The efficacy and safety of stereotactic body radiotherapy (SBRT) plus transcatheter arterial chemoembolization (TACE) versus SBRT or TACE alone(monotherapy) for hepatocellular carcinoma (HCC) patients with portal vein tumour thrombus (PVTT) remains controversial. This meta-analysis was performed to provide more powerful evidence for clinical strategies in inoperable HCC with PVTT.
We searched the PubMed, EMBASE, Web of Science, Cochrane Library, China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), VIP Journal Integration Platform (VIP), and WanFang databases for eligible studies. We pooled the results of 1- and 2-year overall survival rates (OSRs), objective response rates (ORRs), and adverse events (AEs) between the two groups and performed a subgroup meta-analysis for study type, control group, treatment order, and the interval between SBRT and TACE.
Nine studies with 10 cohorts involving 938 patients were included in our meta-analysis. SBRT plus TACE yielded significantly higher 1-year OSR (RR, 1.52[95% CI, 1.33–1.74]), 2-year OSR (RR, 2.00 [95% CI: 1.48–2.70]), ORR (RR = 1.22 [95% CI, 1.08–1.37]), and a lower progression disease (PD) rate (RR = 0.45 [95% CI:0.26–0.79]) than monotherapy. No significant differences were detected in CR, PR, SD, or AEs between the two groups. Subgroup analysis regarding study type, control group, and treatment order indicated that compared with monotherapy, the combination of SBRT with TACE was associated with an increase in 1- and 2-year OSRs but not in ORR. In regard to the interval between SBRT and TACE, subgroup analysis found that the combination therapy for patients with an SBRT-TACE interval <28 days was preferable to monotherapy in the 1- and 2-year OSRs, and ORR. However, for patients with an SBRT-TACE interval ≥28 days, no obvious distinctions were observed in the 1-year OSR, 2-year OSR, or ORR between the two groups.
Citation: Zhang X-f, Lai L, Zhou H, Mo Y-j, Lu X-q, Liu M, et al. (2022) Stereotactic body radiotherapy plus transcatheter arterial chemoembolization for inoperable hepatocellular carcinoma patients with portal vein tumour thrombus: A meta-analysis. PLoS ONE 17(5): e0268779. https://doi.org/10.1371/journal.pone.0268779
Editor: Gregory Tiao, Cincinnati Children’s Hospital Medical Center, UNITED STATES
Received: October 5, 2021; Accepted: May 6, 2022; Published: May 20, 2022
Copyright: © 2022 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This work is supported by Chinese Medical Hand in Hand Project Committee & Beijing Medical Award Foundation (YJHYXKYJJ-359), Science Foundation for Distinguished Young Scholars of Guangxi University of Chinese Medicine (2020JQ001), and Basic Ability Enhancement Program for Young and Middle-aged Teachers in Higher Education Institutions of Guangxi (2021KY0283). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Worldwide, hepatocellular carcinoma (HCC) was the seventh most commonly diagnosed malignancy and the third leading cause of cancer-related death in 2020 . Portal vein tumour thrombus (PVTT), regarded as the most usual form of vascular invasion in liver cancer, is observed in 10–60% of HCC patients at the time of diagnosis [2,3]. Given that PVTT is associated with portal vein hypertension, varix or ascites formation, hepatic dysfunction, and dissemination of tumour cells, the prognosis of HCC with PVTT remains grave, with a median overall survival (mOS) of merely 2–4 months under supportive care [4–6]. What’s more, there are no extremely effective treatment choices for inoperable HCC with PVTT thus far.
HCC with PVTT is fallen into Barcelona Clinic Liver Cancer (BCLC) stage C, and sorafenib is usually regarded as the first-line therapy for patients with PVTT in accordance with the BCLC guidelines for liver cancer [5,7]. Some randomized controlled trials (RCTs) have demonstrated that nearly 3-month survival time of HCC patients with PVTT can be prolonged by sorafenib [5,8,9]. However, unsatisfactory clinical efficacy and potential complications warrant exploration of other treatment modalities. Liver surgery is only suitable for patients with excellent hepatic function, a completely resectable primary tumour, and no extrahepatic metastases [10–12]. Transcatheter arterial chemoembolization (TACE) was firstly regarded a contraindication for HCC with PVTT located in the trunk or first branch of the portal vein, due to the possibility of hepatic ischaemic necrosis from vascular obstruction [6,13]. Subsequently, many studies have shown that TACE could be safe and more effective than palliative care for some highly selected HCC with PVTT. [11,14,15].
Radiotherapy (RT) was also demonstrated to play a huge role in killing malignant cells and the recanalization of PVTT occlusion [16,17]. Nevertheless, conventional fractionated radiotherapy (CFRT) for HCC is restricted owing to the low tolerance of liver tissue for radiotherapy and the potential risk of radiation-induced liver disease (RILD) . With the development of radiotherapy techniques and the progressive understanding of the maximum liver tolerated dose, stereotactic body radiation therapy (SBRT) has been increasingly applied for HCC with PVTT with the advantage of concentrating high-dose radioactive rays precisely on the target lesion, thus sparing the normal liver tissue at risk from high doses of radiation and reducing the incidence of hepatotoxicity to some extent [19,20]. Many studies have shown the preferable survival benefits of SBRT for HCC with PVTT [21–23]. A retrospective study  reported that local progression-free survival (LPFS) rate and 1-year OSR of patients with PVTT in the SBRT group were 69.6% and 34.9%, respectively, significantly better than those in the CFRT group (32.2% and 15.3%). Moreover, the incidence of RILD in SBRT group was marginally lower than that in CFRT group (16.7% vs. 19.8%, p = 0.646). Matsuo et al. concluded that the 1-year OSR of 49.3% in SBRT for HCC patients with PVTT was significantly higher than that in 3-DCRT (29.3%) . However, the effectiveness of SBRT monotherapy is still insufficient, and a combination of other treatment modalities, such as TACE, HAIC, microwave ablation or targeted drugs, is required to further improve the ORR and OSR.
It was reported that the combination of SBRT and TACE might be an excellent choice for HCC with PVTT than SBRT or TACE alone (monotherapy) [24,25]. Choi et al. retrospectively analyzed the outcomes of SBRT combined with or without TACE in patients with HCC and PVTT, the results revealed that patients treated by SBRT plus TACE had better ORR and 1-year survival rate than those treated by SBRT alone (56.3% VS. 50% and 71.4% VS. 14.6%, respectively) . The similar results were also reported by Kang et al . They found that 1- and 2-year survival rates were higher in patients with SBRT plus TACE (58.8% and 29.4%) than in patients with SBRT alone (50.0% and 23.3%). However, no large randomized controlled trial has reported the efficacy of SBRT combined with TACE in the treatment of HCC with PVTT. Herein, we performed this meta-analysis for the evaluation of the effectiveness and security of SBRT plus TACE versus monotherapy in inoperable HCC with PVTT.
Materials and methods
The current meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) Statement . An integrated literature search was performed through the PubMed, Cochrane Library, EMBASE, Web of Science, China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), VIP Journal Integration Platform (VIP), and WanFang databases from the inception dates of the databases to July 1, 2021. The search terms were as follows: (“hepatocellular carcinoma” or “hepatoma” or “liver cancer” or “liver neoplasm” or “HCC”) AND (“portal vein tumour thrombus” or “portal vein thrombosis” or “PVTT”) AND (“stereotactic body radiotherapy” or “stereotactic radiotherapy” or “stereotactic radiosurgery” or “SBRT” or “cyberknife” or “gamma knife”) AND (“transcatheter arterial chemoembolization” or “transarterial chemoembolization” or “TACE”). Besides, all references of the included articles were also manually searched to identify other potentially eligible studies.
The included studies complied with the following criteria: (1) the subjects were inoperable HCC patients with PVTT without metastases, confirmed pathologically or diagnosed by magnetic resonance imaging (MRI) or computed tomography (CT); (2) the included studies consisted of a treatment group treated with SBRT combined with TACE and a control group treated with SBRT or TACE alone (monotherapy); (3) detailed data on 1-year survival rate, 2-year survival rate, complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rate (ORR), and adverse effects (AEs); (4) study type described as randomized controlled trials (RCTs) or non-randomized controlled trials (NRCTs); (5) the language was restricted to English or Chinese. The literature meeting any of the criterion below were excluded: (1) literature reviews, meta-analysis, case reports, comments, letters, conference proceedings or abstracts, animal experiments; (2) without data available, or duplicated data; or (3) the absence of a control group.
Two authors extracted all eligible data in accordance with the inclusion and exclusion criteria as mentioned above independently. Any conflict during the data extraction was settled through discussion or by consultations with the corresponding author. The following information was extracted using a standardized form: (1) Basic features of the included studies, such as first author, publication year, country, study design, sample size, age, gender, performance status score, Child-Pugh class, tumour stage, and the type of PVTT. (2) Intervention characteristics: treatment modalities, radiation dose and fraction, interventional chemoembolization drugs and dose. (3) Outcomes: 1- and 2-year survival rates, ORR, and AEs. Survival rates were either described in the original literature or extracted from the survival curves using Engauge Digitizer 6.1 software . Tumour target was defined as thrombus and primary tumour. The evaluation of tumour response rates was performed on the basis of the modified Response Evaluation Criteria In Solid Tumours (mRECIST) for HCC . Complete response (CR): full regression of the tumour lesions; partial response (PR): more than 30% reduce in the longest diameters of the tumour lesions; progressive disease (PD): more than 20% growth in the longest diameters of target lesions; stable disease (SD): all other variations; objective response rate (ORR) = CR + PR.
Two researchers conducted a quality evaluation of the included studies independently. The Cochrane assessment tool was employed to assess the quality of every RCT for risk of bias from the following six dimensions: production of random sequences, distribution concealment, blinding, incomplete result data, selective reporting, and other biases . The quality of each NRCT was evaluated by the Newcastle–Ottawa scale (NOS) , which involves the following three main indicators: comparability, selection, and result evaluation. The quality of the studies was classified into three levels: high (≥7 points), medium (4–6 points), and low quality (≤3 points).
We conducted all the meta-analysis using Review Manager Statistical Software (RevMan Version 5.3, Nordic Cochrane Centre, Oxford, England) and calculated the risk ratios (RRs) with the corresponding 95% confidence intervals (CIs) in regard to 1- and 2-year survival rates, tumour target lesion response, and the occurrence rates of AEs. Heterogeneity was assessed by I2 statistics and the chi-square test . In case of no obvious heterogeneity (I2 ≤ 50% and p>0.1), the effect sizes was merged with a fixed-effects model; however, in case of obvious heterogeneity (I2 >50% and p≤ 0.1), a random-effects model was applied. A funnel plot was employed to evaluate potential publication bias, and the symmetry of the funnel plot was quantitatively analysed by Egger’s test . A p value < 0.05 was of statistical significance.
Search results and basic features of the included studies
There were 3533 relevant studies initially identified through the systematic literature search. Twenty studies were selected for possible inclusion in our meta-analysis after all of the titles and abstracts were screened. Eleven articles were excluded due to duplication or not satisfying the inclusion and exclusion criterion after reading the full text carefully. Ultimately, 9 studies with 10 cohorts were included in the present review (455 patients in the SBRT plus TACE group and 483 patients in the monotherapy group). The flow chart of the literature screening selection is shown in Fig 1.
Of these 9 studies included, 4 were RCTs, and 5 were non-RCTs. Eight were conducted in China, while only one was conducted in South Korea. Kang et al.’s study  involved two cohorts: Kang 1 (SBRT followed by TACE vs. SBRT alone) and Kang 2 (TACE followed by SBRT vs. SBRT alone). The control group in 5 studies was SBRT alone and that in the remaining 4 studies was TACE alone. For the combined treatment group, SBRT followed by TACE was performed in 5 of 10 cohorts, while TACE followed by SBRT was performed in the other 5 cohorts (Table 1).
Quality evaluation of the included studies
In terms of quality, among all 5 non-RCTs, 2 scored 7 points and 3 scored 8 points (Table 2). Four RCTs were at moderate risk of bias (Fig 2). Overall, 9 included studies were of medium to high quality.
One-year survival rate.
The 1-year survival rates were reported in 8 studies with 9 cohorts, including 415 patients in the SBRT+TACE group and 443 patients in the monotherapy group. Due to no statistically obvious heterogeneity existing among the studies (I2 = 32%; P = 0.16), a fixed-effects model was selected to analyse the 1-year survival rates. The pooled result revealed that SBRT plus TACE significantly improved 1-year survival rate compared with monotherapy(RR, 1.52 [95% CI, 1.33–1.74]) (Fig 3).
Two-year survival rate.
The 2-year survival rates were reported in 5 studies with 6 cohorts, including 327 patients in the SBRT+TACE group and 363 patients in the monotherapy group. A fixed-effects model was applied to analyse the results owing to no statistically significant heterogeneity across the studies (I2 = 0%, P = 0.48). The pooled result indicated that the 2-year survival rate in SBRT plus TACE was significantly higher than that in monotherapy (RR, 2.00 [95% CI: 1.48–2.70]) (Fig 4).
CR, PR, SD, and PD were reported in 5 studies with 6 cohorts but not in Choi et al.’s study , which presented only ORR. Heterogeneity in these studies was not significant, so a fixed-effects model was employed to pool the response rates to treatment. The results showed that SBRT plus TACE significantly improved the ORR of the target lesion in comparison with monotherapy (RR = 1.22 [95% CI: 1.08–1.37]). Moreover, combination therapy appeared to be strongly correlated with a lower rate of PD in comparison with monotherapy (RR = 0.45 [95% CI: 0.26–0.79]). However, no visible differences were found in CR, PR, and SD between the two groups (Fig 5).
By performing subgroup analysis regarding study type, we noticed that the combination of SBRT with TACE had higher 1- and 2-year survival rates than monotherapy in both RCTs and non-RCTs. Nevertheless, the difference of the ORR between the two groups was not significant in either RCTs or non-RCTs. The reason for this may be that a random-effects model was selected to merge the response rates to treatment owing to significant heterogeneity among the RCTs (I2 = 65%, P = 0.06) (Table 3).
A subgroup analysis with regard to monotherapy regimens in the control group showed that compared with either SBRT alone or TACE alone, SBRT plus TACE was able to significantly improve 1- and 2-year survival rates. In addition, SBRT plus TACE seemed to improve the ORR compared with TACE alone (RR = 1.49 [95% CI: 1.17–1.89], P = 0.001) but not compared with SBRT alone (RR = 1.12 [95% CI: 0.97–1.28], P = 0.12) (Table 3).
By conducting subgroup analysis regarding the treatment order, we found that patients receiving TACE followed by SBRT yielded a better ORR than those receiving monotherapy (RR = 1.33 [95% CI: 1.10–1.61], P = 0.004). Whereas patients receiving SBRT followed by TACE had no statistically significant difference in ORR compared with those receiving monotherapy (RR = 1.13 [95% CI: 0.97–1.31], P = 0.11). Regardless of the treatment order, the 1- and 2-year survival rates in the combination treatment group were significantly better than those in the monotherapy group (Table 3).
For patients with SBRT-TACE interval less than 28 days, SBRT plus TACE seemed to be more effective than monotherapy for the 1- and 2-year survival rates and ORR (P < 0.05). Whereas, for patients with an SBRT-TACE interval equal to or longer than 28 days, no obvious distinctions were observed in 1- and 2-year survival rates and ORR between the two groups (P > 0.05). In other words, there was a more significant trend for patients with SBRT-TACE interval less than 28 days to have better long-term survival and objective response rates than for those with SBRT-TACE interval equal to or longer than 28 days (Table 3).
Out of all eligible studies, 6 reported the occurrence rates of treatment-related AEs within 3 months after SBRT, mainly including bone marrow suppression, fever, hepatic toxicity, hepatalgia, anorexia, nausea and vomiting, and duodenum ulcer, most of which were mild to moderate (grade 1–2), with a very few grade ≥3. Almost all adverse events were alleviated or improved after active symptomatic treatment. No radiation-induced liver disease (RILD) was encountered in any HCC patients with PVTT within 3 months following SBRT. Furthermore, there were no AE-induced deaths in either group of patients, who were all restored to normal after treatment. No differences in the incidences of total AEs between the two groups were detected (RR = 1.03 [95% CI: 0.82–1.31], p = 0.80) (Fig 6). For each adverse event, the results showed no significant difference in the incidences of bone marrow suppression, fever, hepatic toxicity, hepatalgia, gastrointestinal reactions, or duodenum ulcers between the two groups of patients (Table 4).
PVTT in patients with HCC is one of the independent risk elements for poor overall survival [40,41]. Although a variety of treatment modalities, such as molecular targeted agents, surgery, TACE, and radiotherapy, have been confirmed to be effective for patients with PVTT, there is currently no consensus or recommendation on the optimal therapeutic modality for HCC with PVTT. So, we performed this meta-analysis for the evaluation of the efficacy and security of SBRT plus TACE for inoperable HCC with PVTT in comparison to monotherapy. We concluded that HCC patients with PVTT in the combined group had higher 1- and 2-year OSRs, ORR, and lower PD rates than those in the monotherapy group. No significant difference was found in terms of CR, PR, SD, or adverse events between the two groups of patients. With respect to study type, control group, and treatment order, subgroup analysis showed that compared with monotherapy, SBRT plus TACE greatly enhanced the 1- and 2-year survival rates but not the ORR. For the SBRT-TACE interval, subgroup analysis showed that patients with an SBRT-TACE interval <28 days had a higher 1- and 2-year OSRs and ORR than those with an SBRT-TACE interval ≥28 days.
There is, at present, considerable interest in the combination of RT with other treatment modalities, such as TACE, targeted therapy, or microwave ablation, which has been gradually recommended as an emerging treatment for HCC with PVTT and has been demonstrated to be superior to any single therapeutic regimen. Kim et al.  reported that the combination of RT and TACE in inoperable HCC patients with PVTT was preferred over TACE alone in terms of OS and time to progression (TTP) (OS, 11.4m vs. 7.4m; TTP, 8.7m vs. 3.6m). A meta-analysis conducted by Zhao et al.  evaluated the safety and effectiveness of SBRT plus TACE in comparison with SBRT alone as the first-line treatment for inoperable HCC. Their results presented that the combination therapy group had a higher disease control rate (DCR) and a longer OS than the monotherapy group in all patients but not in the subgroup of those with PVTT. The main reason for this may be that only three studies were included in their subgroup analysis for PVTT patients. Our meta-analysis involving nine studies concluded that SBRT combined with TACE had significantly higher 1- and 2-year OS and ORR than monotherapy. In general, patients who responded well to treatment had better survival benefits than those who responded poorly. Shui et al.  reported that the mOS of 12 months in patients receiving SBRT combined with TACE was significantly longer than the 3 months among those undergoing SBRT alone. Furthermore, the mOS was 13 months in HCC patients with a good response to PVTT and only 4.0 months in those without a response. Their result was in line with that of Yu et al. , who performed a single-arm clinical research on radiotherapy combined with TACE for HCC with PVTT. They concluded that the mOS in patients who responded well to treatment was 17.6 months, significantly higher than the 4.3 months in those who did not respond.
Subgroup analysis of the control group showed that SBRT plus TACE resulted in a higher ORR than TACE alone; however, there was no significant trend for patients treated by SBRT plus TACE to have a better ORR compared with patients treated by SBRT alone. This may be closely related to the direct killing or inhibitory effect of SBRT on tumor cells in portal vein in addition to intrahepatic tumour lesions. However, TACE has no killing effect on PVTT except for intrahepatic tumour cells. Few studies have focused on the treatment order of SBRT and TACE, the purpose of this subgroup analysis was to determine whether the prognosis of patients with PVTT could be influenced by the treatment order of SBRT and TACE. The results revealed that whether SBRT followed by TACE or TACE followed by SBRT, SBRT plus TACE was significantly better than monotherapy for 1- and 2- year survival rates of patients; however, compared with patients receiving TACE followed by SBRT, there was a nonsignificant trend for patients receiving SBRT followed by TACE to have a higher ORR than monotherapy. However, Kang et al. reported that there was no significant difference in ORR, 1- and 2- year survival rates between groups A (SBRT followed by TACE) and B (TACE followed by SBRT) . Due to the small number of studies included, the reliability of the outcomes should be considered with caution. Therefore, it remains unclear whether patient outcomes are affected by the treatment order of SBRT and TACE.
In addition, we also found that the 1- and 2-year survival rates and ORR of patients with SBRT plus TACE were superior to those with monotherapy in the SBRT-TACE interval <28 days group; However, in the interval ≥28 days group, the combination therapy showed no greater survival benefit than monotherapy. Similar findings were also reported in the meta-analysis of Huo et al , who evaluated the efficacy and safety of TACE combined with radiotherapy compared with TACE alone in the treatment of unresectable HCC. Their results showed that in patients who had RT less than 28 days after TACE, RT plus TACE yielded less no response (NR) and better 3-year survival rates than TACE alone. However, this comparison was nonsignificant in patients who had RT 28 days or more after TACE. This may be because if the interval is too long, tumour cells proliferate rapidly, and the synergistic effect of SBRT and TACE cannot be fully exploited. Therefore, we suggest that the interval time between SBRT and TACE should be less than 28 days to achieve a better prognosis on the premise that it is safe and well-tolerated by the patients.
The location of the PVTT is also a well-known prognostic factor of patients with PVTT, with worse outcomes when it is in the main trunk [24,33,43]. Choi et al.  who evaluated the effectiveness of SBRT for HCC with PVTT concluded that patients with main trunk PVTT had a worse 1-year survival rate (54.7% VS. 75%) and a lower ORR (30% VS. 71.4%) than those with branch PVTT. What’s more, the rate of hepatotoxicity was higher in HCC patients with PVTT located in the main trunk than in those with PVTT located in the branches (40% vs. 14.3%). Hence, the best therapeutic regimen and radiotherapy dose shall be determined according to the location of the PVTT so as to achieve a better tumour remission rate while reducing hepatotoxicity. However, restricted by the insufficient data reported by the included studies, a separate subgroup analysis regarding PVTT classification could not be performed.
In regard to adverse events (AEs), we found that SBRT plus TACE had similar incidence of total AEs with monotherapy. For each treatment-related side effect, such as bone marrow suppression, fever, hepatic toxicity, hepatalgia, gastrointestinal reactions, and duodenum ulcers, there was also no significant difference between the two groups. However, some researchers pointed out that the combination of SBRT and TACE might exacerbate AEs mentioned above [25,43]. In general, treatment-related adverse events (TRAEs), especially 3–5 and AEs, may shorten patient survival in addition to reducing quality of life. Choi et al.’s study indicated that none of the patients with grade 3 or higher hepatotoxicity following SBRT survived for more than a year, while the 1-year survival rate could be as high as 81.1% in those without grade ≥3 hepatotoxicity . But in fact, SBRT plus TACE did not result in a significant increase in the incidences of serious AEs, most of which could be alleviated or eliminated by early aggressive therapy. A meta-analysis performed by Zhao et al.  showed no significant difference in total AEs and grade ≥3 AEs between the two groups, aside from the slightly higher incidences of myelosuppression and fever in unresectable HCC patients undergoing SBRT plus TACE than in those undergoing SBRT alone. Limited by the insufficient data of the included literature, we were unable to carry out a separate analysis regarding grade ≥ 3 AEs. Overall, the combination therapy of SBRT and TACE is a secure and effective treatment for unresectable liver cancer with PVTT. Nevertheless, it is vital to select HCC patients with caution and closely monitor for potential AEs.
In our opinion, the clinical efficacy of SBRT combined with TACE is superior to that of a single treatment for the following reasons: 1) SBRT has the characteristic of precisely delivering a high intensity radiation dose to the target lesions and efficiently shrinking the tumour volume within a short time, which contributes to the recanalization of the portal vein, restoration of portal blood flow, regression of the arterioportal shunt, alleviation of hepatic ischaemia, and improvement of liver function, thereby providing better conditions for the subsequent TACE [40,46]; 2) TACE prior to SBRT can reduce the tumour volume and the corresponding radiation field, thereby increasing the dose in the tumour target area and reducing the radiation damage to adjacent normal tissues and organs; 3) SBRT after TACE may form a second blow to the target lesions, and then kill residual tumour cells after TACE, enhancing the curative effect, shortening the therapeutic process, and preventing the relapse and recoil ; 4) Chemotherapy drugs used in TACE can increase the sensitivity of tumour cells to radiation and further strengthen the lethal effect of radiotherapy on the target tissue. In general, SBRT and TACE play a coordinating role in killing tumour cells through different mechanisms of action [47,48].
Our outcomes should be explained prudently in view of the limitations of the study. First, only 9 studies with 938 patients were included in our meta-analysis, and a smaller number of studies might affect the accuracy of the results. Second, among the nine studies, only four were RCTs, and three of them not reported allocation concealment. Double-blind was not described in any study in detail. All of the studies presented unclear risks in terms of blinding during the outcome assessment. In this case, the results were prone to be affected by selection bias, performance bias, and detection bias. Third, all of the studies were from Asia, with one from South Korea and the remaining eight from China. The aetiology of patients in Asia is different from that in the West to some extent, which is likely to result in regional bias. Finally, the baseline characteristics (e.g., tumour stage, Child-Pugh class, location of the PVTT, radiation dose, chemotherapy agents and the doses used in the TACE) of patients with HCC were not identical across the enrolled studies, which might affect the heterogeneity and the final results.
Our meta-analysis offered compelling evidence that in unresectable hepatocellular carcinoma patients with PVTT, especially in those with SBRT-TACE interval <28 days, SBRT plus TACE was more effective than monotherapy in both long-term survival and short-term response rates. Moreover, the combination therapy was well-tolerated without a significant increase in the incidences of complications compared with monotherapy. Based on the above results, we suggest that SBRT plus TACE is a secure, efficient, and very hopeful treatment modality for inoperable HCC patients with PVTT. In the future, large multicenter RCTs are warranted to definitively confirm the security and effectiveness of SBRT combined with TACE in treating HCC patients with PVTT.
- 1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: a cancer journal for clinicians. 2021;71(3):209–49. pmid:33538338.
- 2. Llovet JM, Bustamante J, Castells A, Vilana R, Ayuso MdC, Sala M, et al. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology (Baltimore, Md). 1999;29(1):62–7 pmid:9862851.
- 3. Cheung TK, Lai CL, Wong BCY, Fung J, Yuen MF. Clinical features, biochemical parameters, and virological profiles of patients with hepatocellular carcinoma in Hong Kong. Alimentary pharmacology & therapeutics. 2006;24(4):573–83 pmid:16907890.
- 4. Lau WY, Sangro B, Chen PJ, Cheng SQ, Chow P, Lee RC, et al. Treatment for hepatocellular carcinoma with portal vein tumor thrombosis: the emerging role for radioembolization using yttrium-90. Oncology. 2013;84(5):311–8. pmid:23615394.
- 5. Bruix J, Raoul JL, Sherman M, Mazzaferro V, Bolondi L, Craxi A, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. Journal of hepatology. 2012;57(4):821–9. pmid:22727733.
- 6. Chan SL, Chong CC, Chan AW, Poon DM, Chok KS. Management of hepatocellular carcinoma with portal vein tumor thrombosis: Review and update at 2016. World journal of gastroenterology. 2016;22(32):7289–300. pmid:27621575.
- 7. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. Journal of hepatology. 2012;56(4):908–43. pmid:22424438.
- 8. Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. Journal of the National Cancer Institute. 2008;100(10):698–711. pmid:18477802.
- 9. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. The Lancet Oncology. 2009;10(1):25–34. pmid:19095497.
- 10. Wakayama K, Kamiyama T, Yokoo H, Kakisaka T, Kamachi H, Tsuruga Y, et al. Surgical management of hepatocellular carcinoma with tumor thrombi in the inferior vena cava or right atrium. World journal of surgical oncology. 2013;11:259. pmid:24093164.
- 11. Kokudo T, Hasegawa K, Matsuyama Y, Takayama T, Izumi N, Kadoya M, et al. Liver resection for hepatocellular carcinoma associated with hepatic vein invasion: A Japanese nationwide survey. Hepatology (Baltimore, Md). 2017;66(2):510–7. pmid:28437844.
- 12. Chok KS, Cheung TT, Chan SC, Poon RT, Fan ST, Lo CM. Surgical outcomes in hepatocellular carcinoma patients with portal vein tumor thrombosis. World journal of surgery. 2014;38(2):490–6. pmid:24132826.
- 13. Omata M, Lesmana LA, Tateishi R, Chen PJ, Lin SM, Yoshida H, et al. Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma. Hepatology international. 2010;4(2):439–74. pmid:20827404.
- 14. Kim JH, Yoon HK, Kim SY, Kim KM, Ko GY, Gwon DI, et al. Transcatheter arterial chemoembolization vs. chemoinfusion for unresectable hepatocellular carcinoma in patients with major portal vein thrombosis. Alimentary pharmacology & therapeutics. 2009;29(12):1291–8. pmid:19392861.
- 15. Leng JJ, Xu YZ, Dong JH. Efficacy of transarterial chemoembolization for hepatocellular carcinoma with portal vein thrombosis: a meta-analysis. ANZ journal of surgery. 2016;86(10):816–20. pmid:25088384.
- 16. Zeng ZC, Fan J, Tang ZY, Zhou J, Qin LX, Wang JH, et al. A comparison of treatment combinations with and without radiotherapy for hepatocellular carcinoma with portal vein and/or inferior vena cava tumor thrombus. International journal of radiation oncology, biology, physics. 2005;61(2):432–43. pmid:15667964.
- 17. Park SH, Kim JC, Kang MK. Technical advances in external radiotherapy for hepatocellular carcinoma. World journal of gastroenterology. 2016;22(32):7311–21. pmid:27621577.
- 18. Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, et al. Tolerance of normal tissue to therapeutic irradiation. International journal of radiation oncology, biology, physics. 1991;21(1):109–22. pmid:2032882.
- 19. Sanuki N, Takeda A, Kunieda E. Role of stereotactic body radiation therapy for hepatocellular carcinoma. World journal of gastroenterology. 2014;20(12):3100–11. pmid:24696597.
- 20. Park HC, Yu JI, Cheng JC, Zeng ZC, Hong JH, Wang ML, et al. Consensus for Radiotherapy in Hepatocellular Carcinoma from The 5th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2014): Current Practice and Future Clinical Trials. Liver cancer. 2016;5(3):162–74. pmid:27493892.
- 21. Lin CS, Jen YM, Chiu SY, Hwang JM, Chao HL, Lin HY, et al. Treatment of portal vein tumor thrombosis of hepatoma patients with either stereotactic radiotherapy or three-dimensional conformal radiotherapy. Japanese journal of clinical oncology. 2006;36(4):212–7. pmid:16613896.
- 22. Yang JF, Lo CH, Lee MS, Lin CS, Dai YH, Shen PC, et al. Stereotactic ablative radiotherapy versus conventionally fractionated radiotherapy in the treatment of hepatocellular carcinoma with portal vein invasion: a retrospective analysis. Radiation oncology (London, England). 2019;14(1):180. pmid:31640728.
- 23. Matsuo Y, Yoshida K, Nishimura H, Ejima Y, Miyawaki D, Uezono H, et al. Efficacy of stereotactic body radiotherapy for hepatocellular carcinoma with portal vein tumor thrombosis/inferior vena cava tumor thrombosis: evaluation by comparison with conventional three-dimensional conformal radiotherapy. Journal of radiation research. 2016;57(5):512–23. pmid:27053259.
- 24. Choi HS, Kang KM, Jeong BK, Jeong H, Lee YH, Ha IB, et al. Effectiveness of stereotactic body radiotherapy for portal vein tumor thrombosis in patients with hepatocellular carcinoma and underlying chronic liver disease. Asia-Pacific journal of clinical oncology. 2021;17(3):209–15. pmid:32757461.
- 25. Kang J, Nie Q, Du R, Zhang L, Zhang J, Li Q, et al. Stereotactic body radiotherapy combined with transarterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombosis. Molecular and clinical oncology. 2014;2(1):43–50. pmid:24649306.
- 26. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS medicine. 2009;6(7):e1000100. pmid:19621070.
- 27. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Statistics in medicine. 1998;17(24):2815–34. https://doi.org/10.1002/(sici)1097-0258(19981230)17:24<2815::aid-sim110>3.0.co;2-8 pmid:9921604.
- 28. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Seminars in liver disease. 2010;30(1):52–60. pmid:20175033.
- 29. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ (Clinical research ed). 2011;343:d5928. pmid:22008217.
- 30. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. European journal of epidemiology. 2010;25(9):603–5. pmid:20652370.
- 31. Higgins J, Thompson S, Deeks J, Altman D. Statistical heterogeneity in systematic reviews of clinical trials: a critical appraisal of guidelines and practice. Journal of health services research & policy. 2002;7(1):51–61. pmid:11822262.
- 32. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ (Clinical research ed). 1997;315(7109):629–34. pmid:9310563.
- 33. Lu XJ, Dong J, Ji LJ, Luo JH, Cao HM, Xiao LX, et al. Safety and efficacy of TACE and gamma knife on hepatocellular carcinoma with portal vein invasion. Gut. 2016;65(4):715–6. pmid:26268743.
- 34. Shui Y, Yu W, Ren X, Guo Y, Xu J, Ma T, et al. Stereotactic body radiotherapy based treatment for hepatocellular carcinoma with extensive portal vein tumor thrombosis. Radiation oncology (London, England). 2018;13(1):188. pmid:30253783.
- 35. Zhu ZS, Yan WH, Peng XM, Li XB, Yang Z. Effect of TACE Combined with Stereotactic Radiotherapy on the Prognosis of Hepatocellular Carcinoma with Portal Vein Thrombosis Prognostic. The Practical Journal of Cancer. 2014;29(06):681–3.
- 36. Han B. Analysis Curative Effect Of Gamma Knife Radiotherapy Combine With Transcatheter Arterial Chemoembolization for Treatment Liver Cancer With Portal Vein Tumor Thrombus. China Continuing Medical Education. 2015;7(23):96–7.
- 37. Zhan YF. Interventional Chemoembolization Combined with Stereotactic Radiotherapy for Treatment of 48 Cases of Liver Cancer With Portal Vein Tumor Thrombus. HEBEI MEDICINE. 2012;18(04):508–10.
- 38. Zhou CZ, Xia YC, Xia HB, Wen ZY, Zhou JP. Effect Of Stereotactic Body Gamma Knife Radiotherapy Combined with TACE On Primary Hepatocellular Carcinoma Associated With Portal Vein Tumor Thrombus. Practical Clinical Medicine. 2019;20(04):26–30.
- 39. Zhang SS, Zhang J, Wang DZ, Wang TJ. Clinical Study Of Stereotactic Body Gamma Knife Radiotherapy On Primary Hepatocellular Carcinoma With Portal Vein Tumor Thrombus. Jilin Medical Journal. 2020;41(06):1445–6.
- 40. Yoon HM, Kim JH, Kim EJ, Gwon DI, Ko GY, Ko HK. Modified cisplatin-based transcatheter arterial chemoembolization for large hepatocellular carcinoma: multivariate analysis of predictive factors for tumor response and survival in a 163-patient cohort. Journal of vascular and interventional radiology: JVIR. 2013;24(11):1639–46. pmid:23962438.
- 41. Lo CH, Yang JF, Liu MY, Jen YM, Lin CS, Chao HL, et al. Survival and prognostic factors for patients with advanced hepatocellular carcinoma after stereotactic ablative radiotherapy. PloS one. 2017;12(5):e0177793. pmid:28545098.
- 42. Kim GA, Shim JH, Yoon SM, Jung J, Kim JH, Ryu MH, et al. Comparison of chemoembolization with and without radiation therapy and sorafenib for advanced hepatocellular carcinoma with portal vein tumor thrombosis: a propensity score analysis. Journal of vascular and interventional radiology: JVIR. 2015;26(3):320–9.e6. pmid:25612807.
- 43. Zhao J, Zeng L, Wu Q, Wang L, Lei J, Luo H, et al. Stereotactic Body Radiotherapy Combined with Transcatheter Arterial Chemoembolization versus Stereotactic Body Radiotherapy Alone as the First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Meta-Analysis and Systematic Review. Chemotherapy. 2019;64(5–6):248–58. pmid:32320982.
- 44. Yu JI, Park JW, Park HC, Yoon SM, Lim DH, Lee JH, et al. Clinical impact of combined transarterial chemoembolization and radiotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis: An external validation study. Radiotherapy and oncology: journal of the European Society for Therapeutic Radiology and Oncology. 2016;118(2):408–15. pmid:26830695.
- 45. Huo YR, Eslick GD. Transcatheter Arterial Chemoembolization Plus Radiotherapy Compared With Chemoembolization Alone for Hepatocellular Carcinoma: A Systematic Review and Meta-analysis. JAMA oncology. 2015;1(6):756–65. pmid:26182200.
- 46. Yoon SM, Lim YS, Won HJ, Kim JH, Kim KM, Lee HC, et al. Radiotherapy plus transarterial chemoembolization for hepatocellular carcinoma invading the portal vein: long-term patient outcomes. International journal of radiation oncology, biology, physics. 2012;82(5):2004–11. pmid:21621346.
- 47. Gkika E, Schultheiss M, Bettinger D, Maruschke L, Neeff HP, Schulenburg M, et al. Excellent local control and tolerance profile after stereotactic body radiotherapy of advanced hepatocellular carcinoma. Radiation oncology (London, England). 2017;12(1):116. pmid:28701219.
- 48. Qiu H, Moravan MJ, Milano MT, Usuki KY, Katz AW. SBRT for Hepatocellular Carcinoma: 8-Year Experience from a Regional Transplant Center. Journal of gastrointestinal cancer. 2018;49(4):463–9. pmid:28710606.