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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 4  |  Page : 754-759

Efficacy and safety of computed tomography-guided 125I brachytherapy for lymph node metastatic from hepatocellular carcinoma


1 Department of Interventional Radiology, Southwest Hospital, Third Military Medical University, Chongqing, China
2 Department of Interventional Radiology, Southwest Hospital, Third Military Medical University; Department of Radiotherapy, Daping Hospital, Third Military Medical University, Chongqing, China

Date of Web Publication27-Jun-2018

Correspondence Address:
Xue-Quan Huang
Department of Interventional Radiology, Southwest Hospital, Third Military Medical University, Chongqing 400038
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_245_17

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 > Abstract 


Purpose: A survival benefit may be associated with the positive control of extrahepatic lymph node metastasis (LNM) of hepatocellular carcinoma (HCC). However, no standard treatment exists. The aim of this study was to evaluate the safety and efficacy of iodine-125 (125I) brachytherapy (BT) of LNM of HCC, especially in patients with multiple lymph nodules or repeated lymph node recurrence.
Materials and Methods: From June 2007 to July 2016, clinical and imaging data of 22 patients were collected at our center. According to the treatment planning system, 37 BT targets were treated by seed implantation with computed tomography (CT)-guidance. The radioactive treatment-related adverse events and surgical complications were recorded. The BT target therapeutic response was evaluated by the RECIST. The median survival time and rates were evaluated by the Kaplan–Meier method.
Results: Twenty-two patients were enrolled (median age: 48 years; 90.9% males), and 58 lymph node areas were diagnosed as metastatic. The incidence of LNM was high in porta hepatis (33.9%) and right para-aortic nodes (14.2%), and lower incidence rates were observed in other areas. The median imaging follow-up time was 12 months (inter-quartile range 5.5–20.5), the complete response was 29, the partial response was 5, the stable disease was 2, the progressive disease was 1, and the local response rate was 91.8%. The median survival time from the beginning of BT was 25 months. The 1, 2, and 3-year overall survival rates were 64.3%, 43.4%, and 27.1%, respectively, and the 5-year overall survival rate from the time of HCC diagnosis was 31.1%. No BT-induced acute morbidity according to the Radiation Therapy Oncology Group criteria was reported. After 5.5 months, one patient diagnosed with a duodenal ulcer underwent gastroduodenoscopy. The surgical complications included mild pancreatitis in 3 patients and stomach bleeding and pneumothorax in 1 patient.
Conclusion: CT-guided 125I BT treatment of LNM of HCC presented good local control rates and controllable complications. It is a safe and effective palliative treatment for patients with LNM of HCC. Further study is needed to evaluate its long-term safety and efficacy.

Keywords: 125I seed, brachytherapy, computed tomography-guided, hepatocellular carcinoma, lymph node metastasis


How to cite this article:
He C, Liu Y, Li Y, Yang L, Li YT, Li SL, Huang XQ. Efficacy and safety of computed tomography-guided 125I brachytherapy for lymph node metastatic from hepatocellular carcinoma. J Can Res Ther 2018;14:754-9

How to cite this URL:
He C, Liu Y, Li Y, Yang L, Li YT, Li SL, Huang XQ. Efficacy and safety of computed tomography-guided 125I brachytherapy for lymph node metastatic from hepatocellular carcinoma. J Can Res Ther [serial online] 2018 [cited 2019 Nov 14];14:754-9. Available from: http://www.cancerjournal.net/text.asp?2018/14/4/754/235083




 > Introduction Top


Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide.[1] Primary HCC lesions can be reasonably controlled using modalities such as resection, liver transplantation, radiofrequency ablation (RFA), and transcatheter arterial chemoembolization (TACE), but the odds of extrahepatic metastasis are increased. The prognoses of patients with extrahepatic metastasis of HCC were poor in the current study. Sorafenib is the treatment of choice for HCC with extrahepatic spread, but an overall response rate of <5% and the absence of a survival benefit in subgroups with extrahepatic metastases receiving sorafenib monotherapy has indicated that this agent is likely ineffective in the absence of local therapies.[2],[3],[4],[5] Lymph node metastasis (LNM) is the main risk factor that influences overall survival in patients with HCC with extrahepatic metastasis.[6],[7],[8] The guidelines regarding whether LNM requires local treatment are not clearly indicated. The treatments for LNM of HCC include surgical resection, RFA, external radiotherapy, photodynamic therapy, TACE, and supportive care, among others.[9],[10],[11],[12],[13],[14],[15],[16],[17] However, it remains difficult to effectively treat extrahepatic LNM of HCC, especially in the case of multiple LNMs and repeated lymph node recurrence. The aims of this study were to present our experiences of iodine-125 (125 I) implantation for LNM of HCC and to discuss the safety and efficacy in selected patients with good intrahepatic lesion control.


 > Methods Top


Patients and diagnosis

This retrospective study was approved by the Institutional Ethics Committee, and all patients provided written informed consent. This study included 22 patients who underwent brachytherapy (BT) for LNM of HCC between June 2007 and July 2016 [Table 1]. The primary tumor size was 5.5 ± 3.95 cm. All patients were pathologically (n = 18) or clinically (n = 4) diagnosed with HCC, based on the guidelines of the Ministry of Health of the People's Republic of China, and the cases were classified as follows:[18] well-differentiated in 1 case, moderately differentiated in 9 cases, poorly differentiated in 2 cases, and unknown in 6 cases. LNM was diagnosed by computed tomography (CT) or magnetic resonance imaging enhancement. The diagnosis criteria included the following:[19] (1) lymph nodes measuring 1 cm or more in minimum diameter, (2) contrast-enhanced lymph nodes were observed in the arterial phases, and (3) an interval size increase was observed in previously identified lymph nodes. All patients underwent CT-guided percutaneous 125 I seed implantation. Thirty-seven therapeutic targets were present in our group, of which 24 were single LNMs, and 13 were multiple LNMs. Symptoms related to LNM occurred in 3 cases.
Table 1: Patient characteristics

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Criteria for enrollment

Inclusion criteria: (1) Child-Pugh Grade A or B, (2) no hepatic encephalopathy, (3) no cerebral or spinal canal metastasis, (4) local control of intrahepatic recurrence of lesions, (5) extrahepatic non-LNM ≤2, (6) simultaneous and metachronous single and multiple LNMs and repeated LNM, and (7) Karnofsky >80.

Exclusion criteria: (1) Child-Pugh Grade C, (2) noncontrollable intrahepatic recurrence of lesions, (3) extrahepatic non-LNM ≥3 or poor local control, and (4) incomplete follow-up data.

Computed tomography-guided implantation and puncture methods

All patients underwent CT scanning (Somatom plus 4; Siemens) with thorax, abdominal, and neck imaging parameters of 120 kV, 200 mA, and a slice thickness of 5 mm.125 I seeds (Beijing ZHIBO Bio-Medical Technology Co., Ltd, China), each with a specific activity of 0.8 mCi, were used, as well as a treatment planning system (TPS) (Image Processing Center; Beihang University; Beijing). The CT-enhanced image was imported to the TPS, and single lymph nodes or neighboring multiple lymph nodes were defined as the therapy targets. The gross target volume (GTV) included all enlarged lymph node margins. The planning target volume was defined as the GTV. The appropriate position was selected according to the preoperative planning, regular disinfection was performed, a surgical drape was placed, local anesthesia with 0.5% lidocaine was administered, and CT-guided puncture needle interpolation was performed. The images were transferred to the TPS for postoperative validation. If treatment of the nonradiated region was administered, reimplantation was performed. The puncture methods were as follows:[20] single needle, parallel needle, by organ, widened path, coaxial needle, and reliance on the vessel wall.

Evaluation of the curative effect

The therapeutic response of the target lesion was evaluated by the RECIST.[21] A complete response (CR) was defined as the disappearance of the tumor; a partial response (PR) was defined as a ≥30% reduction in the largest diameter of the tumor; progressive disease (PD) was defined as a ≥20% increase in the largest diameter of the tumor or the appearance of one or more new lesions; stable disease (SD) was defined as a response that did not qualify as a PR or PD. The local response rate (LRR) was calculated as: (CR number + PR number)/total number of cases × 100%. All patients underwent follow-up enhancement CT scans after implantation. The time of evaluation was considered the last CT examination or target-lesion progression.

Follow-up, toxicity, and surgical complications

After the completion of BT, patients were followed-up at 1 month, every 3 months for the first 2 years, and every 6 months thereafter. The cutoff date for follow-up was July 2016 and was the final cutoff date for the last imaging examination in two cases. The overall survival rate from the time of HCC diagnosis was the overall survival after seed implantation from the time of surgery to the cutoff date. Toxicity was evaluated according to the Radiation Therapy Oncology Group (RTOG) criteria.[22] Surgery-related complications were diagnosed by CT or laboratory examination.

Statistical analysis

SPSS 13.0 Software was used for the statistical analysis. Continuous variables are presented as the mean values ± standard deviation. Nonnormally distributed data are expressed as medians (Interquartile range [IQR] 25%–75%). Preoperative and postoperative parameters were compared with a nonparametric paired t-test, and a value of P < 0.05 was considered statistically significant. The median survival times and rates were evaluated by the Kaplan–Meier method.


 > Results Top


Patients and tumor characteristics

The patient characteristics at the time of BT are summarized in [Table 1]. Simultaneous and metachronous LNMs were diagnosed in 8 and 14 cases, respectively. The locations of LNM were divided into lymph node divisions based on a cross-sectional nodal  Atlas More Details [23] and were as follows: hepatic portal nodes in 19 cases; right para-aortic nodes in 8 cases; superior mesenteric, left paraaortic nodes, celiac trunk, and aortic-pulmonary window nodes in 4 cases; diaphragm and portopulmonary nodes in 3 cases; right paratracheal and esophageal nodes in 2 cases; and left paratracheal, right renal hilum, pretracheal, right side of the colon, and right neck nodes in 1 case. The retroperitoneal LNM-related symptoms included mild lumbar pain in 3 cases. The remaining LNMs showed no clinical symptoms.

Dosimetry description

The median prescription dose was 100 Gy (IQR 90–100 Gy). The specific activity of the seeds was 0.8 mCi. The preoperative planning parameters were as follows: GTV = 24.1 cc (IQR: 12.3–50.9), Dose 90 (D90, 90% of the tumor volume receiving the prescription dose) =105.5 ± 10.8 Gy, and number of seeds = 21 (IQR: 14–40.5). The postoperative parameters were as follows: GTV = 26.4 cc (IQR: 14–55.6), D90 =87.6 ± 20.4 Gy, and number of seeds = 26 (IQR: 15–43). Statistically significant differences were found for the GTV, D90, and number of seeds between the preoperative and postoperative periods (P< 0.05) [Table 2].
Table 2: Dosimetry description

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Response to treatment and overall survival

Regarding the evaluation of the tumor response, 22 patients underwent follow-up liver CT imaging. The number of BT targets was 37; 29 targets (78.3%) achieved a CR, 5 (13.5%) achieved a PR, 2 (5.4%) achieved SD, and 1 (2.7%) achieved PD. The LRR was 91.8%. One of the BT targets was classified as PD [Figure 1], 2 were classified as SD, and 3 patients underwent reimplantation. During the follow-up period, 9 patients remained alive, and 13 patients died. The median survival time from the beginning of BT was 25 months, and the 1-, 2-, and 3-year overall survival rates were 64.3%, 43.4%, and 27.1%, respectively. The 5-year overall survival rate from the time of HCC diagnosis was 31.1% [Figure 2]. The causes of death were hepatic failure following the progression of HCC and underlying liver cirrhosis in 11 patients, distant metastasis in 1 patient, and 1 patient was lost to follow-up. An excellent palliative effect of BT was observed, and all 3 patients with LNM-related symptoms recovered.
Figure 1: A 47-year-old man with moderately differentiated hepatocellular carcinoma with lymph node metastasis located in the area where the inferior vena cava enters the atrium. (a) The puncture method with a “parallel needle” was used for needle interpolation with computed tomography guidance. (b) The postoperative validation D90was 39.1 Gy (c/d) Three months later, the lesion was classifed as progressive disease (e)

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Figure 2: Overall survival and overall survival after seed implantation curves for lymph node metastasis of hepatocellular carcinoma

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Toxicity and surgical complications

According to the RTOG criteria, no transient acute gastrointestinal toxicity was observed. A duodenal ulcer appeared in one patient 5.5 months after treatment. The symptoms were relieved after treatment to protect the gastric mucosa and induce acid suppression. The survival time was 26 months after BT, and the patient died due to recurrence of intrahepatic tumors. The postoperative serum amylase level was increased in 3 patients. The treatment of mild pancreatitis included fasting, somatostatin, and acid suppression. Because the puncture was performed through the stomach, gastric bleeding was diagnosed after puncture surgery in one patient. A small amount of pneumothorax appeared in 1 case of mediastinal LNM after puncture surgery that was resolved with supportive care or spontaneously. No surgical infection occurred in this group. No needle transfer was reported during the follow-up period. No treatment-related hepatic failures or treatment-related deaths were observed.


 > Discussion Top


Our data showed that the BT target D90 was 87.6 ± 20.4 Gy, which is less than that of the prescription dose (105.5 ± 10.8 Gy) (t = 4.845, P = 0.000); the LRR was 91.8%. One target lesion was classified as PD in the area in which the inferior vena cava enters the atrium [Figure 2]. The D90 was 39.1 Gy. Local recurrence was found 3 months later. In the follow-up, local recurrence was not diagnosed after seed reimplantation. Gao et al.[24] showed that the local control rates after 3, 6, 10, and 15 months were 75.0, 50.0, 42.9, and 33.3%, respectively. These findings showed the good controllability of LNM of HCC. Radiotherapy studies have shown that a higher radiotherapy dose was associated with higher LRR values.[12],[19] The LRR became significantly higher as the radiation dose increased from <45–45 to 54–55 Gy10(biologically effective dose, α/β =10).[5] Another study showed that the LRR was 83% and was significantly higher in patients who had received ≥58 Gy10 than in those who had received <58 Gy10(P = 0.014).[25] Similarly, the BT efficacy may be dose related. No studies have examined the dose of BT for LNM of HCC; therefore, the optimal BT dose is unclear. In our study, the preoperative and postoperative doses were recorded [Table 2]. Statistically, significant differences were found for the GTV, D90, and the sum of seeds between the preoperative and postoperative periods (P< 0.05). Although various surgical techniques were used for seed implantation, the BT dose was still below the prescription dose. In our opinion, this occurred because we did not perform real-time dose verification.

The main prognostic factors were the controllability of intrahepatic lesions and performance status.[25],[26] The lymph nodes were the most frequent site of extrahepatic metastases for primary HCC.[8] The discomfort of mild abdominal pain was the most common clinical symptom. Three common lethal patterns of LNMs of HCC, as summarized by Zeng et al.,[27] were observed as follows: Jaundice is often induced by biliary obstruction, pyloric (or duodenal) obstruction results in abdominal pain, and inferior vena cava obstruction is usually followed by ascites and edema of the lower extremities. The presence of lymph node-related symptoms was closely associated with poor survival.[28] Positive control of extrahepatic LNMs of HCC may reduce lymph node-related symptoms and prolong the survival time.[9],[10],[17],[27],[29],[30] It remains difficult to treat multiple LNMs or repeated lymph node recurrence. The modality of treatment for LNM of HCC has not been fully discussed.[9] Excellent radiotherapy response rates for patients with LNM of HCC have been reported. The overall survival was associated with the lymph node response to radiotherapy, which suggested that radiotherapy for LNM of HCC might improve overall survival in these patients.[5],[27] Therefore, the positive control of LNM may prolong overall survival. In our study, good control of extrahepatic LNM by radioactive 125 I seeds led to a good treatment outcome of 125 I seed therapy in HCC patients with LNM. The median survival time from the beginning of BT was 25 months; the 1, 2, and 3-year overall survival rates were 64.3%, 43.4%, and 27.1%, respectively, and the 5-year overall survival rate from the time of HCC diagnosis was 31.1%.

Typically, radiotherapy-induced acute gastrointestinal toxicity, upper abdominal pain, and gastric or duodenal ulcers occur in treated patients.[5],[11],[12] As the radiation dose increases, the radiation-related complications increase, and the serious complication of gastrointestinal bleeding, which is related to the radiation dose, occurs. Few reports have examined radioactive 125 I seed implantation for the treatment of LNM of HCC, and no study has reported the acute and long-term toxicity. Zeng et al.[27] reported that fatal gastroduodenal ulcer bleeding occurred in 4 (44.4%) of 9 patients who had received a dose of >56 Gy. The incidence of treatment-related gastroduodenal ulcer was 37.5% in patients who received a BED >50 Gy10 but was 0% for patients who received a BED <50 Gy10.[12] The time to ulcer development was 2–7 months (median, 4 months) after radiotherapy.[12] In this study, late gastrointestinal toxicity, defined as gastric or duodenal ulcers surrounding the BT field, was observed in 1 patient (Grade 1) at 5.5 months after BT. The lesion was located in the pancreatic head region and duodenum and was wrapped tightly. The target D90 was 91.6 Gy, and the gastroduodenal D2cc(2 cc of the tumor volume subjected to the prescription dose) was 114 Gy. We suspect that the main reason for delayed ulcer development was the high D2cc dose. Lesions close to the organ at risk (OAR), low-activity seeds, or the maintenance of a certain distance from the OAR may reduce the risk of late radiation toxicity.

There are some limitations of our study. The number of patients was very small, and the follow-up periods were short. No BT dose trial of 125 I seed implantation was conducted in patients with LNM of HCC. The optimal BT dose requirements are unclear. However, a prospective randomized trial is necessary to draw definitive conclusions.


 > Conclusion Top


In our study, a new method was introduced for the treatment of LNM of HCC. The results of this retrospective study suggest that LNM of HCC is sensitive to 125 I seeds. The D90 of the target lesions was 87.6 ± 20.4 Gy, and the LRR was 91.8%. The radiation toxicity and surgical complications were well controlled in our study. Thus, the method is a safe and effective palliative treatment for patients with LNM of HCC and may prolong overall survival.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgments

The Department of Pathology, Ultrasound and Radiology Southwest Hospital, Third Military Medical University performed the diagnosis of HCC and played a crucial role in the generation of this manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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