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The prognosis of HCC patients with PVTT is poor, and PVTT is the factor limiting current treatment.
•
125I brachytherapy has a high LTCR in HCC patients with PVTT.
•
Patients aged <60 years, with type I+II PVTT, and with a tumor diameter <5 cm have a more favorable OS.
•
125I brachytherapy is safe for treating PVTT of HCC.
Rationale and objectives
Portal vein tumor thrombus (PVTT) seriously reduces the survival of patients with hepatocellular carcinoma (HCC). CT-guided iodine-125 (125I) brachytherapy has the advantage of a high local control rate and is minimally invasive. This study aims to evaluate the safety and efficacy of 125I brachytherapy for treating PVTT in HCC patients.
Materials and methods
Thirty-eight patients diagnosed with HCC complicated with PVTT and treated with 125I brachytherapy for PVTT were included in this retrospective study. The local tumor control rate, local tumor progression-free survival, and overall survival (OS) were analyzed. Cox proportional hazards regression analysis was performed to identify predictors affecting survival.
Results
The local tumor control rate was 78.9% (30/38). The median local tumor progression-free survival was 11.6 (95% confidence interval [CI]: 6.7, 16.5) months, and the median overall survival was 14.5 (95% CI: 9.2, 19.7) months. Multivariate Cox analysis showed that age <60 years (hazard ratio [HR] = 0.362; 95% CI: 0.136, 0.965; p = 0.042), type I+II PVTT (HR = 0.065; 95% CI: 0.019, 0.228; p < 0.001), and tumor diameter <5 cm (HR = 0.250; 95% CI: 0.084, 0.748; p = 0.013) were significant predictors of OS. There were no serious adverse events related to 125I seed implantation during the follow-up period.
Conclusion
CT-guided 125I brachytherapy is effective and safe for treating PVTT of HCC, with a high local control rate and no severe adverse events. Patients younger than 60 years old with type I+II PVTT and a tumor diameter less than 5 cm have a more favorable OS.
Portal vein tumor thrombosis (PVTT) is the most common form of vascular invasion in hepatocellular carcinoma (HCC) and significantly reduces patient survival (
An Eastern Hepatobiliary Surgery Hospital/Portal Vein Tumor Thrombus Scoring System as an Aid to Decision Making on Hepatectomy for Hepatocellular Carcinoma Patients With Portal Vein Tumor Thrombus: A Multicenter Study.
). PVTT can increase intrinsic tumor invasiveness, impair the liver function reserve, cause or worsen portal hypertension, and decrease tolerance to antitumor therapy (
Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
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.
Short- to mid-term evaluation of CT-guided 125I brachytherapy on intra-hepatic recurrent tumors and/or extra-hepatic metastases after liver transplantation for hepatocellular carcinoma.
), but there are few studies on 125I brachytherapy for PVTT. The use of transcatheter arterial chemoembolization (TACE) combined with 125I brachytherapy to treat HCC with PVTT can significantly improve patient survival compared with TACE alone (
Safety and Efficacy of Irradiation Stent Placement for Malignant Portal Vein Thrombus Combined with Transarterial Chemoembolization for Hepatocellular Carcinoma: A Single-Center Experience.
). However, the safety and efficacy of percutaneous 125I seed implantation in terms of local control of PVTT have rarely been reported. Therefore, this study will evaluate the efficacy and safety of CT-guided 125I brachytherapy for treating PVTT and further identify prognostic survival factors.
MATERIALS AND METHODS
Patients
This retrospective study was performed in accordance with the Declaration of Helsinki of the World Medical Association. The Institutional Review Board approved this study, and the requirement for patient informed consent was waived because of the low risks associated with the study. From March 2016 to May 2021, 49 patients were enrolled according to the following inclusion and exclusion criteria. Eleven patients were excluded because of previous 125I brachytherapy (n = 4), a lack of baseline data (n = 5), and loss to follow-up (n = 2). A total of 38 patients were eventually included in this study (Fig 1).
Fig. 1Patient flow diagram. Patients who previously received 125I brachytherapy (n = 4), lack of baseline data (n = 5), and loss of follow-up (n = 2) were excluded from the study. HCC, hepatocellular carcinoma; 125I, Iodine-125; PVTT, portal vein tumor thrombus.
The inclusion criteria were as follows: i) met the criteria for pathological diagnosis or clinical diagnosis of HCC; ii) met the criteria for type I, II, or III PVTT based on Cheng's classification; iii) aged 18–75 years; iv) had an Eastern Cooperative Oncology Group (ECOG) score of 0–2; and v) had an intrahepatic tumor evaluated as stable disease (SD) and underwent 125I seed implantation to treat PVTT. The exclusion criteria were as follows: i) history of intrahepatic cholangiocarcinoma and other types of primary malignant tumors; ii) acute and chronic thrombosis of the portal vein; iii) type IV PVTT based on Cheng's classification; iv) concurrent uncontrollable infections or other underlying severe diseases; v) severe complications of portal hypertension, such as variceal bleeding and refractory ascites; and vi) end-stage tumor without indications for local treatment. According to the degree of portal vein invasion, Cheng's classification (
) divides PVTT into four types: type I, tumor thrombus invading the portal vein branches of the hepatic lobe or segment of the liver; type II, tumor thrombus invading the left or right branches of the portal vein; type III, tumor thrombus invading the main portal vein; and type IV, tumor thrombus invading the superior mesenteric vein.
125I Seed Brachytherapy
The 125I seeds (Yunke Medical Co., Ltd., Chengdu, China) used in the study were housed in a titanium packaging cylinder with a length of 4.5 mm and a diameter of 0.8 mm that contained a silver column with a length of 3.0 mm and a diameter of 0.5 mm. The radioactivity was 0.8 mCi, with an average energy of 27–35 keV and a half-life of 59.6 days (
). The wall thickness of the titanium in the housing case was 0.05 mm. CT with a cross-section thickness of 5 mm was performed for the patients before 125I seed implantation. The obtained CT images were used to delineate the tumor target volume, identify the protected organs, and aid in preoperative treatment planning, as shown in Figure 2. The preoperative CT images of each patient were imported into the treatment planning system (TPS, Beijing Tianhang Kelin Technology Development Co., Ltd) to create the treatment plan and to determine the number, dose, and placement sites of the implanted 125I seeds; the analyzed characteristics included the total volume of the tumor, the planned target volume, and the surrounding vital organs. The planned target volume was defined as the tumor's total volume with a margin expanded by 1.5 cm (
). The number and spatial distribution of particles in the tumor target area were optimized according to the dose-volume histogram (DVH) generated, to ensure that the dose in the target region reached 90% of the prescribed dose (V100)>90% and that 90% of the gross tumor targets received a prescribed dose (D90)>120 Gy. Moreover, the needle path and depth of the particle implantation needle were determined to achieve accurate implantation and avoid damage to vital organs or structures.
Fig. 2Treatment planning system (TPS) of 125I brachytherapy. (A) CT scanning images showed the preoperative 125I seed implantation and needle path planning. (B) Preoperative DVH diagram, D90 = 119.20 Gy, V100 = 92.7%. (C) Three-dimensional visualization of preoperative TPS plan. (D) CT scanning images showed the distribution of 125I seeds radiation dose after implantation. (E) Postoperative DVH diagram, D90 = 116.22 Gy, V100 = 91.2%. (F) Three-dimensional visualization of postoperative dose verification.
The patients underwent an electrocardiogram, blood pressure monitoring, and local infiltration anesthesia with lidocaine in the supine or prone position during the operation. Implantation was performed under the guidance of a Philips Spiral CT (Philips Brilliance Big Gore HOST-7610, kv120, mA235), with a scanning slice thickness of 5 mm. According to the preoperative treatment plan and needle insertion route, the 18G puncture needle was precisely implanted into the distal end of the target lesion, the needle was withdrawn gradually from the deep to the shallow end, and the 125I seeds were pushed into the nidus of the PVTT at intervals of 0.5–1.0 cm. After implantation, a CT scan was performed for the TPS plan to verify the radiation dose and range of the 125I seeds. For lesions that received insufficient radiation doses during the actual operation, namely, those with cold radiation areas, the TPS plan was appropriately adjusted for a second supplement procedure to meet the radiation dosimetry requirements. After implantation, the CT scan was repeated to observe whether there were related adverse events (AEs), such as pneumothorax, hemorrhage, or pneumatosis of the biliary tract. Nausea, vomiting, abdominal pain, abdominal distension, and other adverse reactions were recorded.
Follow-Up and Efficacy Evaluation
Patients underwent abdominal CT examinations every 6–8 weeks after 125I seed implantation and efficacy evaluations. The end of follow-up was death, loss to follow-up or December 7, 2021. According to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) (
The Modified Response Evaluation Criteria in Solid Tumors (RECIST) Yield a More Accurate Prognoses Than the RECIST 1.1 in Hepatocellular Carcinoma Treated with Transarterial Radioembolization.
), the local effect of 125I seeds on the PVTT was evaluated as complete response (CR), partial response (PR), SD, and disease progression (PD). Local tumor control rate (LTCR, consisting of CR, PR, SD), local tumor progression-free survival (LTPFS), and overall survival (OS) were analyzed. The AEs related to 125I seed implantation, including hemorrhage, bile duct injury, abdominal pain, fever, and seed migration, were recorded during the follow-up period.
Statistical Analysis
Continuous variables are presented with standard descriptive statistics, including means, standard deviations, medians, and ranges, and compared using the t test. Categoric variables are presented as frequencies and compared with the Pearson χ2 test. LTPFS and OS were analyzed using the Kaplan‒Meier method, and the groups were compared with the log-rank test (Mantel‒Cox). Univariate and multivariate Cox proportional hazard regression models were used to determine the predictors associated with OS. Using Cox proportional hazard regression models, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Statistical analysis was performed using SPSS Statistics 26.0 software (IBM). A P value ≤0.05 was considered to indicate a statistically significant difference, and all statistical tests were two-sided.
RESULTS
Baseline Data of the Patients
The average age was 53.3 ± 11.6 years, and the mean Model for End-stage Liver Disease (MELD) score was 7.7 ± 1.6. Eleven (28.9%) patients had tumors <5 cm in maximum diameter, and 27 (71.1%) patients had tumors ≥5 cm. There were six (15.8%), 14 (36.8%), and 18 (47.4%) patients with type I, II, and III PVTT, respectively. Thirty-two (84.2%) patients had hepatitis B, 10 (26.3%) patients had a history of previous surgical resection, and 18 (47.4%) patients had a history of prior targeted drug therapy. All patients were classified as Barcelona Clinic Liver Cancer (BCLC) stage C, with a Child‒Pugh class of A, and had a history of previous TACE treatment; none had a history of external beam radiotherapy. The baseline data of the included patients are shown in Table 1.
Preoperative Prescribed Dose and Postoperative Dose Verification
The radioactivity of all 125I seeds was 0.8 mCi, and the median number of implanted 125I seeds was 20 (range: 15–32). The mean of the preoperative prescribed dose was V100 = 92.37% (range: 87.3–96.7%), and the average D90 was 122.24 Gy (range: 111.42–131.73 Gy). In the postoperative dose verification, the mean V100 = 86.53% (range: 76.9–98.1%), and the mean D90 = 121.46 Gy (range: 110.76–139.57 Gy).
Local Control
According to mRECIST criteria and the follow-up imaging data, the patients with HCC and PVTT were evaluated for local tumor response after 125I seed implantation.
In the efficacy evaluations, there were eight (21.1%), 18 (47.4%), four (10.5%), and eight (21.1%) patients who had CR, PR, SD, and disease progression, respectively. The LTCR was 78.9% (30/38). An example is shown in Figure 3.
Fig. 3A 46-year-old man with hepatocellular carcinoma and portal vein tumor thrombus (PVTT) received 125I brachytherapy and was evaluated as PR. (A) Preoperative CT enhanced scanning images. (B) Intraoperative needle puncture process. (C) An intraoperative CT scan showed that 125I seeds were evenly distributed in the tumor. (D) Four months after 125I seeds implantation, a CT scan showed most PVTT activity disappeared, and 125I seeds aggregation was left.
The median LTPFS was 11.6 (95% CI: 6.7, 16.5) months (Fig 4 A), and the median OS was 14.5 (95% CI: 9.2, 19.7) months (Fig 4 B). In the Cox proportional hazard regression model, as shown in Table 2, the multivariate analysis showed that age <60 years (HR = 0.362; 95% CI: 0.136, 0.965; p = 0.042), type I+II PVTT (HR = 0.065; 95% CI: 0.019, 0.228; p < 0.001), and tumor diameter <5 cm (HR = 0.250; 95% CI: 0.084, 0.748; p = 0.013) were significant predictors of OS. Patients aged <60 years, with type I+II PVTT, and with a tumor diameter <5 cm had a better OS than those aged ≥60 years, with type III PVTT, and with a tumor diameter ≥5 cm. In the subgroup analysis, the median LTPFS was significantly better for type I+II PVTT than for type III PVTT (16.2 [95% CI: 12.5, 19.9] vs. 4.6 [95% CI: 2.4, 6.8], months, p = 0.001) (Fig 4 C). The median OS was significantly better for type I+II PVTT than for type III PVTT (31.2 [95% CI: 15.8, 46.7] vs. 5.6 [95% CI: 4.2, 7.0], months, p < 0.001) (Fig 4 D).
Fig. 4Kaplan-Meier analysis of local tumor progression-free survival (LTPFS) and overall survival (OS). The LTPFS (A) and OS (B) of all 38 patients. Subgroup analysis of the LTPFS (C) and OS (D) based on the different PVTT types.
As shown in Table 3, among the patients who underwent 125I seed implantation, three (7.9%) had local hemorrhage under the liver capsule afterwards according to the repeat CT, and two units of blood coagulase were injected to stop the bleeding. After observation, CT scans showed no increase in hemorrhage, and no further intervention was needed. Minor cases of local biliary pneumatosis were found in two (5.3%) patients. Five (13.2%) patients had mild abdominal pain within 24 hours after implantation. Fever and a body temperature ≥38.0 °C occurred in two (5.3%) patients within 24 hours. The symptoms of the above short-term AEs improved after symptomatic treatment. In three (7.9%) patients, the particles migrated to the mesenteric venous system during follow-up, but there were no clinical symptoms or thrombosis. None of the patients had symptoms such as abdominal pain or diarrhea. There were no severe 125I brachytherapy-related AEs.
Table 3125I seed implant-related adverse events
Adverse events
n
%
Local hemorrhage under the liver capsule
3
7.9
A minor local pneumatosis of bile ducts
2
5.3
Mild abdominal pain
5
13.2
Fever
2
5.3
Seeds migrated
3
7.9
Notes: Unless otherwise indicated, data are the number of patients, with percentages in parentheses.
PVTT is one of the most typical features of advanced HCC and is a severe threat to patient survival. The median OS of HCC patients with PVTT without antitumor therapy is only 2.7–4.0 months (
). It is worth noting that the risk of intravascular metastasis increases when PVTT is present, and obstruction of the blood flow in the portal vein may increase portal pressure (
). Further deterioration may cause or aggravate portal hypertension complications of cirrhosis, such as esophageal and gastric variceal bleeding, refractory ascites, and hepatic encephalopathy (
). Therefore, minimally invasive interventional therapy plays an essential role in treating HCC with PVTT, with the advantages of minor trauma and potential improvement of liver function.
125I brachytherapy seeds can continuously release radiation and affect the whole tumor cell cycle, providing high rates of local control (
). When 125I seeds are implanted into the target lesions, high-dose radiation is released in close range and simultaneously reduced in longer ranges to avoid damaging the surrounding liver tissues (
). Because of the unique characteristics of HCC patients with PVTT, this study retrospectively analyzed 38 patients with stable intrahepatic lesions who received 125I brachytherapy for PVTT lesions, analyzed the effects of 125I seeds on the LTCR and safety, and identified survival-related factors. The LTCR and the median LTPFS were 78.9% and 11.6 months, respectively, and no severe 125I brachytherapy-related AEs were observed, which was similar to real-world data.
Considering the complexity of HCC patients with PVTT in the clinic, this retrospective study had strict inclusion and exclusion criteria. All patients included in this study were classified as Child‒Pugh class A, had a history of TACE treatment and had no previous external radiation therapy. A total of 84.2% of patients had hepatitis B, 71.1% of the tumors were more than 5 cm in diameter, and nearly half of the patients had received targeted therapy. Patients with type IV PVTT based on Cheng's classification were not included in the study because these patients are usually complicated with severe portal hypertension and have poor survival. The median OS was 14.5 months, and multivariate analysis showed that age <60 years, type I+II PVTT, and tumor diameter <5 cm were significant factors affecting OS. In particular, patients with type III PVTT had poor LTPFS and OS with 125I brachytherapy. Therefore, for HCC patients with type III PVTT, 125I brachytherapy should be considered more carefully. Huang et al. showed that TACE plus 125I brachytherapy significantly improved the median OS of HCC patients with hepatitis B and type III PVTT compared with TACE alone (11.0 vs. 7.5 months). Arterioportal fistula was an independent predictor of poor prognosis (
Survival benefit of chemoembolization plus Iodine125 seed implantation in unresectable hepatitis B-related hepatocellular carcinoma with PVTT: a retrospective matched cohort study.
). In addition, no severe 125I brachytherapy-related AEs were found in this study during the intraoperative and follow-up periods.
PVTT has no response to coagulation, and portal vein recanalization through endovascular stent implantation can improve hepatic perfusion and relieve portal hypertension complications. Lu et al. showed that the technical success rate of self-expanding stents carrying 125I seeds in treating HCC with PVTT was 92.0%, and TACE was performed after stent placement (
Safety and Efficacy of Irradiation Stent Placement for Malignant Portal Vein Thrombus Combined with Transarterial Chemoembolization for Hepatocellular Carcinoma: A Single-Center Experience.
). Self-expanding stents carrying 125I seed plus TACE can prolong the patency of the portal vein for 8.0 months, for a median OS was 12.5 months. In addition, Li et al. showed that TACE combined with portal vein stents and 125I implantation had good safety and clinical efficacy in treating HCC with PVTT (
). Compared with TACE combined with stent implantation alone, the 125I brachytherapy group had a better median OS, less progression, and significantly improved long-term stent patency rate. Thus, 125I brachytherapy plays an essential role in improving portal vein recanalization.
This study also has some limitations. First, the factors affecting patient survival are relatively complex and due to the inherent limitations of retrospective studies, there is a certain degree of bias or error in the research process. Second, the reliability of imaging in evaluating treatment response may be poor because of the presence of multiple metallic seeds and possible beam hardening effects on CT. In addition, this study lacked a control group. Matching the patients to an appropriate control group is tricky in the real world because the current treatments for patients with HCC and PVTT are relatively diverse and complex. Therefore, the results of this study will be further verified by a large-sample, multicenter retrospective study or randomized controlled study.
In conclusion, CT-guided 125I brachytherapy is effective and safe for treating PVTT of HCC, with a high local control rate and no severe AEs. Patients younger than 60 years old with type I+II PVTT and a tumor diameter less than 5 cm have a more favorable OS.
Contributions
All authors contributed to and approved the final version of this manuscript. S. W. contributed to the study concept and design. Z-K. Q., Q. L., X-F. Q., and Z.C. were responsible for data acquisition, data abstraction, and study selection. Z-K. Q., S. Z., J. L., and G. F. performed the statistical analysis. Z-K.Q. and C-P. Y. drafted the manuscript. All authors made critical revisions to the manuscript.
Funding
This study was not funded.
Ethics
This retrospective study was performed in accordance with the Declaration of Helsinki of the World Medical Association. It was waived by The Affiliated Hospital of Qingdao University, and the informed consent of patients was waived because of its low risk.
Declaration of Competing Interest
None.
Acknowledgments
We thank colleagues who gave precious suggestions to this study.
An Eastern Hepatobiliary Surgery Hospital/Portal Vein Tumor Thrombus Scoring System as an Aid to Decision Making on Hepatectomy for Hepatocellular Carcinoma Patients With Portal Vein Tumor Thrombus: A Multicenter Study.
Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
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.
Short- to mid-term evaluation of CT-guided 125I brachytherapy on intra-hepatic recurrent tumors and/or extra-hepatic metastases after liver transplantation for hepatocellular carcinoma.
Safety and Efficacy of Irradiation Stent Placement for Malignant Portal Vein Thrombus Combined with Transarterial Chemoembolization for Hepatocellular Carcinoma: A Single-Center Experience.
The Modified Response Evaluation Criteria in Solid Tumors (RECIST) Yield a More Accurate Prognoses Than the RECIST 1.1 in Hepatocellular Carcinoma Treated with Transarterial Radioembolization.
Survival benefit of chemoembolization plus Iodine125 seed implantation in unresectable hepatitis B-related hepatocellular carcinoma with PVTT: a retrospective matched cohort study.
Conflicts of Interest: All other authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
means ± standard deviation.
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