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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 7  |  Page : 1553-1560

Computed tomography-guided iodine-125 brachytherapy for unresectable hepatocellular carcinoma


1 Department of Oncology, The Third Hospital of Qinhuangdao City, Qinhuangdao City, Hebei Province, China
2 Department of Interventional Medicine, Nanping First Hospital Affiliated to Fujian Medical University, Nanping City, Fujian Province, China
3 Department of Interventional Medicine, The Second Hospital of Shandong University, Institute of Tumor Intervention, Shandong University, Jinan City, Shandong Province, Nanping City, Fujian Province, China

Date of Submission21-Aug-2019
Date of Decision02-Sep-2019
Date of Acceptance24-Sep-2019
Date of Web Publication13-Jan-2020

Correspondence Address:
Prof. Wujie Wang
Department of Interventional Medicine, The Second Hospital of Shandong University, Institute of Tumor Intervention, Shandong University, 247 Beiyuan Street, Jinan City, Shandong Province, 250033
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_629_19

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 > Abstract 


Purpose: This study aimed to retrospectively assess the outcome of interstitial iodine-125 brachytherapy for unresectable hepatocellular carcinoma (HCC).
Materials and Methods: Between February 2013 and March 2019, 57 patients with 108 unresectable HCC lesions treated with computed tomography (CT)-guided iodine-125 seed brachytherapy were retrospectively analyzed. The primary endpoint was overall survival (OS). The secondary endpoints included local tumor control and progression-free survival (PFS). Potential factors associated with OS were assessed.
Results: The mean follow-up duration was 24.3 ± 15.6 months (median, 20.5 months; range, 3.9–66.8 months). The median OS time was 23.6 months (95% confidence interval [CI], 18.4–28.8 months). The 1-, 2-, and 3-year actuarial OS rates were 80.0%, 46.1%, and 24.3%, respectively. The median PFS time was 12 months (95% CI, 9.9–14.5 months). The 1- and 2-year actuarial PFS rates were 50% and 20.1%, respectively. Local progression was noted in 11 (11.3%) of 108 lesions with mean local control time of 20.5 ± 8.8 months. The 1- and 2-year local control rates were 96.5% and 88.8%, respectively. Barcelona clinic liver cancer stage and Child–Pugh score were independent risk factors affecting the prognosis (hazard ratio [HR] = 0.330 [95% CI, 0.128–0.853] and HR = 0.303 [95% CI, 0.151–0.610], respectively). Hepatic artery pseudoaneurysm was found in 1 (1.8%) patient with lesion located in the porta hepatis. No other major complications developed during follow-up.
Conclusion: CT-guided iodine-125 brachytherapy may be an effective and safe alternative with promising survival and increased local control rate in unresectable HCC treatment.

Keywords: Brachytherapy, iodine-125, unresectable hepatocellular carcinoma


How to cite this article:
Song Z, Ye J, Wang Y, Li Y, Wang W. Computed tomography-guided iodine-125 brachytherapy for unresectable hepatocellular carcinoma. J Can Res Ther 2019;15:1553-60

How to cite this URL:
Song Z, Ye J, Wang Y, Li Y, Wang W. Computed tomography-guided iodine-125 brachytherapy for unresectable hepatocellular carcinoma. J Can Res Ther [serial online] 2019 [cited 2020 Jul 7];15:1553-60. Available from: http://www.cancerjournal.net/text.asp?2019/15/7/1553/275562

Zhaoming Song and Jiacheng Ye contribute equally to this work.





 > Introduction Top


Hepatocellular carcinoma (HCC) ranks third among the leading causes of cancer-related death worldwide.[1] The incidence and mortality of HCC increased recently according to the statistics of the National Cancer Center.[2] Nowadays, surgical resection was the first-line treatment for HCC with 5-year survival rates of up to 51%.[3] However, a majority of patients are ineligible for resection due to advanced tumor stage, poor liver function, diffuse lesions, and comorbidity.[4] As the only potentially curative method, liver transplantation is restricted by the shortage of grafts and Milan criteria.[5] Radiofrequency ablation (RFA) is the advocated therapy for HCC lesions <3 cm in size with confirmed effectiveness.[1] The application of this method is limited by many factors, such as tumor location, size, and vascularization.[6] Complete ablation is potentially prohibited in tumors >5 cm in size, adjacent to large blood vessels, and close to vital organs.[7] Transarterial chemoembolization (TACE) was proved to be an effective method for unresectable HCC.[8] However, the survival was not satisfied in patients with Barcelona clinic liver cancer (BCLC) Stage B (16–16.9 months) and C (6–10.7 months) treated with this palliative method.[9],[10] Recently, iodine-125 seeds have been widely used in many types of tumors, and its efficacy has been confirmed by several randomized studies.[11],[12],[13] With a 1.7-cm tissue half-value layer, this low-energy radioactive seed was safe for the surrounding critical tissue. In contrast, the effect of iodine-125 was not restricted by portal vein tumor thrombus, tumor size, or heat sink effect of surrounding vessels.[14] However, there were limited studies related to iodine-125 brachytherapy for HCC.[15],[16] Our study investigates the therapeutic effect and prognostic factor of iodine-125 seed in treating unresectable HCC in 57 patients with long-term follow-up in two medical centers.


 > Materials and Methods Top


Patients and tumors

A total of 88 patients were treated with computed tomography (CT)-guided iodine-125 seed brachytherapy in three medical centers between January 2013 and March 2019. Thirty-one of 88 patients were lost to follow-up. The remaining 57 patients with 108 unresectable HCC lesions with detailed follow-up information were retrospectively analyzed. The diagnosis of HCC was based on imaging criteria and histopathology assessment. The inclusion of patients was decided by a consensus of the institutional multidisciplinary tumor board after other potential therapeutic methods were discussed. Patients were eligible if they met the following criteria: (1) largest tumor diameter <7 cm and tumor number <5, (2) liver function grade of Child–Pugh A or B, (3) total serum bilirubin level <51 μmol/L, (4) platelet count >50 × 109/L, (5) prothrombin time ratio >50%, and (6) Eastern Cooperative Oncology Group performance status ≤2. The exclusion criteria were as follows: (1) largest tumor diameter >7 cm or tumor number >5, (2) liver function grade of Child–Pugh C, (3) dyscrasia and multiple organ dysfunction or failure, and (4) refractory coagulation dysfunction. All patients provided written informed consent before the procedure. This retrospective study was approved by the institutional review board. All procedures conformed to the ethical standards of the institutional research committee and 1964 Declaration of Helsinki. Baseline characteristics of the patients and tumors are summarized in [Table 1].
Table 1: Baseline patient characteristics

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Procedure

Iodine-125 seed

We used the iodine-125 seeds (Chinese Jaco Pharmaceuticals Co., Ltd., Ningbo, China) with an activity of 0.6 mci and half-life of 59.6 days. Low-dose γ-ray (5% of 35 keV) was continuously released to damage the DNA of the target tumor with a 1.7-cm tissue half-value layer. About 93%–97% of the seed energy was delivered into the tumor after decaying for 8–10 months.

Preoperative planning

Abdominal contrast-enhanced CT images were acquired using a gemstone energy spectrum CT (General Electric Medical System, Milwaukee, WI) <7 days before the procedure. The DICOM format images were imported into the radioactive seed implantation treatment planning system (TPS) (Beijing University of Aeronautics and Astronautics, Beijing, China). The planning target volume (PTV) of each HCC lesions was carefully delineated in every slice. PTV was defined as the margin of gross target volume expanded 5 mm outward. A dose-volume histogram was generated by the TPS with a prescribed matched peripheral dose (MPD) of 110–160 Gy. The seed number and isodose curves were calculated. The dose distribution of the target tumor and risk organs was demonstrated. The implantation position and approach were also planned according to the location of the target tumor. The preoperative planning was simultaneously conducted by a specialist medical physicist and radiologist.

Computed tomography-guided iodine-125 brachytherapy

All procedures of seed implantation were performed by the interventional radiologists who have engaged in CT-guided iodine-125 brachytherapy for >10 years. Four hours of ambrosia was required before the procedure, which was accomplished under intravenous anesthesia using dexmedetomidine combined with local anesthesia using lidocaine. Vacuum cushion was applied to fix the appropriate position according to the preoperative plan. The location of tumor was identified by CT before the procedure. The puncture sites were marked on the skin, which were consistent with the plan. Moreover, 18-G needles (Hakko Co., Ltd., Chikuma, Japan) were inserted into the tumor and pushed forward until the tips reached the distal margin of the tumor. This process should be completed step-by-step to keep the puncture approach in line with the plan. Needles were retraced, and the seeds were implanted after all needles were located in the proper position according to the plan. The distance between the seeds was usually 1 cm or in compliance with the plan. Repeat CT was performed to check for possible complications. The image was imported into the TPS to verify the dose distribution. An appropriate number of seeds were implanted to ensure the quality of brachytherapy if a cold area was detected [Figure 1].
Figure 1: Images from an 85-year-old man with hepatocellular carcinoma. The patient was previously treated with transarterial chemoembolization. (a) Contrast-enhanced computed tomography showed a lesion located in liver segment VI with partial lipiodol deposition. The lesion was adjacent to the hepatic flexure of the colon. (b) Preoperative dose-volume histogram was generated by the treatment planning system. (c) Moreover, 18-G needles were inserted into the tumor. (d) Seeds were implanted. (e) Postoperative dose-volume histogram demonstrated a qualified dose distribution. (f) Contrast-enhanced computed tomography after 2 years showed that complete response was achieved

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Radiation protection

Patients who received iodine-125 brachytherapy were recommended to wear lead-containing radiation protection pad for 6 months. Patients need to keep a distance of >75 cm from the population, especially from vulnerable groups, such as pregnant women and children.[17],[18]

Follow-up and study endpoints

Contrast-enhanced CT or magnetic resonance imaging (MRI) was performed 1 month after the procedure and then every 3 months to assess the therapeutic effectiveness of brachytherapy. Liver function and alpha-fetoprotein were also examined.

Local tumor control (LTC) was defined based on the Response Evaluation Criteria in Solid Tumors. LTC referred to the proportion of tumors treated with iodine-125 brachytherapy and achieved complete response (CR), partial response (PR), and stable disease (SD).[19] Progression-free survival (PFS) was defined as the absence of new intrahepatic or extrahepatic lesion, local progression, or death. Time from the date of seed implantation to last follow-up or death was defined as overall survival (OS). Adverse events were assessed based on the guidelines of the Society of Interventional Radiology.[20] Radiation-induced liver disease (RILD) was characterized by increased alkaline phosphatase levels accompanied by ascites or total bilirubin level >51 μmol/L and ascites without tumor progression or obstructive jaundice 1 or 2 months after brachytherapy.

Statistical analysis

Data analysis was performed using SPSS (version 24; SPSS, Chicago, IL, USA). Continuous variables were expressed as mean ± standard deviation Data of abnormal distribution are presented as median and interquartile range (IQR) (25%–75%). OS, LTC, and PFS probabilities were calculated using the Kaplan–Meier method. Potential factors associated with OS were assessed using Cox proportional hazards regression model. Statistical significance was defined as P < 0.05. Stratified and analyzed study variables were stage of liver cancer (BCLC A or B), age (≤60 or >60 years), liver function grade (Child–Pugh A or B), largest tumor diameter (<5 or ≥5 cm), and tumor pattern (single or multifocal tumor).


 > Results Top


Seed implantation and dosimetry description

Seven (8.8%) of 57 patients underwent a second seed implantation session to match the requirements of dosimetry when the cold area was detected based on postoperative dose verification. The other 50 (91.2%) patients underwent a single brachytherapy session. The actuarial median MPD was 130 Gy (range, 110–160 Gy). The seed activity was 0.6 mCi. Among 108 tumors, the diameters of 34 lesions were >5 cm, and the other 64 lesions had a diameter <5 cm. The mean diameter of 108 lesions was 40.9 ± 16.3 mm. The actuarial PTV was 51.4 mL (IQR, 12.1–112.1), and 45 seeds were implanted (IQR, 16-–70). The actuarial dose 90 (D90, minimum absorbed dose at 90% target volume) was 131.6 Gy (IQR, 123.9–139.9).

Follow-up and complications

The mean follow-up duration was 24 ± 12.9 months (range, 3.2–60 months; median, 24 months). Eleven (19.3%) patients were alive during the last follow-up. Hepatic artery pseudoaneurysm was noted in one (1.8%) patient with the lesion located in the porta hepatis 3 days after the procedure. The patient was aged 58 years and had abdominal pain and melena after the procedure. The diagnosis was confirmed by contrast-enhanced CT and hepatic artery angiography. The pseudoaneurysm was located at the branch of the right hepatic artery. A microcatheter was inserted into the feeding artery, and embolization with coils was performed to prevent bleeding. This patient recovered well after the procedure. No other major complications developed during the follow-up. No procedure-related deaths were reported. No hepatic infection and RILD were observed. No needle tract metastases were diagnosed.

Local tumor control and disease progression

Local progression was found in 11 (11.3%) of 108 lesions with a mean local control time of 21.5 ± 7.5 months. Of the other 97 (89.8%) lesions, CR, PR, and SD were observed in 21 (19.4%), 53 (49.1%), and 23 (21.3%) lesions, respectively, during the follow-up. Generally, the 1- and 2-year local control rates were 97.8% and 89.8%, respectively [Figure 2]. Five (45.4%) of 11 cases of local progression were observed in tumors >5 cm in size. The other 6 (54.6%) cases of local progression were found in tumors <5 cm in size. Percutaneous ethanol injection was performed in 4 of 11 patients with local progression. Repeated iodine-125 brachytherapy was performed in the other 3 patients with local progression. Persistent LTC was achieved in these 7 patients during follow-up. Another 4 patients were treated with sorafenib for concurrent systemic progression. The median PFS time was 14.2 ± 2.3 months (95% confidence interval (CI), 9.7–18.7 months). The 1- and 2-year actuarial PFS rates were 55.9 and 26.8%, respectively [Figure 3]. Forty-seven (82.5%) of 57 patients developed intrahepatic or extrahepatic metastases during the follow-up.
Figure 2: Kaplan–Meier curves for local control of 108 unresectable hepatocellular carcinoma lesions treated with computed tomography-guided iodine-125 seed implantation

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Figure 3: Kaplan–Meier curves for progression-free survival time of this cohort treated with computed tomography-guided iodine-125 seed implantation

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Overall survival and prognostic factors

The median OS time was 23.6 months (95% CI, 18.4–28.8 months). The 1-, 2-, and 3-year actuarial OS rates were 80.0%, 46.1%, and 24.3%, respectively [Figure 4]. The analysis of prognostic factors related to OS is presented in [Table 2]. OS was not influenced by age or tumor pattern. The largest lesion diameter showed no statistically significant effect on OS after iodine-125 brachytherapy [Figure 5]. BCLC and Child–Pugh classification were shown to be independent factors affecting OS. Patients with BCLC A stage and Child–Pugh A liver function achieved better prognosis [Figure 6] and [Figure 7].
Figure 4: Kaplan–Meier curves for overall survival time of this cohort treated with computed tomography-guided iodine-125 seed implantation

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Table 2: Cox proportional hazards regression analysis of prognostic factors related to overall survival

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Figure 5: Overall survival curves based on the largest lesion diameter. The largest lesion diameter showed no statistically significant effect on overall survival after iodine-125 brachytherapy

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Figure 6: Overall survival curves based on the Barcelona clinic liver cancer classification according to Cox proportional hazards regression model. Barcelona clinic liver cancer classification was shown to be independent factors affecting overall survival. HR = Hazard ratio

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Figure 7: Overall survival curves based on Child–Pugh classification according to Cox proportional hazards regression model. Child–Pugh classification was shown to be independent factors affecting overall survival. HR = Hazard ratio

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 > Discussion Top


The treatment of unresectable HCC, which has a poor prognosis, remains challenging.[21] In this present study, the data on CT-guided iodine-125 brachytherapy in 57 patients with 108 tumors were reviewed. The promising results of this present study demonstrated that CT-guided iodine-125 brachytherapy was an effective and safe palliative therapeutic strategy in the treatment of unresectable HCC.

There were several studies that focused on brachytherapy for the treatment of intrahepatic malignancy, including 192 Ir and 90 Y for HCC and metastatic liver tumors.[22],[23],[24],[25],[26] However, there is limited literature on the application of iodine-125 seed implantation in unresectable HCC. Nag et al. reported their experience with iodine-125 brachytherapy in 64 patients with intrahepatic malignant tumors, but the tumor types were metastatic tumors and cholangiocarcinoma. The implantation methods used consisted of intraoperative ultrasound-guided volume implantation and planar surface implantation.[27] Other studies, referring to iodine-125 seed implanted to the liver masses reported by Martinez-Monge et al., Armstrong et al., and Donath et al., also focused on metastatic liver tumors.[28],[29],[30] In a small cohort reported by Lin et al., 23 patients with 65 HCC lesions were treated with MRI-guided iodine-125 brachytherapy. They achieved a local control rate of 84.5% and a 1-year survival rate of 95.7%.[31] To the best of our knowledge, our cohort of 57 patients with HCC represents one of the largest series of iodine-125 interstitial implantation in the treatment of unresectable HCC.

In this present review, iodine-125 was employed in 108 HCC tumors. The 1- and 2-year local control rates were 97.8 and 89.8%, respectively. This result is satisfactory, considering that the mean diameter of the 108 lesions was 40.9 ± 16.3 mm, and multifocal lesions were noted in 57.9% of 57 patients. Moreover, iodine-125 brachytherapy also demonstrated effectiveness in treating large tumors (diameter ≥5 cm) based on the results of our cohort, in which local tumor progression developed only in 5 (14.7%) of 34 lesions with diameters >5 cm, and the prognostic factor analysis showed that the largest lesion diameter was not an independent risk factor influencing survival. The same results were reported by earlier studies using high-dose-rate brachytherapy.[23],[32],[33]

Another major finding of this study was that the median OS time (23.6 months) was favorable compared with the data obtained from a meta-analysis, including 55 randomized controlled trials with 5,763 patients, comparing different liver-directed therapy options for unresectable HCC reported by Katsanos et al., where the estimated median survival time was 18.1 months in TACE and 20.6 months in drug-eluting bead TACE.[34] Furthermore, the assessment of prognostic factor identified that OS was affected by BCLC and Child–Pugh classification but was not influenced by tumor pattern after iodine-125 brachytherapy.

Historically, HCC had a low radiosensitivity, owing to the poor results from inadequate radiation dose delivered to the tumor, and the risk of radiation-related liver toxicity was a cause for concern.[35] However, this notion was proven to be incorrect with the advancement of radiotherapy technology, such as stereotactic conformal radiotherapy, which increased the delivery of radiation dose while reducing the harm to surrounding tissues.[36] Bujold et al. conducted a Phase I and II study using stereotactic body radiotherapy to treat 102 patients diagnosed with unresectable HCC. The median radiotherapy dose was 36 Gy. The 1-year local control rate was 87%, while the median OS time was 17 months.[37]

Iodine-125 brachytherapy is one of the methods of precision radiotherapy, which demonstrates favorable effectiveness in the treatment of several kinds of malignant carcinomas, such as prostate cancer, lung cancer, pancreatic carcinoma, secondary adrenal carcinoma, and lymph node metastatic carcinoma.[38],[39],[40],[41],[42] Under image guidance, iodine-125 seeds are directly implanted into the tumor. Owing to the 1.7-cm tissue half-value layer of iodine-125 seeds, the dose absorbed by the surrounding normal tissue falls off sharply; so, critical organs are spared from radiation toxicity. Simultaneously, sufficient dose is produced to kill the tumor cells. In this study, the actuarial median MPD and D90 was 130 Gy and 131.6 Gy, respectively. These results were higher compared with those in stereotactic body radiotherapy.[37] The high local control rate in this study may be attributed to this.

TACE remains the current standard strategy for intermediate unresectable HCC based on the clinical guidelines of the BCLC system.[9] The efficacy of this method in symptom control and prolonging survival was proved by several randomized controlled trials.[8] However, there is still a debate on its effectiveness due to the high heterogeneity in the therapeutic modalities.[43]

Recently, the multi-mode comprehensive treatment of unresectable HCC combined with TACE and other locoregional treatment methods, such as RFA, and high-dose-rate brachytherapy, was considered superior to TACE alone.[25],[44] In our study, TACE using lobaplatin, which was a third-generation platinum with radiation sensitization, was previously performed in a majority of this cohort.[45] The combination of TACE and iodine-125 brachytherapy may be another reason for the encouraging results of this study.

Special attention should be paid to the management of hilar lesions using iodine-125 brachytherapy for the complicated anatomical structure composed of hepatic artery, portal vein, and bile duct. In this present study, hepatic artery pseudoaneurysm relevant to needle puncture during the procedure was diagnosed in one (1.8%) patient with hilar lesion. The step-by-step techniques of intraoperative contrast enhancement and needle puncture were applied, and these complications were subsequently prevented. No other major complications, such as RILD, which is a serious complication related to liver irradiation and has a rate of up to 18.5% associated with stereotactic body radiotherapy, were noted in this study.[46] These results were consistent with the report by Nag et al.[27] Lin et al. punctured 65 HCC lesions to implant seeds, and no severe complications were observed.[31]

There are several limitations in this study. First, this is a retrospective study with a small cohort. The inherent selection bias should be taken into account. Second, a small number of patients were followed with contrast-enhanced CT rather than contrast-enhanced MRI, which has little influence on seed artifacts, so they can be used to accurately determine whether the lesion was active. Finally, no control group treated with the standard method, such as TACE, was set to compare the efficacy. For the abovementioned reasons, our results should be cautiously interpreted, and large sample randomized controlled trials with high quality were expected to confirm the reliability.


 > Conclusion Top


Our study suggests that CT-guided iodine-125 brachytherapy may be an effective and safe method to achieve better local control and prolonged survival for unresectable HCC. Iodine-125 seed implantation can be expected as another alternative locoregional therapeutic method to complement current options. Moreover, the evidence is still insufficient to justify the role of iodine-125 in the treatment of HCC.

Financial support and sponsorship

This work is supported by the Shandong Provincial Natural Science Foundation, China (ZR2018PH033, ZR2018PH032) and the National Natural Science Foundation of China (61671276).

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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