matching, it was found that patients who did not receive therapy had an OS of 2 months and a CSS of 3 months, while those who received chemotherapy and/or radiotherapy had an OS of 6 months and a CSS of 7 months, showing that chemotherapy and radiotherapy can significantly improve patients’ survival.

At present, chemotherapy modalities mainly include traditional systemic chemotherapy and hepatic artery infusion chemotherapy (HAIC). Traditional systemic chemotherapy is limited in clinical application due to severe systemic adverse reactions, while HAIC is widely used because it can carry anti-cancer drugs directly to the tumor site and reduce systemic adverse reactions. HAIC was first proposed by Japanese researchers and recommended by Japanese guidelines as the standard treatment for PVTT-HCC. Most of these HAIC-based studies focused on patients with PVTT-HCC, and 5-fluorouracil and systemic interferon or cisplatin were reported to be the most effective combination chemotherapy for PVTT-HCC with a median survival time of approximately 7 months (13, 14). The results of a phase III clinical study conducted by Lyu et al. showed that the objective response rate of the FOLFOX⁃HAIC protocol for the treatment of advanced HCC with high tumor burden (52.3% of patients had portal vein tumor thrombus) reached 31.5% (RECIST criteria), and 12.3% of the patients were successfully converted (15). Wu et al. investigated the effect of TACE combined HAIC versus TACE alone on patient survival and showed that the TACE combined HAIC had a longer median OS than the TACE group (P < 0.05) (16). Ahn YE et al. compared the effect of sorafenib and HAIC on survival in patients with PVTT and found no significant difference in OS (6.4 vs. 10.0 months, P = 0.139), but HAIC had a longer time to tumor progression (TTP) (6.2 vs. 2.1 months, P = 0.006) and higher disease control rate (DCR) (76% vs 37%, P = 0.001) (17).

Conventional radiotherapy is not suitable for HCC because the liver is a radiation-sensitive viscus and the lack of precise irradiation of the target area usually involves the surrounding normal liver tissue, leading to an increased incidence of radiation liver disease. However, with the advent of new radiation technologies such as 3-Dimensional Conformal Radiation Therapy(3D-CRT), Stereotactic Body Radiation Therapy (SBRT), and proton beam therapy (PBT), the clinical application of external radiotherapy for liver cancer is becoming more widespread. Previous studies reported that the OS of patients with PVTT/HVTT-HCC could be appropriately prolonged from 6 to 18 months regardless of radiotherapy modality (18–21). A retrospective study found that PBT improved local control and survival with PVTT-HCC, with a median progression-free survival time (PFS) of 2.3 years. Two of the patients lived 4.3 and 6.4 years, respectively, without relapse and severe adverse reactions (22). Shui et al. reported 70 patients with PVTT-HCC treated with SBRT. The median follow-up period was 9.5 months (range 1.0-21.0 months). Median survival time was 10.0 months (95%CI, 7.7-12.3 months) and overall survival rate (OS) at 6 and 12 months was 67.3% and 40.0%, Patients who respond well to radiation generally have better survival (23). The results of this study also found that either chemotherapy or radiotherapy prolonged patients’ OS from 2 to 6 months and CSS from 3 to 7 months, which is consistent with the results of previous studies.

For the treatment strategy of chemotherapy combined with radiotherapy, previous single-center, small sample size studies have found that HAIC combined with radiotherapy was effective in extending the OS of patients with PVTT from 7.5 months to 12 months (24–26). In a study with only a small sample size, the treatment efficiency of HVTT could be increased from 37% to 79% when HAIC was combined with radiotherapy (27). A Japanese study showed that surgical resection was safe and long-term beneficial for patients with PVTT after downstaging treatment though chemotherapy combined radiotherapy (28). In our study, chemotherapy combined with radiotherapy was found to be effective in prolonging patients’ OS (10 vs. 5 months, P < 0.001) and CSS (10 vs. 6 months, P < 0.001) compared to mono-therapy. It can be seen that this combined therapy strategy can better prolong the OS and CSS of patients and benefit them.

Next, we explored the prognostic factors affecting patients with concomitant PVTT/HVTT. In the survival analysis of all patients, we found that AFP, tumor size, N and M stage, and therapy strategy were independently associated with patient OS. To further explore the impact of different treatment strategies (COR and CAR) on patient survival. We used Cox proportional hazards model and competing-risk model to analyze OS and CSS in the whole treatment group and in each group, and found that AFP and distant metastasis were always the main independent factors affecting OS and CSS regardless of therapy strategy, which is consistent with previous findings (19, 25, 29, 30).

In 2017, based on the CheckMate 040 study, the FDA approved the PD-1 inhibitor (Nivolumab) for advanced HCC patients who did not respond to sorafenib therapy, marking the arrival of the era of HCC immunotherapy (31). Subsequently, the combination of PD-L1 inhibitor (atezolizumab) and vascular endothelial growth factor (VEGF) inhibitor (bevacizumab) proved to be the first drug with significantly better efficacy than sorafenib in more than a decade, ushering in a new era of combination therapy for HCC immunotherapy (5). At present, the main program of combined therapy with ICI is CTLA-4 inhibitor combined with PD-1/PD-L1 inhibitor. The current second-line regimen of nabuliumab in combination with CTLA-4 inhibitor (ipilimumab) is the best option, based on results from Cohort 4 in CheckMate 040. The combination regimen with the highest dose of ipilimumab showed the best efficacy, but also a higher incidence of adverse reactions (32).

The latest results of KEYNOTE-524, a phase I single-arm trial, showed that the mOS, mPFS and ORR of Lenvatinib combined with Pembrolizumab for advanced HCC were 22 months, 8.6 months and 36.0%, this combination regimen has been granted by the US FDA as a breakthrough therapy for the first-line treatment of unresectable HCC (33). In recent years, a number of ICI-based combination therapies have achieved good results in clinical trials, benefiting more patients with end-stage HCC, especially those with PVTT/HVTT.

Obviously, our study also has several limitations. First of all, this study is a retrospective study, and selection bias caused by incomplete data is inevitable. Although we adopted PSM to avoid selection bias, potential confounding factors cannot be ruled out. Second, because the SEER database only records yes or no for chemotherapy and radiotherapy, the lack of detailed information on chemotherapy and radiotherapy makes it difficult to conduct further studies, which also bodes well for more precise studies of the impact of each treatment on patient benefit. Undeniably, with the development of targeted and immunotherapy in recent years, the treatment of HCC has undergone earth-changing changes, greatly improving the survival of patients with advanced HCC. Unfortunately, the SEER database did not record information of targeted or immunotherapy for patients from 2004 to 2015. So we put it up in limitation; Finally, portal vein tumor thrombus and hepatic vein tumor thrombus were uniformly recorded in the SEER database as macrovascular invasion, which could not be studied separately. Even so, we demonstrated the benefit of radiotherapy combined with chemotherapy for long-term survival in PVTT/HVTT-HCC patients using a country-scale database.

It is recommended that surgically unresectable advanced PVTT/HVTT-HCC be treated with radiotherapy combined with chemotherapy. Positive AFP and distant metastasis are risk factors affecting patients’ long-term survival, and it is suggestive to actively treat these patients to prolong the survival of patients.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. Written informed consent was not obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

XQ, JC, and HC contributed to the conception and design of the study. JY, CX, RL, JX, JZha, XS, and TL collected the details of the patients and extracted and analyzed the data. XQ, JC, and HC drafted the manuscript. JZhe, YZ, and YY contributed with a critical revision of the manuscript. All authors contributed to the article and approved the submitted version.