This study evaluated if iodine-125 brachytherapy prophylaxis after radiofrequency ablation (RFA) prolongs time to recurrence (TTR) and overall survival (OS) of patients in high risk of locoregional hepatocellular carcinoma (HCC) recurrence. 116 patients with total tumor necrosis after RFA were divided into iodine-125 brachytherapy prophylaxis treatment group and control group. The primary endpoint was TTR, and secondary endpoints were OS and treatment-related adverse events. There were no significant differences among the baseline characteristics of two subgroups patients. The mean iodine-125 particles were 29.8 (26.59 ± 12.51 mCi) per patient. The mean follow-up was 25 months, and mean TTR of treatment and control groups were 21.7 and 15.9 months (P = 0.733); mean OS of two subgroups were 41.7 and 40.9 months (P = 0.316). There were no significant differences of 1-, 2-, 3-, 4-and 5-years TTR and OS and patients’ immunity pre- and 1 month post-treatment. Extrahepatic metastasis was found to have a statistically significant influence on TTR, and AFP, extrahepatic metastasis were found to have a statistically significant influence on OS by multivariate analysis. There was no major complications and procedure related death. Iodine-125 brachytherapy prophylaxis after RFA can’t improve TTR and OS of HCC patients who were in high risk of locoregional tumor recurrence.
Radiofrequency ablation (RFA) has been shown to be a safe and efficient treatment for hepatocellular carcinoma (HCC)1,2,3. However, clinical studies have reported a high rate of inadequate RFA treatment for large tumors (>3 cm) and high locoregional tumors recurrence rate4, 5. The long term prognosis, however, remains unsatisfactory because of frequent development of locoregional tumor recurrence6. Especially to the patients who with irregular liver lesions, or the tumor locate adjacent to liver capsule, diaphragm, gallbladder, and important blood vessels7. Hirooka, et al.7 reported that the median time to recurrence of patients with HCC in the tumor blood drainage area following RFA was significantly shorter than patients who with HCC not in the tumor blood drainage area (434 days vs 1,474 days; P = 0.0037), and the cumulative locoregional tumors recurrence rates at 1, 3, and 5 years post-operatively were 0, 0, and 1.5%, vs 3.8%, 17.0%, and 22.8% (P < 0.0001), respectively. Tumor lesions locate adjacent to liver capsule, diaphragm, gallbladder, and important blood vessels has a high rate of inadequate RFA, and those patients were in high risk of tumor recurrence after RFA8, 9.
Iodine-125 brachytherapy can get high locoregional tumors control and low complication rate in the treatment of malignant tumors10,11,12,13,14. It was reported that adjuvant iodine-125 brachytherapy can significantly prolong time to recurrence (TTR) and increase the overall survival (OS) of patients who with HCC15.
The purpose of this study was to evaluate if iodine-125 brachytherapy prophylaxis after RFA prolongs TTR and OS of HCC patients who were in high risk of locoregional tumor recurrence.
Materials and Methods
This retrospective study was approved by the institutional review board and was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki. All patients who received iodine-125 brachytherapy prophylaxis after RFA at our institution were included. Cases were identified through departmental procedural logs. Patient demographics, clinical information, and procedural data were gathered from patients’ medical records.
Inclusion criteria were: age between 18–80 years; clinic or histologically proven HCC; no portal vein tumor thrombus; the tumor lesions were locate adjacent to liver capsule, diaphragm, gallbladder, or important blood vessels; patients who with total tumor necrosis after RFA; Karnofsky performance status (KPS) > 70; Child-Pugh A or B; adequate hepatic function (albumin > 2.5 g/dL, total bilirubin < 3.0 mg/dL), and complete clinic follow-up.
Exclusion criteria were: severe cardiac, pulmonary, cerebral, or renal dysfunction; with other active malignancy; any other contraindication like: gastrointestinal hemorrhage in the past month, refractory ascites, encephalopathy, impaired coagulation, severe portal hypertension; contraindications to lidocaine; patients who received other treatment pre RFA; patients with a history of concomitant use of some targeting agents, chemotherapy and immunotherapy; and patients who were lost to follow-up. Informed consent was obtained in all patients, and the study was approved by the Ethics Committee of Lishui Central Hospital (Lishui, China). All the methods were carried out in accordance with the approved guidelines.
Groups and Definitions
Patients were divided into two subgroups, including treatment group: patients underwent iodine-125 brachytherapy prophylaxis after RFA; and control group: only follow-up. The primary endpoint was TTR, and the secondary endpoints were OS and treatment-related adverse events.
High risk of locoregional HCC recurrence was defined as tumor lesions locate adjacent to liver capsule, diaphragm, gallbladder, and important blood vessels. TTR was measured from the date of first RFA to the date when the diagnosis of locoregional tumors recurrence was established (only locoregional tumor recurrences were calculated, and the distant recurrences were excluded). Patients who died without recurrence were censored at their date of death. OS was calculated from the date of first RFA to the time of death or the last follow-up.
RFA technique was described in our previous study16. Enhanced computed tomography (CT) or magnetic resonance imaging (MRI) was underwent 4–6 weeks after the procedure. Patients who with the tumor locate adjacent to liver capsule, diaphragm, gallbladder, important blood vessels, and identified total tumor necrosis after RFA, were divided into treatment and control groups. Patients of treatment group received iodine-125 brachytherapy prophylaxis.
Iodine-125 particles (0.8 mm in diameter and 4.5 mm in length, Tianjin Saide Bio-Pharmaceutical Co. Ltd. Tianjin, China) were implanted under CT guidance. The radioactivity of each iodine-125 seed is 25.9 MBq with a half-life of 59.4 days. The principal photon emissions are 27.4–31.4 keV X-ray and 35.5 keV γ-ray. The half-value thickness of tissue for iodine-125 seeds is 17 mm, and the initial dose rate is 7 cGy/h. The effective irradiating range is 20 mm. The radioactivity per seed ranged from 0.8 to 1.0 millicuries (mCi).
Iodine-125 particles were implanted in the place of high risk of tumor recurrence according to the tumor location. The number of the iodine-125 particles was determined by the area of tumor margin near the liver capsule, diaphragm, gallbladder, or important blood vessels. The distance between iodine-125 particles was within 0.5–1.0 cm according to the literature17, 18.
Repeated RFA was applied to the patients who was diagnosed of locoregional tumor recurrence. Iodine-125 brachytherapy with or without transarterial chemoembolisation (TACE) was carried out if the locoregional tumor was unsuitble for repeat RFA.
Evaluation and Clinical Follow-Up
The evaluation criteria of imaging mass as “viable tumor” was the evaluated object as proposed by American Association for the Study of Liver Diseases (AASLD), which is modified Response Evaluation Criteria In Solid Tumors criteria (mRECIST)8. After discharge, outpatient clinic visits were offered every month at first 3 months, and every 3 months thereafter. More frequent evaluations were necessary when indicated. Symptom status, complete blood count, liver function, alpha-fetoprotein (AFP), and enhanced CT scan or MRI were obtained during follow-up.
The statistical analyses were performed by using SPSS 23.0 software (SPSS, Chicago, Ill). Comparisons between the two subgroups were performed by using the Student t test for continuous data and the Chi-square test for categorical data. TTR and OS were calculated by using the life-table method. Survival curves were constructed by using the Kaplan-Meier method and were compared by using the log-rank test. The relative prognostic significance of the variables in predicting the OS rate and the time to tumor recurrence or metastasis were assessed by using multivariate Cox proportional hazards regression analysis and logistic regression analysis, respectively. All statistical tests were two sided, and P < 0.05 was considered to indicate a significant difference.
Patients and treatment-related data
From Feb 2009 to Aug 2016, a total of 138 HCC patients who with the lesions locate adjacent to liver capsule, diaphragm, gallbladder, or important blood vessels, were identified total tumor necrosis after RFA. Of the 138 cases, a total of 22 cases were excluded for received targeting agents therapy (n = 8), lost to follow-up (n = 14), and a total of 116 cases were at last included in the final analysis, including 46 patients (42 men, 4 women; mean age, 59.1 ± 10.4 years; range, 29–78 years) of treatment group, and 70 patients (62 men, 8 women; mean age, 56.2 ± 11.8 years; range, 18–80 years) of control group (Fig. 1). Table 1 lists the characteristics of the 2 subgroups patients. There were no significant differences among the baseline characteristics of the two subgroups patients.
Treatment group: a total of 1223 iodine-125 particles (29.8 iodine-125 particles and 26.59 ± 12.51 mCi per case) were used through 20 iodine-125 procedures (one iodine-125 procedure per case). Of the 46 patients who received iodine-125 brachytherapy prophylaxis, abdominal pain and fever was observed in 16 patients and none required medical intervention. There was no major complications and procedure relate death.
The mean follow-up was 25 months (range, 1–77 months), and the mean TTR of treatment and control groups were 21.7 and 15.9 months, respectively (P = 0.733, Fig. 2); and the mean OS of treatment and control groups were 41.7 and 40.9 months, respectively (P = 0.314, Fig. 3). Table 2 lists the 1-, 2-, 3-,4- and 5-years TTR and OS, and there were no significant differences between the two groups (p > 0.05).
Predictors of TTR and OS
Of the 7 clinical factors analyzed by Cox regression model, univariate analysis identified extrahepatic metastasis associated with TTR and 3 significant factors associated with survival, including AFP (P < 0.001), diameter of tumor (P = 0.044), and extrahepatic metastasis (P = 0.024). However, only extrahepatic metastasis (P = 0.036) was found to have a statistically significant influence on TTR, and AFP (P < 0.001), extrahepatic metastasis (P = 0.009) were found to have a statistically significant influence on OS by multivariate analysis (Table 3).
There were no significant difference of the patients’ immunity, including IgG, IgA, IgM, IgE, C3, and C4 pre- and 1 month post-iodine-125 brachytherapy (Table 4).
The present study demonstrates iodine-125 brachytherapy prophylaxis after RFA cannot improve TTR and OS of HCC patients who were in high risk of locoregional tumor recurrence, with the mean TTR were 21.7 and15.9 months, and mean OS were 41.7 and 40.9 months of two subgroups, respectively.
RFA has emerged as a new curative treatment owing to its safety and effectiveness for early-stage small HCC19. However, the patients who with the tumor location close to blood vessels, liver capsule, and vital structures were in high risk of locoregional tumor recurrence8, 9, 20, 21. It was reported that the combination of RFA and TACE or percutaneous ethanol injection (PEI) in the management of HCC in high-risk locations has a slightly higher primary effectiveness rate than does RFA alone9, 22. Many other techniques can also improve the results of RFA for HCC in high-risk locations23, 24.
Iodine-125 brachytherapy can get high locoregional tumor control rate of malignant tumors10,11,12,13,14. Also, the adjuvant iodine-125 brachytherapy can significantly prolonged TTR and OS of patients who with HCC15. However, there was no report about the iodine-125 brachytherapy prophylaxis for patients who have risk factors of locoregional tumors recurrence. Can the iodine-125 brachytherapy prophylaxis after RFA prolongs TTR and OS of patients with HCC. This study was carried out to answer those questions.
The patients of the current study were all in high risk of locoregional tumor recurrence. The results of the current study proved that although the TTR and OS of treatment groups patients were longer than the control groups patients, there were no significant differences among them. The negative results of this study maybe have close relationship with the total tumor necrosis was achieved in all the treatment group patients one month after RFA, the disease was stable of such patients and the iodine-125 brachytherapy prophylaxis cannot benefit such patients. The results of this study proved that iodine-125 brachytherapy prophylaxis after RFA cannot benefit the patients who were in high risk of locoregional tumor recurrence.
A number of factors that have been reported to limit the TTR and OS for patients with HCC. Our study further reveals that extrahepatic metastasis (P = 0.036) to be independent prognostic factors for TTR, and AFP (P < 0.001), extrahepatic metastasis (P = 0.009) to be independent prognostic factors for OS.
Iodine-125 brachytherapy has been proved to a safe manner in the treatment of malignant tumors. Recently, Iodine-125 brachytherapy has also been used for treating HCC, and it has a larger local irradiation dose and results in less damage to normal liver tissues8, 9. A possible reason for this is that the irradiation has a stronger therapeutic effect on the thermal-damaged lesions due to the synergistic effect of radiotherapy and thermotherapy. More importantly, the killing radius of 125I is short (1.7 cm), which almost has no effect on the normal tissues around the lesions18, 25. Patients of this study were in high risk of locoregional tumor recurrence, and received iodine-125 brachytherapy. The results of this study proved iodine-125 brachytherapy is safe after RFA.
The major limitation of this nonrandomized study is that its retrospective nature. Also, the amount of patients and the observation time was short. Furthermore, there were many factors, such as treatment of the locoregional tumors recurrence, metastasis, may influence on the overall prognosis, which might bias the results.
Iodine-125 brachytherapy prophylaxis after RFA cannot improve TTR and OS of HCC patients who were in high risk of locoregional tumor recurrence.
Ikeda, K. et al. Stage progression of small hepatocellular carcinoma after radical therapy: comparisons of radiofrequency ablation and surgery using the Markov model. Liver international: official journal of the International Association for the Study of the Liver 31, 692–699 (2011).
Sohn, W. et al. Role of radiofrequency ablation in patients with hepatocellular carcinoma who undergo prior transarterial chemoembolization: long-term outcomes and predictive factors. Gut and liver 8, 543–551 (2014).
Xie, H. et al. The efficacy of radiofrequency ablation combined with transcatheter arterial chemoembolization for primary hepatocellular carcinoma in a cohort of 487 patients. PloS one 9, e89081 (2014).
Orlacchio, A. et al. Radiofrequency thermoablation of HCC larger than 3 cm and less than 5 cm proximal to the gallbladder without gallbladder isolation: a single center experience. BioMed research international 2014, 896527 (2014).
van Duijnhoven, F. H. et al. Factors influencing the local failure rate of radiofrequency ablation of colorectal liver metastases. Annals of surgical oncology 13, 651–658 (2006).
Zhang, N. et al. Incomplete Radiofrequency Ablation Enhances Invasiveness and Metastasis of Residual Cancer of Hepatocellular Carcinoma Cell HCCLM3 via Activating β-Catenin Signaling. PloS one 9, e115949 (2014).
Hirooka, M. et al. Local recurrence of hepatocellular carcinoma in the tumor blood drainage area following radiofrequency ablation. Molecular and clinical oncology 2, 182–186 (2014).
Lu, D. S. et al. Influence of large peritumoral vessels on outcome of radiofrequency ablation of liver tumors. Journal of vascular and interventional radiology: JVIR 14, 1267–1274 (2003).
Wong, S. N. et al. Combined percutaneous radiofrequency ablation and ethanol injection for hepatocellular carcinoma in high-risk locations. AJR. American journal of roentgenology 190, W187–195 (2008).
Li, C. et al. Feasibility of (125)I brachytherapy combined with sorafenib treatment in patients with multiple lung metastases after liver transplantation for hepatocellular carcinoma. Journal of cancer research and clinical oncology 136, 1633–1640 (2010).
Meng, N. et al. Permanent implantation of iodine-125 seeds as a salvage therapy for recurrent head and neck carcinoma after radiotherapy. Cancer investigation 30, 236–242 (2012).
Ruge, M. I., Kickingereder, P., Simon, T., Treuer, H. & Sturm, V. Stereotactic iodine-125 brachytherapy for treatment of inoperable focal brainstem gliomas of WHO grades I and II: feasibility and long-term outcome. Journal of neuro-oncology 109, 273–283 (2012).
Zelefsky, M. J. et al. Comparison of the 5-year outcome and morbidity of three-dimensional conformal radiotherapy versus transperineal permanent iodine-125 implantation for early-stage prostatic cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 17, 517–522 (1999).
Zhongmin, W., Yu, L., Fenju, L., Kemin, C. & Gang, H. Clinical efficacy of CT-guided iodine-125 seed implantation therapy in patients with advanced pancreatic cancer. European radiology 20, 1786–1791 (2010).
Liu, R. Z. & Zhang, F.-J. Lobaplatin-TACE combined with radioactive 125I seed implantation for treatment of primary hepatocellular carcinoma. Asian Pacific Journal of Cancer Prevention 15, 5155–5160 (2014).
Tu, J. et al. Effectiveness of Combined 131I-chTNT and Radiofrequency Ablation Therapy in Treating Advanced Hepatocellular Carcinoma. Cell biochemistry and biophysics 1–8 (2014).
Chen, K. et al. Increased survival in hepatocellular carcinoma with iodine-125 implantation plus radiofrequency ablation: a prospective randomized controlled trial. Journal of hepatology 61, 1304–1311 (2014).
Peng, S. et al. Lobaplatin-TACE combined with radioactive 125I seed implantation for treatment of primary hepatocellular carcinoma. Asian Pacific journal of cancer prevention: APJCP 15, 5155–5160 (2014).
Llovet, J. M., Burroughs, A. & Bruix, J. Hepatocellular carcinoma. The Lancet 362, 1907–1917 (2003).
Berber, E. & Siperstein, A. Local recurrence after laparoscopic radiofrequency ablation of liver tumors: an analysis of 1032 tumors. Annals of surgical oncology 15, 2757–2764 (2008).
Mulier, S. et al. Local recurrence after hepatic radiofrequency coagulation: multivariate meta-analysis and review of contributing factors. Annals of surgery 242, 158–171 (2005).
Morimoto, M. et al. Radiofrequency ablation combined with transarterial chemoembolization for subcapsular hepatocellular carcinoma: a prospective cohort study. European journal of radiology 82, 497–503 (2013).
Kim, S. W. et al. Percutaneous radiofrequency ablation of hepatocellular carcinomas adjacent to the gallbladder with internally cooled electrodes: assessment of safety and therapeutic efficacy. Korean journal of radiology 10, 366–376 (2009).
Lee, C. H. et al. Radiofrequency ablation assisted by real-time virtual sonography for hepatocellular carcinoma inconspicuous under sonography and high-risk locations. The Kaohsiung journal of medical sciences 31, 413–419 (2015).
Nakamura, H. et al. DNA repair defect in AT cells and their hypersensitivity to low-dose-rate radiation. Radiation research 165, 277–282 (2006).
The authors would like to thank Zhongzhi Jia PhD, Department of Interventional Radiology, No. 2 People’s Hospital of Changzhou, China, for his help with revising the manuscript. This study was supported by the Program for Health Department of Zhejiang Province (Project Number: 2010KYA191) and the Program for Science and Technology Bureau of Lishui City (Project Number: 20120303).
The authors declare that they have no competing interests.
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.