Efficacy of Radiation Plus Transarterial Chemoembolization and Lenvatinib in Hepatocellular Carcinoma With Portal Vein Tumor Thrombus

doi:10.21203/rs.3.rs-2729634/v1

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Research Article

Efficacy of Radiation Plus Transarterial Chemoembolization and Lenvatinib in Hepatocellular Carcinoma With Portal Vein Tumor Thrombus

https://doi.org/10.21203/rs.3.rs-2729634/v1

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Objective

We aimed to investigate the efficacy of a novel regimen, external beam radiation (RT) combined with transarterial chemoembolization (TACE) and lenvatinib (LEN), in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombus.

Methods

We prospectively observed 102 participants from three tertiary medical centers in China between October 2018 and October 2020, who chose either RT plus TACE and LEN (RT-TACE-LEN) or TACE and LEN (TACE-LEN). LEN (12 mg or 8 mg daily) was administrated orally and continued until progression or intolerable side effects were noted. TACE was given one day after administration of LEN, and RT began within 4 weeks after the first TACE. The median dose/fraction of RT was 50 Gy/25 fractions (range: 45–60 Gy/25 fractions). Overall survival and progression free survival were compared between two groups, and complications were assessed.

Results

Both 51 patients received RT-TACE-LEN and TACE-LEN, respectively. Most patients had tumor size > 5 cm (73.8%) and tumor number ≥ 2 (69.9%). The overall incidence of toxicities was significantly higher in RT-TACE-LEN group than TACE-LEN group (100% vs. 64.7%, p < 0.001), but incidences of grade 3–4 toxicities were comparable (54.9% vs. 49.0%, p = 0.552). Both median overall survival (22.8 vs. 17.1 months, p = 0.031) and median progression-free survival (12.8 vs. 10.5 months, p = 0.035) were significantly longer after RT-TACE-LEN treatment than TACE-LEN.

Conclusions

The addition of RT to TACE and LEN was safe, and might improve clinical outcomes of patients with advanced HCC, which needs conformation from further studies.

hepatocellular carcinoma

portal vein tumor thrombus

external beam radiation

TACE

Lenvatinib

Hepatocellular carcinoma (HCC) is one of the most aggressive malignant tumors, leading to the third leading cause of cancer death worldwide[1, 2]. More than 60% of patients are diagnosed at an advanced stage presenting with portal vein tumor thrombus (PVTT) [3, 4], which is a critical prognostic factor contributing to poor survival outcomes[5–7]. Currently, lenvatinib (LEN) and sorafenib are recommended as first-line treatments for advanced HCC[8–10], however, the clinical benefit is limit and novel treatment modalities such as systemic-locoregional combination therapy have been under investigation so as to further improve prognosis[11, 12].

Transarterial chemoembolization (TACE) is one of the most commonly used local treatments for HCC[13], and is the recommended standard of care in the treatment of intermediate HCC charactered by large or multinodular intrahepatic tumors[14]. A recently-published phase III randomized controlled clinical trial (LAUNCH) demonstrated clinically meaningful and statistically significant improvements in overall survival (OS) and progression-free survival (PFS) with LEN plus TACE over LEN in patients with advanced HCC[15], which may be a potential first-line treatment for advanced HCC. However, presence of PVTT is closely correlated to internal and external liver metastasis and ultimately leads to treatment failure[16, 17]. Efficacy of the current therapies, including combination therapy of TACE and LEN, is far from satisfaction in the treatment of PVTT[17]. Therefore, developing novel combination therapies that are effective against advanced HCC with PVTT is still under great need.

During the past few years, external beam radiation (RT) has been increasingly applied in the treatment of PVTT, reporting significant survival benefits with objective response rates ranged from 45–60% and median OS ranged from 10-19.5 months[18, 19]. Previous studies have demonstrated that combination therapy of RT and other local or systemic treatments including TACE and sorafenib, could achieve significantly better clinical survival outcomes than monotherapy in advanced HCC with PVTT[20–22], which indicated RT as an optimal option in the consideration of efficient combination treatment modality for HCC with PVTT. However, the safety and efficacy of adding RT to TACE and LEN in the treatment of HCC with PVTT has not been illustrated so far.

Therefore, we conducted this study to estimate the safety and efficacy of RT plus TACE and LEN in HCC patients with PVTT, aiming to provide clinical evidence for this novel regimen in the treatment of advanced HCC.

Study Design and Participants

This prospective observation study was conducted from October 2018 to October 2020 in three tertiary medical centers in China, including the First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University Cancer Center and Lishui Hospital of Zhejiang University. It was approved by the institution’s Ethics Committee (approval number: [2020]247) and conformed to the standards of the Declaration of Helsinki. Before enrollment, all the participants provided written informed consent comprising a data privacy item for data collection and analysis for research purposes.

Patients with HCC showing PVTT were eligible for inclusion if they had the following characteristics: (a) age 18–75 years; (b) at least one measurable intrahepatic lesion on the basis of modified Response Evaluation Criteria in Solid Tumors (mRECIST); (c) an intrahepatic lesion consisting of a single tumor (≤ 10.0 cm) or multiple tumors (≤ 3 foci) with the tumor burden < 50%; (d) Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1; (e) Child-Pugh class A or B7; (f) life expectancy of at least 3 months; and (g) satisfactory blood, liver, and kidney function parameters. The acceptable blood, liver, and kidney parameters were (i) neutrophil count ≥ 1.5 × 10⁹/L; (ii) platelet count ≥ 60 × 10⁹/L; (iii) hemoglobin concentration ≥ 90 g/L; (iv) serum albumin concentration ≥ 30 g/L; (v) bilirubin ≤ 50 µmol/L; (vi) aspartate aminotransferase and alanine aminotransferase < 5 × upper limit of normal and alkaline phosphatase < 4 × upper limit of normal; (vii) extended prothrombin time < 6 seconds of upper limit of normal; and (viii) serum creatinine < 1.5 × upper limit of normal.

Exclusion criteria included: (a) history of liver and adjacent tissue radiation; (b) medical history of hepatic decompensation, such as hepatic encephalopathy and esophageal or gastric variceal bleeding; (c) extrahepatic spread; (d) combination with other malignant diseases; (e) contraindications for TACE; (f) pregnant and lactating women; (g) severe dysfunction of the heart, kidney, or other organs.

Treatment Protocol

Treatment schema

Treatment allocation for each patient was decided by a multi-disciplinary team consisted of hepatologist, interventional radiologists, radiation oncologists and liver surgeon, as well as patient’s request. Treatment schema was summarized in Supplementary Fig. 1. In both groups, LEN was initially provided to patients first, and then TACE was given one day after administration of LEN. Repeat TACE was performed if there was incomplete necrosis or tumor regrowth based on imaging evaluation, but no more than three sessions were performed. In the RT-TACE-LEN group, RT began within 4 weeks after the first TACE.

Lenvatinib administration

LEN (Lenvima; Eisai Co., Ltd., Tokyo, Japan) was administered orally based on the prescribing information, at a standard dose of 12 mg (for body weight ≥ 60 kg) or 8 mg (for body weight < 60 kg) daily. Dose reductions were permitted according to drug-related toxicity grade as recommended. LEN treatment would be terminated if there was disease progression or unacceptable toxicity during treatment. LEN was continuously administered without interruption during TACE and RT.

TACE

The choice of conventional TACE or drug-eluting beads TACE was determined by consensus between interventional radiologists and hepatologists, and each patient was required to use the same chemoembolization agent throughout the study duration. Procedures were performed as previously recommended[23]. Briefly, conventional TACE was performed with a maximum dose of 50 mg and 8 mL epirubicin and Lipiodol (Guerbet, Pairs, France), respectively. Epirubicin was infused into the selective catheterization of the feeding artery as the chemotherapeutic agent. The feeding arteries were then embolized using an emulsion of epirubicin and iodized oil mixture, followed by an absorbable gelatin sponge (Gelpart: NipponKayaku, Tokyo, Japan). Drug-eluting beads TACE was performed with 100–300 µm DC beads (BTG, London, UK) loaded with 50 mg of epirubicin or 50–100 µm Hepasphere (Nippon-Kayaku, Tokyo, Japan) loaded with 50 mg of fine powder cisplatin (IA-call; Nippon-Kayaku). Embolization was performed until stasis in the tumor feeding vessels, preserving flow in the segmental and lobar arteries. Thereafter, TACE was repeated every 6–8 weeks at the discretion of the investigators.

External beam radiation

External beam radiation therapy was delivered using an intensity-modulated radiation therapy technique and carried out using 6-MV X-ray with a linear accelerator (Varian Medical Systems). Gross target volume was defined as intrahepatic tumors and vascular invasion, referring to the CT, MRI, and angiography findings. The clinical target volume involved a 5 mm margin around the gross target volume. Planning target volume was expanded to include a 5mm margin from the clinical target volume. The treatment goal was 45–60 Gy in 25 fractions to the isocenter of the planning target volume. The prescription dose was adjusted based on proximity to the at-risk organ. RT was continued until completion or unacceptable toxicity.

Treatment Response And Safety Analyses

The participants were evaluated by physical examination, monitoring of symptoms and toxicity weekly during RT, and after each TACE. Contrast-enhanced dynamic CT or MRI was performed 6–8 weeks after each TACE and one month after the completion of RT to assess tumor response. Thereafter, patients received CT or MRI examination every 3 months at follow-up. Two independent radiologists assessed tumor response blindly according to the mRECIST[24], and any inconsistency of assessment results was resolved by discussion. The short-term efficacy was evaluated based on the tumor response at 3 months after the completion of the last TACE in each group, or at 3 months after the completion of RT if no TACE was performed after RT. The objective response rate (ORR) was defined as the proportion of participants with a complete response (CR) or partial response (PR), and the disease control rate (DCR) was defined as the proportion of participants with CR, PR, or stable disease (SD). OS was defined as the interval between the date of initial treatment and the date of death or last follow-up. PFS was defined as the date of initial treatment and the date of progression, death, or last follow-up. Treatment-related toxicity was graded according to the Common Terminology Criteria for Adverse Events (ver. 5.0). The follow-up was censored on December 31, 2022.

Statistical analysis

The two groups were compared by using Student’s t test for continuous data and Chi-square test for categorical data. Stratified Cox proportional hazards models were used for univariable and multivariable analyses. To reduce selection and confounding biases, propensity score matching (PSM) was used and the propensity scores were estimated using variables that were different between the two treatment groups (p < 0.1). Survival analysis was estimated by the Kaplan-Meier method, and differences between groups were assessed by log-rank test. A 2-tailed p value of < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS, version 22.0 (SPSS Inc., Chicago, IL).

Baseline characteristics

From October 2018 to October 2020, 148 eligible participants were diagnosed, among which 51 participants received RT-TACE-LEN and 97 participants received TACE-LEN. After 1:1 PSM, two matched groups were derived including 51 participants in the RT-TACE-LEN group and 51 participants in the TACE-LEN group. The baseline characteristics of the two matched groups are described in Table 1. No significant difference was found in any variables between these two groups (all p > 0.05). Most patients had tumor size > 5 cm (73.8%) and tumor number ≥ 2 (69.9%). According to the Cheng’s classification[5], 42.7% patients were classified as I-II grade of PVTT and the rest were III-IV grade. The most common HCC etiology was chronic HBV infection (81.6%). Majority of patients presented with well-compensated liver function (Child-Pugh class A, 80.6%) and good ECOG performance status (ECOG performance status = 0, 88.3%). The median dose/fraction was 50 Gy/25 fractions (range: 45–60 Gy/25 fractions). 50 Gy with 25 fractions of 2 Gy per fraction was the most common dose regimen (18 of 51 patients, 35.3%), followed by 45 Gy in 25 fractions of 1.8 Gy (16 of 51 patients, 31.4%), 55 Gy in 25 fractions of 2.2 Gy (13 of 51 patients, 25.5%), and 60 Gy in 25 fractions of 2.4 Gy (3 of 51 patients, 5.9%).

Table 1

Baseline characteristics of hepatocellular carcinoma patients with PVTT after propensity score matching
Variable	Patients, No. (%)			p value^a
	Total (n = 102)	RT-TACE-LEN (n = 51)	TACE-LEN (n = 51)
Age, median (range), year	53.5 (18–75)	54 (18–75)	53 (27–75)	0.507
Gender				0.136
Male	94 (91.3)	46 (90.2)	48 (94.1)
Female	8 (7.8)	5 (9.8)	3 (5.9)
Tumor size, cm				0.650
≤ 5	26 (25.2)	14 (27.5)	12 (23.5)
> 5	76 (73.8)	37 (72.5)	39 (76.5)
Tumor, No.				0.385
1	30 (29.1)	17 (33.3)	13 (25.5)
≥ 2	72 (69.9)	34 (66.7)	38 (74.5)
Portal vein tumor invasion				0.110
I-II grade	44 (42.7)	26 (51.0)	18 (35.5)
III-IV grade	58 (56.3)	25 (49.0)	33 (64.7)
ECOG performance status				0.750
0	91 (88.3)	45 (88.2)	46 (90.2)
1	11 (10.7)	6 (11.8)	5 (9.8)
Child-Pugh class				0.799
A	83 (80.6)	42 (82.4)	41 (80.4)
B	19 (18.4)	9 (17.6)	10 (19.6)
α-Fetoprotein, ug/L				0.692
≤ 400	54 (52.4)	28 (54.9)	26 (51.0)
> 400	48 (46.6)	23 (45.1)	25 (49.0)
Hepatitis B virus infection				0.603
Negative	18 (17.5)	10 (19.6)	8 (15.7)
Positive	84 (81.6)	41 (80.4)	43 (84.3)
Hepatitis C virus infection				> 0.999
Negative	97 (94.2)	48 (94.1)	49 (96.1)
Positive	5 (4.9)	3 (5.9)	2 (3.9)
^aCategorical variables were estimated by Chi-square test, and continuous variables were estimated by Student's t test.
Abbreviations:
RT, radiation; TACE, transarterial chemoembolization; LEN, lenvatinib; No., number; ECOG, Eastern Cooperative Oncology Group.

Safety

Any-grade toxicities were noted in 51 (100%) and 33 (64.7%) patients in the RT-TACE-LEN group and the TACE-LEN group, respectively (Table 2). Although the overall incidence of toxicities of any grade was higher in RT-TACE-LEN compared with TACE-LEN (p < 0.001), the rates of grade 3–4 toxicities were comparable (54.9% vs. 49.0%, p = 0.552). Toxicity profiles showed no significant difference between these two groups. Elevated aspartate aminotransferase was the most common grade 3–4 toxicity in both RT-TACE-LEN (n = 10, 19.6%) and TACE-LEN (n = 9, 17.6%) groups, following by elevated alanine aminotransferase (15.7% vs. 15.7%) and Hyperbilirubinemia (11.8% vs. 9.8%) All these toxicities were treated expectantly and recovered or restored to grade 1–2 post-treatment.

Table 2

Acute toxicity in patients treated by RT-TACE-LEN or TACE-LEN
Toxicity	Any Grade		p value	Grade 3–4		p value
	Group, No. (%)			Group, No. (%)
	RT-TACE-LEN (n = 51)	TACE-LEN (n = 51)		RT-TACE-LEN (n = 51)	TACE-LEN (n = 51)
Ascites	7 (13.7)	6 (11.8)	0.767	3 (5.9)	2 (3.9)	0.645
Elevated ALT	12 (23.5)	10 (19.6)	0.630	8 (15.7)	8 (15.7)	> .999
Elevated AST	13 (25.5)	11 (21.6)	0.641	10 (19.6)	9 (17.6)	0.799
Hyperbilirubinemia	10 (19.6)	9 (17.6)	0.799	6 (11.8)	5 (9.8)	0.750
Hypoalbuminemia	9 (17.6)	7 (13.7)	0.586	1 (2.0)	1 (2.0)	> 0.999
Total	51 (100.0)	33 (64.7)	< 0.001	28 (54.9)	25 (49.0)	0.552
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; RT, radiation; TACE, transarterial chemoembolization; LEN, lenvatinib.

Efficacy Analysis

The median follow-up for all patients was 24.0 months (range: 20.0-25.6 months). By the time of assessment of the short-term efficacy, 2 patients achieved CR and 27 patients achieved PR after treatment in the RT-TACE-LEN group, with an ORR of 56.9% and a DCR of 92.1%. As for TACE-LEN group, the overall frequencies of CR (2.0%, 1/51) and PR (49.0%, 25/51) were comparable to those of RT-TACE-LEN group, with an ORR of 51.0% and a DCR of 90.2% (Supplementary Table 1).

As for survival outcomes, the 1-year and 2-year PFS rates were 56.2% and 14.9% in the RT-TACE-LEN group, respectively, which were higher than those in the TACE-LEN group (39.2% and 8.5%, respectively). Patients in the RT-TACE-LEN group had a significantly longer median PFS than those in TACE-LEN group (12.8 vs. 10.5 months, p = 0.035; Fig. 1a). As for OS, patients in the RT-TACE-LEN group showed higher 1-year and 2-year OS rates than patients in the TACE-LEN group (1-year OS rate: 91.8% vs. 74.4%; 2-year OS rate: 48.1% vs. 31.3%). And RT-TACE-LEN group presented with a significantly longer median OS than TACE-LEN as well (22.8 vs. 17.1 months, p = 0.031; Fig. 1b).

Uni- And Multivariate Analyses

In the univariable analysis, treatment allocation with RT-TACE-LEN was a significantly favorable factor for both PFS and OS, while older age, gender of male, lager tumor size, tumor number of more than 1, higher grade of PVTT, Child-Pugh class A, higher AFP level, Hepatitis B virus infection and Hepatitis C virus infection showed no statistical difference (Table 3). Multivariable analysis demonstrated that RT-TACE-LEN treatment was associated with better PFS (HR 0.577; 95% CI 0.364–0.915; p = 0.019) and OS (HR 0.529; 95% CI 0.298–0.938; p = 0.029) over TACE-LEN treatment, while ECOG performance status = 0 only contributed to better PFS (HR 0.397; 95% CI 0.160–0.989; p = 0.047) but not OS (HR 0.387; 95% CI 0.120–1.248; p = 0.112).

Table 3

Univariate and multivariate analyses of predictors of overall survival and progression free survival after treatment
Variable	Overall survival				Progression free survival
	Univariate analysis	Multivariate analysis			Univariate analysis	Multivariate analysis
	p value	Hazard Ratio	95% CI	p value	p value	Hazard Ratio	95% CI	p value
Age (≤ 60/> 60yrs)	0.288				0.182
Gender (Male/Female)	0.432				0.423
Tumor size (≤ 5/> 5cm)	0.735				0.178
Tumor number (1/≥2)	0.898				0.244
Portal vein tumor invasion (I-II/III-IV)	0.567				0.204
ECOG performance status (0/1)	0.109	0.387	0.120–1.248	0.112	0.027	0.397	0.160–0.989	0.047
Child-Pugh class(A/B)	0.505				0.501
α-Fetoprotein (≤ 400/> 400 ug/L)	0.834				0.915
Hepatitis B virus infection (Positive/Negative)	0.262				0.403
Hepatitis C virus infection (Positive/Negative)	0.216				0.999
Treatment allocation (RT-TACE-LEN/TACE-LEN)	0.002	0.529	0.298–0.938	0.029	0.002	0.577	0.364–0.915	0.019
Abbreviations: CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; RT, radiation; TACE, transarterial chemoembolization; LEN, Lenvatinib.

To the best of our knowledge, this is the first clinical trial to estimate the safety and efficacy of RT plus TACE and LEN in HCC with PVTT. Our study demonstrated that RT-TACE-LEN favored significantly longer PFS and OS over TACE-LEN, and the therapeutic modality was an independent prognostic factor for both PFS and OS. Besides, treatment-related toxicities of RT-TACE-LEN were acceptable and manageable.

PVTT was an important prognostic factor for poor survival outcomes among patients with HCC. It not only promotes intrahepatic tumor spread but also rapidly decreases blood supply to the liver, causing rapid deterioration of liver function and increased risk of portal hypertensive complications[25], which greatly limits the application of TACE in the treatment of PVTT. So far, there have been no worldwide consensuses or guidelines on the treatment of HCC with PVTT. Western guidelines regard PVTT as an advanced stage of HCC with little hope for a cure, and thus only recommend sorafenib or LEN monotherapy as standard of care[9, 26], resulting in a median OS of no more than 13 months. While in the eastern countries, anticancer treatments are more aggressive: surgical resection, RT and TACE are recommended for selected HCC patients with PVTT by Chinese, Japanese, South Korean, and Asia-Pacific clinical practice guidelines because of their promising survival outcomes in the clinical practice[27, 28]. Although, combination of TACE and LEN has been demonstrated clinical benefit in the treatment of advanced HCC by our previous study, its efficacy against PVTT is limited and the prognosis of HCC patients with PVTT is still dismal[15]. Therefore, novel therapy modality including efficient local approach against PVTT should attach great importance.

The potential benefits of applying RT to the treatment of PVTT has been reported by previous studies[20, 21, 29, 30], and one of the primary indications for RT is the macrovascular invasion. Yoon et al reported in a randomized clinical trial that patients with HCC showing macroscopic vascular invasion in the TACE-RT group had a significantly higher radiologic response rate than the sorafenib group at 24 weeks (33.3% vs. 2.2%, p < 0.001), a significantly longer median time to progression (31.0 vs. 11.7 weeks, p < 0.001), and significantly longer OS (55.0 vs. 43.0 weeks, p = 0.040) [21]. As in the current study, consistent results have been described that adding RT to TACE and LEN could further prolong the median OS and PFS to 22.8 and 12.8 months, respectively. The possible rationale for this triple combination therapy might be attributed to the quick reduction in tumor thrombus volume through radiation, which may relieve portal blood flow, allowing the maintenance of liver function, limiting intrahepatic tumor spread, and thereby allowing additional TACE[31, 32].Conversely, failure outside the radiation field could be complement by combining TACE and LEN treatment.

In terms of safety, most adverse events in our study were mild to moderate and could be manageable, which was similar to previous studies that combined therapy was used to treat advanced HCC[20, 21]. More than 90% of patients receiving TACE-RT treatment experienced any-grade adverse events and 12% were reported with serious adverse events reported by Yoon et al. And the most common toxicities ≥ grade 3 included AST/ALT increase (13.3%), diarrhea (2.2%), abdominal pain (2.2%), and bilirubin increase (2.2%)[21]. As in our study, hepatic toxicity was the most common adverse event in TACE-LEN group, announcing approximately 20% of ALT/AST increase. Toxicity profile was similar in the RT-TACE-LEN group to that of TACE-LEN, and adding RT did not significantly increase the incidences of serious adverse events. Given these findings, toxicities caused by RT-TACE-LEN seemed to be acceptable and tolerable.

Several limitations should be considered in the current study. First, it was a nonrandomized controlled trial involving only three medical centers in China. Second, the number of included patients was relatively small. Thus, larger-sample sized, more medical centers and randomized-designed clinical trials are warranted to confirm the clinical benefit of this triple combination therapy.

In conclusion, our study demonstrated that, for patients with HCC showing PVTT, the combination therapy of RT-TACE-LEN was well tolerated and provided significantly improved PFS and OS compared with TACE-LEN. This novel triple combination therapy may be a promising treatment for patients with advanced HCC showing PVTT. Further studies are needed to confirm our findings.

Author Contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Xiaofang He, Aoran Dong, Meiyan Zhu and Zeyu Zhang. The first draft of the manuscript was written by Xiaofang He and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding This study was supported by the National Natural Science Foundation of China (No. 82072029), the National high level talents special support plan - “Ten thousand plan” - Young top - notch talent support program, and the Guangdong Basic and Applied Basic Research Foundation (No. 2021A1515111101).

Conflict of Interest The authors report no potential conflict of interest.

Ethics approval This study was approved by the institution’s Ethics Committee (approval number: [2020]247) and conformed to the standards of the Declaration of Helsinki. Before enrollment, all the participants provided written informed consent comprising a data privacy item for data collection and analysis for research purposes.

Villanueva A. Hepatocellular Carcinoma. The New England journal of medicine 2019;380:1450-1462.
Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA: a cancer journal for clinicians 2022;72:7-33.
Yang JD, Heimbach JK. New advances in the diagnosis and management of hepatocellular carcinoma. BMJ 2020;371:m3544.
Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2018;68:723-750.
Shi J, Lai EC, Li N, et al. A new classification for hepatocellular carcinoma with portal vein tumor thrombus. J Hepatobiliary Pancreat Sci 2011;18:74-80.
Park JW, Chen M, Colombo M, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study. Liver Int 2015;35:2155-2166.
Bruix J, Raoul JL, Sherman M, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. Journal of hepatology 2012;57:821-829.
Cheng AL, Qin S, Ikeda M, et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol 2022;76:862-873.
Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 2018;67:358-380.
Vogel A, Martinelli E. Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice Guidelines. Ann Oncol 2021;32:801-805.
Cheng AL, Kang YK, Chen Z, 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. Lancet Oncol 2009;10:25-34.
Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018;391:1163-1173.
Tsurusaki M, Murakami T. Surgical and Locoregional Therapy of HCC: TACE. Liver cancer 2015;4:165-175.
Sieghart W, Hucke F, Peck-Radosavljevic M. Transarterial chemoembolization: modalities, indication, and patient selection. J Hepatol 2015;62:1187-1195.
] Peng Z, Fan W, Zhu B, et al. Lenvatinib Combined With Transarterial Chemoembolization as First-Line Treatment for Advanced Hepatocellular Carcinoma: A Phase III, Randomized Clinical Trial (LAUNCH). Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2022:Jco2200392.
Schöniger-Hekele M, Müller C, Kutilek M, et al. Hepatocellular carcinoma in Central Europe: prognostic features and survival. Gut 2001;48:103-109.
Zhang ZM, Lai EC, Zhang C, et al. The strategies for treating primary hepatocellular carcinoma with portal vein tumor thrombus. Int J Surg 2015;20:8-16.
Yu JI, Park HC. Radiotherapy as valid modality for hepatocellular carcinoma with portal vein tumor thrombosis. World J Gastroenterol 2016;22:6851-6863.
Llovet JM, De Baere T, Kulik L, et al. Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2021;18:293-313.
Abulimiti M, Li Z, Wang H, et al. Combination Intensity-Modulated Radiotherapy and Sorafenib Improves Outcomes in Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis. J Oncol 2021;2021:9943683.
Yoon SM, Ryoo BY, Lee SJ, et al. Efficacy and Safety of Transarterial Chemoembolization Plus External Beam Radiotherapy vs Sorafenib in Hepatocellular Carcinoma With Macroscopic Vascular Invasion: A Randomized Clinical Trial. JAMA oncology 2018;4:661-669.
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;1:756-765.
Peng Z, Chen S, Wei M, et al. Advanced Recurrent Hepatocellular Carcinoma: Treatment with Sorafenib Alone or in Combination with Transarterial Chemoembolization and Radiofrequency Ablation. Radiology 2018;287:705-714.
Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010;30:52-60.
Yoon SM, Lim YS, Won HJ, 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;82:2004-2011.
EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2018;69:182-236.
Omata M, Cheng AL, Kokudo N, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int 2017;11:317-370.
Lu J, Zhang XP, Zhong BY, et al. Management of patients with hepatocellular carcinoma and portal vein tumour thrombosis: comparing east and west. The lancet Gastroenterology & hepatology 2019;4:721-730.
Buckstein M, Kim E, Özbek U, et al. Combination TACE and SBRT for Unresectable Single Large HCC: Results from a Prospective Phase II Trial. Int J Radiat Oncol Biol Phys 2022.
]Pérez-Romasanta LA, González-Del Portillo E, Rodríguez-Gutiérrez A, et al. Stereotactic Radiotherapy for Hepatocellular Carcinoma, Radiosensitization Strategies and Radiation-Immunotherapy Combination. Cancers (Basel) 2021;13.
Zeng ZC, Fan J, Tang ZY, et al. A comparison of treatment combinations with and without radiotherapy for hepatocellular carcinoma with portal vein and/or inferior vena cava tumor thrombus. Int J Radiat Oncol Biol Phys 2005;61:432-443.
Yu JI, Park JW, Park HC, et al. Clinical impact of combined transarterial chemoembolization and radiotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis: An external validation study. Radiother Oncol 2016;118:408-415.

No competing interests reported.

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Efficacy of Radiation Plus Transarterial Chemoembolization and Lenvatinib in Hepatocellular Carcinoma With Portal Vein Tumor Thrombus

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Abstract

Objective

Methods

Results

Conclusions

Figures

Introduction

Materials And Methods

Study Design and Participants

Treatment Protocol

Treatment schema

Lenvatinib administration

TACE

External beam radiation

Treatment Response And Safety Analyses

Statistical analysis

Results

Baseline characteristics

Safety

Efficacy Analysis

Uni- And Multivariate Analyses

Discussion

Declarations

References

Additional Declarations

Supplementary Files

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