Abstract
Background
The efficacy of radiotherapy (RT) combined with targeted therapy and immunotherapy in treating hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT) is still unclear. This study investigated the efficacy and safety of RT combined with targeted therapy and immunotherapy in HCC with PVTT.
Materials and Methods
Seventy-two patients with HCC with PVTT treated with tyrosine kinase inhibitor (TKI) plus programmed cell death protein-1 (PD-1) inhibitor with or without RT from December 2019 to December 2023 were included. After propensity score matching (PSM) for adjusting baseline differences, 32 pairs were identified in RT + TKI + PD-1 group (n = 32) and TKI + PD-1 group (n = 32). Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs).
Results
Median OS (mOS) in RT + TKI + PD-1 group was significantly longer than TKI + PD-1 group (15.6 vs. 8.2 months, P = .008). Median PFS (mPFS) in RT + TKI + PD-1 group was dramatically longer than TKI + PD-1 group (8.1 vs. 5.2 months, P = .011). Patients in TKI + PD-1 + RT group showed favorable ORR and DCR compared with TKI + PD-1 group (78.1% vs. 56.3%, P = .055; 93.8% vs. 81.3%, P = .128). Subgroup analysis demonstrated a remarkable OS and PFS benefit with TKI + PD-1 + RT for patients with main PVTT (type III/IV) and those of Child-Pugh class A. Multivariate analysis confirmed RT + TKI + PD-1 as an independent prognostic factor for longer OS (HR 0.391, P = .024) and longer PFS (HR 0.487, P = .013), with no mortality or severe TRAEs.
Conclusion
RT combined with TKI and PD-1 inhibitor could significantly improve mOS and mPFS without inducing severe TRAEs or mortality.
Keywords: hepatocellular carcinoma, portal vein tumor thrombosis, radiotherapy, targeted therapy, immunotherapy, efficacy
This study investigated the efficacy and safety of radiotherapy combined with targeted therapy and immunotherapy in treating hepatocellular carcinoma and portal vein tumor thrombosis.
Implications for practice.
Portal vein tumor thrombosis (PVTT) has been well acknowledged to be associated with poor prognosis of hepatocellular carcinoma (HCC), with a median survival period of less than 3 months. Systemic therapy may not be sufficient for advanced patients with HCC with PVTT. In this study, radiotherapy (RT) combined with the targeted therapy and immunotherapy was used to treat the patients with HCC with PVTT. To assess the outcome of this combination therapy in a real-world setting, we retrospectively included a cohort of 72 patients with HCC with PVTT. Our data showed that RT combined with TKI and PD-1 inhibitor could significantly improve mOS and mPFS without inducing severe TRAEs or mortality.
Introduction
Hepatocellular carcinoma (HCC), the predominant subtype of primary liver cancer, tends to invade the portal vein system, which eventually leads to portal vein tumor thrombosis (PVTT).1,2 Generally, PVTT has been well acknowledged to be associated with poor prognosis of HCC, with a median survival period of approximately 2.7 months without treatment.3
Atezolizumab plus bevacizumab has been approved as the first-line treatment regimen for advanced HCC based on the IMbrave150 trial, with a median overall survival (mOS) of 19.2 months.4 Subsequently, trials such as CARES-310,5 LEAP-002,6 ORIENT-32,7 and COSMIC-312,8 with various combinations of targeted agents and immunotherapy, have further expanded the treatment options for advanced HCC. However, subgroup analysis of the IMbrave150 study revealed that patients with Vp4-type PVTT (Cheng’s classification system: type III) had a significantly shorter mOS of 7.6 months, similar to the sorafenib group.9 This implies that systemic therapy alone may not be sufficient for advanced patients with HCC with PVTT, and further attention should be paid to the development of other treatment regimens.
HCC with PVTT was classified into IIIA stage based on China liver cancer (CNLC) staging system, and its treatment has been highly relied on transarterial chemoembolization (TACE), systematic therapy and radiotherapy (RT).10 To date, attempts have been made to investigate the feasibility of RT combing with targeted therapy and immunotherapy in treating HCC with PVTT, which is highly relied on the rationale that RT could improve the treatment outcome of immunotherapy plus bevacizumab.11 Specifically, RT is reported to yield satisfactory local control on PVTT,12-14 as PVTT from HCC is sensitive to RT.15 Moreover, radiation can promote the infiltration of cytotoxic T cells, upregulate the programmed cell death ligand-1 (PD-L1) expression, and enhance the immune checkpoint blockade (ICB).16,17 Concurrently, anti-angiogenic agents can synergize to the RT and ICB by normalizing tumor vasculature and facilitating immune cell infiltration.18 To assess the outcome of this combination therapy in a real-world setting, we retrospectively included a cohort of 72 patients with HCC with PVTT. Then we compared the outcome of patients received tyrosine kinase inhibitor (TKI) plus programmed cell death protein-1 (PD-1) inhibitor with or without RT.
Materials and Methods
Study population
A total of 72 HCC patients with PVTT treated with TKI plus PD-1 inhibitor with or without RT from December 2019 to December 2023 were included in this retrospective analysis. The study flowchart was shown in Supplementary Figure S1. Patients were divided into TKI + PD-1 + RT group (n = 32) and TKI + PD-1 group (n = 40) based on the treatment regimen. HCC was diagnosed clinically or pathologically according to the diagnostic criteria of the American Liver Association. PVTT classification was performed based on Cheng’s classification system that has been widely adopted in China.19,20 According to the tumor thrombus involvement in the portal venous system, PVTT was categorized into: type I involved the invasion of secondary or higher-order portal vein branches; type II involved invasion of the left or right portal vein branches; type III involved invasion of the main portal vein; and type IV involved invasion of the superior mesenteric vein.
Inclusion criteria were: (a) age ≥ 18 years, (b) confirmed diagnosis of HCC with PVTT by histopathological or clinical examinations, (c) liver function classified as Child-Pugh A or B, (d) absence of refractory ascites or hepatic encephalopathy, (e) those with Eastern Cooperative Oncology Group (ECOG) performance status scales of 0 or 1, (f) receiving at least one cycle of targeted therapy plus immunotherapy. Exclusion criteria were: (a) those with a history of concurrent malignancies, (b) liver function classified as Child-Pugh C, (c) those with refractory ascites or hepatic encephalopathy, (d) ECOG performance status scale of 2 or more, (e) with contraindications to RT, targeted therapy, or immunotherapy, (f) received HCC-related treatment within 4 weeks or during the study period. This retrospective study was approved by the Institutional Review Board (No. AF-IRB-032-06).
Treatment protocol
RT was given within the first week of initiating TKI and PD-1 inhibitor. The target area was depicted by experienced radiation oncologists under the guidance of CT. The gross tumor volume (GTV) included the portal vein filling defect and adjacent primary liver lesions. The clinical target volume (CTV) was generated by expanding the GTV by 5 mm, and the planning target volume (PTV) was created by further expanding the CTV by 5 mm margins. Radiation prescription doses and fractionation patterns were determined based on tumor location, volume, and constraints of surrounding critical organs.21 Radiotherapy methods and radiotherapy doses were given to each individual based on the tumor size, scale, and the proximity of intrahepatic lesions. A total of 12 patients received a single dose of 1.8-2.5 Gy, 10 patients received a single dose of 3-5 Gy, and 10 patients received a single dose of 6-8 Gy. The bioequivalent dose was calculated according to the linear quadratic (LQ) formula α/β=10 Gy, ranging from 53.1 to 86.4 Gy. The 10 patients with a single dose of 6-8 Gy received stereotactic body radiation therapy (SBRT), which was verified by 4D-CT, abdominal compression, and image guidance; the remaining patients received intensity-modulated radiation therapy (IMRT), which was verified by cone beam computer tomography (CBCT). The biologic equivalent dose (BED) ranged from 53.1 to 86.4 Gy (α/β=10 Gy).
For the immunotherapy, Camrelizumab or Sintilimab was given via intravenous injection (200 mg, day 1), lasting for 3 weeks. Patients received targeted therapy were given oral administration of Lenvatinib (q.d., 12 mg/60 kg or more; 8 mg/<60 kg), Apatinib (q.d., 250 mg), Sorafenib (b.i.d., 400 mg), or Regorafenib (q.d., 160 mg), respectively. We used 3 weeks as a treatment cycle, and the overall treatment time for patients was 3 to 24 months, with 4 to 32 cycles. No drug reduction was noticed in the immunotherapy.
Study endpoints
The primary endpoints were OS and progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs). Patient response was assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria.
Statistical analysis
Propensity score matching (PSM) analysis was performed to reduce selection bias due to confounding factors. Matched covariates included gender, age, tumor number, tumor size, lymphatic metastasis, extrahepatic metastasis, PVTT classification, ALBI grade, Child-Pugh grade, ECOG score, AFP level, and HBV infection status. Categorical variables were compared using Chi-square test or Fisher’s exact test. Kaplan-Meier method and log-rank test were used to assess OS and PFS. Univariate and multivariate Cox regression analyses were conducted to identify independent prognostic factors. Subgroup analyses were performed for patients with main/non-main PVTT or those of Child-Pugh class A/B. Statistical analyses were performed using SPSS 27.0 and Rstudio 4.2.2, with 2-sided P < .05 considered to be statistically significant.
Results
Patient characteristics
Initially, we included 72 patients in this study, which consisted of 32 received TKI + PD-1 + RT and 40 received TKI + PD-1. Patients with termination of drugs due to adverse events were excluded from this study. Three patients in targeted therapy reduced lenvatinib from 12 mg/day to 8 mg/day due to adverse reactions. After PSM, 32 matched pairs were identified with no significant differences in baseline characteristics (Table 1).
Table 1.
Baseline characteristics of patients in the entire and propensity score matching cohorts.
| Variable | Entire cohort | PSM cohort | ||||
|---|---|---|---|---|---|---|
| TKI + PD-1 + RT | TKI + PD-1 | P value | TKI + PD-1 + RT | TKI + PD-1 | P value | |
| Patients | 32 | 40 | 32 | 32 | ||
| Male sex | 28 (87.5) | 37 (92.5) | .756 | 28 (87.5) | 29(90.6) | 1 |
| Age ≥ 60 years | 10 (31.2) | 13 (32.5) | .910 | 10 (31.2) | 11(34.4) | .790 |
| Child-Pugh score | .958 | .939 | ||||
| 5 | 8 (25) | 8 (20) | 8 (25) | 8(25) | ||
| 6 | 10 (31.2) | 11 (27.5) | 10 (31.2) | 8(25) | ||
| 7 | 6 (18.8) | 8 (20) | 6 (18.8) | 8(25) | ||
| 8 | 5 (15.6) | 8 (20) | 5 (15.6) | 6(18.8) | ||
| 9 | 3 (9.4) | 5 (12.5) | 3 (9.4) | 2(6.2) | ||
| ALBI grade | .044 | .185 | ||||
| Grade 1 | 8 (25) | 3 (7.5) | 8 (25) | 3 (9.4) | ||
| Grade 2 | 24 (75) | 34 (85) | 24 (75) | 29 (90.6) | ||
| Grade 3 | 0 (0) | 3 (7.5) | 0 (0) | 0 (0) | ||
| Number of tumors ≥ 2 | 16 (50) | 24 (60) | .396 | 16 (50) | 18 (56.2) | .616 |
| Tumor diameter ≥ 5cm | 11 (34.4) | 24 (60) | .031 | 11 (34.4) | 18 (56.2) | .079 |
| Serum AFP ≥ 400ng/ml | 10 (31.2) | 23 (57.5) | .026 | 10 (31.2) | 16 (50) | .127 |
| Cheng’s type of PVTT | .882 | .872 | ||||
| II | 12 (37.5) | 16 (40) | 12 (37.5) | 13 (40.6) | ||
| III | 13 (40.6) | 14 (35) | 13 (40.6) | 11 (34.4) | ||
| IV | 7 (21.9) | 10 (25) | 7 (21.9) | 8 (25) | ||
| HBV | 25 (78.1) | 32 (80) | .846 | 25 (78.1) | 24 (75) | .768 |
| Lymph node metastasis | 5 (15.6) | 3 (7.5) | .476 | 5 (15.6) | 3 (9.4) | .705 |
| Extrahepatic metastases | 7 (21.9) | 13 (32.5) | .317 | 7 (21.9) | 9 (28.1) | .564 |
| ECOG | .476 | .606 | ||||
| 0 | 19 (59.4) | 27 (67.5) | 19 (59.4) | 21 (65.6) | ||
| 1 | 13 (40.6) | 13 (32.5) | 13 (40.6) | 11 (34.4) | ||
Abbreviations: AFP, alpha fetoprotein; ALBI, Albumin-Bilirubin; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; PSM, propensity score matching.
Survival outcome
In the PSM cohort, the mOS in the TKI + PD-1 + RT group was significantly longer than the TKI + PD-1 group (15.6 vs. 8.2 months, P = .008, Figure 1A). The median PFS (mPFS) was also significantly longer in TKI + PD-1 + RT group compared with that of TKI + PD-1 group (8.1 vs. 5.2 months, P = .011, Figure 1B).
Figure 1.
Kaplan-Meier curves for OS (A) and PFS (B) in the propensity score matched cohort. In the PSM cohort, the mOS and mPFS of the TKI + PD-1 + RT group were significantly longer than those of TKI + PD-1 group (15.6 months vs 8.23 months, P = .008; 8.13 months vs. 5.20 months, P = .011). Abbreviations: OS, overall survival; PFS, progression-free survival; PSM, propensity score matching.
Treatment response
In the PSM cohort, neither TKI + PD-1 + RT group nor TKI + PD-1 group achieved complete response (CR). TKI + PD-1 + RT group showed favorable ORR and DCR, although the differences were not statistically significant compared with TKI + PD-1 group (ORR: 78.1% vs. 56.3%, P = .055; DCR: 93.8% vs. 81.3%, P = .128; Table 2).
Table 2.
Tumor response assessed by mRECIST in the propensity score matching cohort.
| All patients (n = 64) |
TKI + PD-1 + RT (n = 32) |
TKI + PD-1 (n = 32) |
P | |
|---|---|---|---|---|
| CR | 0 | 0 | 0 | |
| PR | 43 (67.19) | 25 (78.125) | 18 (56.25) | |
| SD | 13 (20.31) | 5 (15.625) | 8 (25) | |
| PD | 8 (12.5) | 2 (6.25) | 6 (18.75) | |
| ORR | 43 (67.19) | 25 (78.125) | 18 (56.25) | .055 |
| DCR | 56 (87.5) | 30 (93.75) | 26 (81.25) | .128 |
Prognostic factors for OS and PFS
Multivariate analysis indicated that TKI + PD-1 + RT was associated with a longer OS (HR 0.391, 95% CI 0.173-0.882, P = .024) and longer PFS (HR 0.487, 95% CI 0.276-0.857, P = .013). Independent factors associated with shorter OS were Child-Pugh class (HR 3.193, 95% CI 1.220-8.355, P = .018), tumor size (HR 2.649, 95% CI 1.017-6.902, P = .046), and PVTT type (P = .032). Independent factors for shorter PFS included Child-Pugh class (HR 2.137, 95% CI 1.158-3.943, P = .015), tumor number (HR 1.827, 95% CI 1.014-3.291, P = .045), tumor size (HR 2.128, 95% CI 1.149-3.942, P = .016), and the presence of extrahepatic metastasis (HR 2.106, 95% CI 1.092-4.062, P = .026; Figures 2 and 3).
Figure 2.
Forest plot of univariate (A) and multivariate (B) analyses for OS. Multivariate regression analysis showed that RT (HR: 0.391, P = .024), tumor size (HR: 2.649, P = .046), PVTT type (P = .032), Child-Pugh class (HR: 3.193, P = .018) were independent risk factors for OS in HCC with PVTT.
Figure 3.
Forest plot of univariate (A) and multivariate (B) analyses for PFS. Multivariate regression analysis showed that RT (HR: 0.487, P = .013), Child-Pugh class (HR: 2.137, P = .015), tumor number (HR: 1.827, P = .045), tumor size (HR: 2.128, P = .016), extrahepatic metastasis (HR: 2.106, P = .026) were independent risk factors for PFS in HCC with PVTT.
Subgroup analysis
Patients with main PVTT (type III/IV) were benefited from TKI + PD-1 + RT in OS and PFS compared with those received TKI + PD-1 (mOS: 15.6 vs. 7.1 months, P = .023; mPFS: 6.1 vs. 4.8 months, P = .045; Figure 4A and B). Among patients with type II tumor thrombus not involving the main portal vein, the mOS and mPFS in the TKI + PD-1 + RT group were both superior to those of TKI + PD-1 group, although showing no statistical differences. Patients of Child-Pugh class A received TKI + PD-1 + RT showed favorable OS and PFS compared with those received TKI + PD-1 (mOS: 18.3 vs. 9.7 months, P = .032; mPFS: 8.3 vs. 6.4 months, P = .032; Figure 5A and B). In Child class B patients, the mOS and mPFS of the 2 groups showed no statistical differences, although the OS and PFS of TKI + PD-1 + RT group tended to be longer compared with those of the TKI + PD-1 group.
Figure 4.
Subgroup analysis of OS (A) and PFS (B) in patients with main PVTT (type III/IV). The mOS and mPFS in the main PVTT (type III/IV) from the patients of the TKI + PD-1 + RT group were dramatically longer than those of the TKI + PD-1 group (15.6 months vs. 7.1 months, P = .023; 6.1 months vs. 4.83 months, P = .045). Abbreviation: PVTT, portal vein tumor thrombosis.
Figure 5.
Subgroup analysis of OS (A) and PFS (B) in patients with different Child-Pugh classes. The mOS and mPFS in the patients with Child-Pugh class A were significantly longer in TKI + PD-1 + RT group than those of TKI + PD-1 group (18.33 months vs. 9.67 months, P = .032; 8.33 months vs. 6.40 months, P = .032).
Safety and TRAEs
For the TRAEs, the majority of cases showed grades 1 and 2 AEs, with leukopenia as the most common TRAEs presenting in 13 cases (39.1%), followed by decreased appetite (25%), elevated AST (20.3%), elevated ALT (18.8%), and fatigue (18.8%). No grade 4 TRAEs or treatment-related deaths were reported in this study (Table 3).
Table 3.
Treatment-related adverse events in the propensity score matching cohort.
| Adverse events | All patients (n = 64) |
TKI + PD-1 + RT (n = 32) |
TKI + PD-1 (n = 32) |
|||
|---|---|---|---|---|---|---|
| Grades 1-2 | Grades 3 | Grades 1-2 | Grades 3 | Grades 1-2 | Grades 3 | |
| Fatigue | 12 (18.8) | 1 (1.6) | 7(21.9) | 0 | 5 (15.6) | 1(3.1) |
| Fever | 3 (4.7) | 0 | 2 (6.3) | 0 | 1 (3.1) | 0 |
| Skin eruptio | 8 (12.5) | 1 (1.6) | 5 (15.6) | 1(3.1) | 3 (9.4) | 0 |
| Pruritus | 4 (6.3) | 0 | 2 (6.3) | 0 | 2 (6.3) | 0 |
| Diarrhea | 9 (14.1) | 0 | 6 (18.8) | 0 | 3 (4.7) | 0 |
| Decreased appetite | 16 (25) | 3 (4.7) | 9 (28.1) | 2 (6.3) | 7 (21.9) | 1(3.1) |
| Nausea and vomiting | 8 (12.5) | 2 (3.1) | 5 (15.6) | 1(3.1) | 3 (9.4) | 1(3.1) |
| Anemia | 7 (10.9) | 0 | 4 (12.5) | 0 | 3 (9.4) | 0 |
| Leukopenia | 25 (39.1) | 5 (7.8) | 13 (40.6) | 3 (9.4) | 12 (37.5) | 2 (6.3) |
| Thrombocytopenia | 22 (34.4) | 3 (4.7) | 12 (37.5) | 1(3.1) | 10 (31.3) | 2 (6.3) |
| AST | 13 (20.3) | 3 (4.7) | 7 (21.9) | 2 (6.3) | 6 (18.8) | 1(3.1) |
| ALT | 12 (18.8) | 1 (1.6) | 7 (21.9) | 1(3.1) | 5 (15.6) | 0 |
| Hypertension | 2 (3.1) | 0 | 1 (3.1) | 0 | 1 (3.1) | 0 |
| Hypothyroidism | 3 (4.7) | 0 | 1 (3.1) | 0 | 2 (6.3) | 0 |
Discussion
The prognosis of HCC with PVTT is extremely poor with mOS of less than 3 months. Previous data showed that RT could extend the survival time of HCC with PVTT.22,23 According to the NCCN Clinical Guidelines and the Chinese Expert Consensus on Multidisciplinary Diagnosis and Treatment of HCC with PVTT,24,25 TACE, RT and systemic treatment are recommended for treating these patients. Unfortunately, the treatment outcome of patients with HCC and PVTT is not satisfactory after sorafenib therapy with mOS of approximately 4.8 months, which was significantly lower than the patients underwent RT with mOS of 10.9 months (P = .025).26 In this retrospective study, we investigated the efficacy and safety of RT combined with targeted therapy and immunotherapy (TKI + PD-1 + RT) for treating HCC with PVTT. PSM was used to minimize selection bias due to confounding factors. Our findings demonstrated that the addition of RT to targeted therapy and immunotherapy significantly prolonged the mOS and mPFS in these patients compared to those underwent TKI and PD-1. Additionally, RT combined with targeted therapy and immunotherapy showed an acceptable safety profile, with no grade 4 TRAEs or treatment-related deaths.
In this study, the favorable survival time after the addition of RT to targeted therapy and immunotherapy can be attributed to the local control effects of RT on PVTT. First, the PVTT from HCC was sensitive to RT with reported response rates of 40% to 57.7%,27,28 which was superior to the other local treatments (eg, TACE) in controlling main PVTT.12-14 In line with this, our subgroup analysis further corroborated significant improvements in OS and PFS among patients with main PVTT (type III/IV) who received TKI + PD-1 + RT. There were indeed synergistic interactions between RT, targeted therapy, and immunotherapy, and here were the potential explanations. Firstly, ionizing radiation triggers immunogenic cell death. The mechanism is that radiotherapy stimulates the recruitment and differentiation of T lymphocytes, promoting T lymphocytes to recognize and effectively attack tumor cells.29 Other studies have shown that radiation therapy can upregulate tumor MHC-I expression, thereby enabling better presentation of tumor-specific antigens and enhancing tumor visibility to cytotoxic T cells.30,31 Secondly, radiation-induced DNA damage activates innate and adaptive immune responses through the cGAS/STING pathway and upregulates the expression of the type I interferon pathway, promoting the anti-cancer activity of T cells.32 Thirdly, radiotherapy can regulate the tumor microenvironment and increase the levels of chemokines CXCL10 and CXCL16 in the tumor microenvironment,33 which promote the migration of killer T cells to tumors. All these are associated with the synergistic effects of radiotherapy and immunotherapy. In addition, anti-angiogenic drugs can normalize the tumor vascular system. On one hand, it could promote the infiltration of cytotoxic immune cells and induce the mutual benefits with immunotherapy. On the other hand, it can enrich hypoxic tumor cells with oxygen to a certain extent, improve the efficacy of radiotherapy, and induce mutual benefits with radiotherapy.33 In summary, radiotherapy, immunotherapy, and targeted therapy enhance each other, which becomes the theoretical basis of our combined treatment. Indeed, many clinical trials have confirmed this. In a previous study,34 the authors compared the efficacy of targeted therapy/immunotherapy combined with or without radiotherapy on advanced HCC, in which the triple therapy group had a significant advantage in both mOS (18.5 vs 12.6 months, P = .043) and mPFS (8.7 vs 5.4 months, P = .013). In a prospective study35 compared the efficacy of carrelizumab plus apatinib with or without SBRT in the treatment of HCC with PVTT. The mOS of the 2 groups were 12.7 months (95% CI, 10.2-NA) and 8.6 months (95% CI, 5.6-NA), respectively. The mPFS was 4.6 months (95% CI, 3.3-7.0) and 2.5 months (95% CI, 2.0-7.6), respectively. The DCR and ORR of the combined radiotherapy group were 72.5% and 47.5%, respectively.
There are indeed not many attempts to treat HCC with PVTT based on radiotherapy combined with systemic therapy. A multicenter single-arm prospective study by Wang et al36 reported 30 patients with inoperable liver cancer and PVTT who received IMRT combined with targeted immunotherapy (atezolizumab combined with bevacizumab) with a mOS of 9.8 months, an mPFS of 8.0 months, and an ORR of 76.6%. Both mPFS and ORR were similar to our results, but mOS was slightly shorter than our results. The reason for this, according to our analysis of the independent influencing factors of OS, may be that the tumor size of the patients they enrolled was significantly higher than that of our study. A prospective study by Hu et al35 compared the efficacy of carrelizumab plus apatinib with or without SBRT in the treatment of HCC with PVTT. The mOS of the 2 groups was 12.7 months (95% CI, 10.2-NA) and 8.6 months (95% CI, 5.6-NA), respectively. The mPFS was 4.6 months (95% CI, 3.3-7.0) and 2.5 months (95% CI, 2.0-7.6), respectively. The DCR and ORR of the combined radiotherapy group were 72.5% and 47.5%, respectively. The conclusion was that SBRT + carrelizumab + apatinib showed clinical benefit in patients with HCC with PVTT. Although the mPFS in Hu’s study was significantly shorter than our results, this was due to the difference in the baseline levels of the patients in the 2 studies. The patients in their study had larger and more numerous tumors and more extrahepatic metastases, therefore, they were not comparable. However, these differences led to differences in mPFS of patients and also verified the accuracy of our analysis results of independent influencing factors of mPFS. There were statistical differences in the treatment outcomes, which may be related to the patient characteristics and treatment regimens; however, all these supported the feasibility of RT combined with targeted therapy and immunotherapy for treating HCC with PVTT. In this study, compared with the TKI + PD-1 group, there was significant increase in the mOS and mPFS in the TKI + PD-1 + RT group, which validated the efficacy of the combination of RT with targeted therapy and immunotherapy for treating HCC with PVTT.
In our subgroup analysis, the OS and PFS of Child-Pugh class A patients after TKI + PD-1 + RT were significantly prolonged compared with the TKI + PD-1 group. Similarly, a retrospective study in Japan in 2016 included 6474 patients with HCC with PVTT showed that the mOS of Child class A patients who underwent liver resection was significantly longer than that of patients without liver resection (2.8 years vs. 1.1 years).37 All these indicate that liver function is very important for the selection of treatment options for patients with HCC. For patients with cirrhosis, the time window for liver function at Child A level is very short. Therefore, targeted therapy and immunotherapy combined with RT should be used as soon as possible to achieve greater survival benefits for patients.
Not many studies have reported the TRAEs of RT combined with targeted and immunotherapy due to rarity of studies. Wang et al reported that the most common TRAEs were neutropenia, and the most common grade 3/4 was hypertension.36 Hu et al reported that the most common TRAEs of such regimen were hypertension, hand-foot syndrome, and leukopenia, together with grade ≥3 AEs in 13 (21.7%) patients.35 In our study, the majority of TRAEs were of grades 1/2, with leukopenia, thrombocytopenia, decreased appetite, elevated AST/ALT, and fatigue being the most common. Importantly, no grade 4 adverse events or treatment-related deaths occurred, suggesting an acceptable safety profile.
However, there are certain limitations in our study. First, since our study is a retrospective study, it is impossible to unify the drugs used for the immunotherapy and targeted therapy, as well as radiotherapy methods and doses. Its effects on the prognosis cannot be ruled out. Second, this study is a single-center study. Although we used PSM, selection bias cannot be eliminated. Specifically, the patients we included were all Chinese patients with HCC. Compared with patients with HCC in Western countries who are often accompanied by a history of alcoholic liver disease, Chinese patients are often accompanied by a history of viral hepatitis, especially hepatitis B. Third, our follow-up time was relatively short, and some patients were not followed up to the end of the study. Long-term follow-up will be conducted in the future. Fourth, our sample size is relatively small, and it can reach 80% power after calculation. The sample size will continue to be expanded in the future to achieve higher statistical efficiency. In the future, prospective, multi-center studies with larger sample sizes and longer follow-up times are needed to verify our research results.
Conclusions
In conclusion, the combination of RT with targeted therapy plus immunotherapy significantly improved the mOS and mPFS in patients with HCC with PVTT. The combination therapy exhibited an acceptable safety profile, with severe TRAEs or no treatment-related deaths. These findings suggest that RT combined with targeted therapy and immune therapy represents a promising treatment strategy for HCC patients with PVTT.
Supplementary Material
Contributor Information
Jianing Ma, Department of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, People’s Republic of China.
Haifeng Zhang, Department of Interventional Therapy, The First Hospital of Jilin University, Changchun 130021, People’s Republic of China.
Ruipeng Zheng, Department of Interventional Therapy, The First Hospital of Jilin University, Changchun 130021, People’s Republic of China.
Shudong Wang, Department of Cardiology, The First Hospital of Jilin University, Changchun 130021, People’s Republic of China.
Lijuan Ding, Department of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun 130021, People’s Republic of China.
Author contributions
L.D. and S.W. designed the study. J.M. and H.Z. analyzed the data and interpreted the results. J.M. and R.Z. collected and analyzed the data. J.M., L.D., and S.W. interpreted the results with scientific discussion. J.M., H.Z., and R.Z. designed and generated all figures and tables. J.M. wrote the manuscript. All authors revised and approved the final manuscript.
Conflicts of interest
All authors declare no potential conflicts of interest.
Data availability
The data underlying this article will be shared on reasonable request to the corresponding author.
Ethics approval
This study was approved by the Institutional Review Board of The First Hospital of Jilin University (No. AF-IRB-032-06) with a waiver of informed consent.
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