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    -  Song Z
    -  Guo X
    -  Yin C
    -  Wang Y

 
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ORIGINAL ARTICLE
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Therapeutic efficacy of TACE125I seed implantation and its combination with intra-tumor injection of cisplatin for the treatment of hepatocellular carcinoma


1 Department of Oncology, Third Hospital of Qinhuangdao, Qinhuangdao, China
2 Hepatology Department, The Third People's Hospital of Taiyuan, Taiyuan, China
3 Center for Disease Control of Beidaihe, Qinhuangdao, China
4 Intervention Medicine, The Second Hospital of Shandong University, Jinan, China

Date of Submission25-Sep-2018
Date of Decision02-May-2019
Date of Acceptance05-May-2019
Date of Web Publication02-Nov-2020

Correspondence Address:
Yongzheng Wang,
Intervention Medicine, The Second Hospital of Shandong University, Jinan
China
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_635_18

  Abstract 


Background: This study aimed to compare the therapeutic efficacy of transcatheter arterial chemoembolization (TACE) combined with either125I seed implantation or125I seed implantation and intra-tumor injection of cisplatin in treating hepatocellular carcinoma (HCC).
Methods: A total of 100 patients with HCC were analyzed. The control group (n = 50) received TACE combined with125I seed implantation therapy. The therapy group (n = 50) was treated with an intra-tumor injection of cisplatin along with TACE and125I seed implantation therapy. After treatment, routine blood, liver and kidney function, tumor volume, T lymphocyte subset count (CD3, CD4, and CD8), implanted metastases, and survival were studied.
Results: The tumor volume decreased by 27.4% on average in the control group, and by 38.6% in the therapy group. Alpha fetoprotein (AFP) level decreased in all cases, and it was significantly lower in the therapy group than in the control group. Remote metastasis was observed in both groups (7 in the control group and 3 in the therapy group). No significant difference in routine blood, liver and kidney function, and T-lymphocyte subset counts were found between the two groups. Eight patients died of metastases in the control group and 2 in the therapy group at 1-year follow-up (P < 0.05).
Conclusion: TACE combined with either125I seed implantation or125I seed implantation and intra-tumor injection of cisplatin was effective for the treatment of HCC. Of the 2 combination therapies, TACE combined with125I seed implantation and intra-tumor injection of cisplatin was more effective for the treatment of HCC.


Keywords: Brachytherapy,125I seed implantation, intra-tumor injection of cisplatin, trans-catheter arterial chemoembolization
Key Message Transcatheter arterial chemoembolization (TACE) combined with125I seed implantation and intra-tumor injection of cisplatin is more effective than only125I seed implantation for the treatment of hepatocellular carcinoma (HCC).



How to cite this URL:
Song Z, Guo X, Yin C, Wang Y. Therapeutic efficacy of TACE125I seed implantation and its combination with intra-tumor injection of cisplatin for the treatment of hepatocellular carcinoma. Indian J Cancer [Epub ahead of print] [cited 2020 Nov 24]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=299723

Zhaomin Song and Xiaoqing Guo contributed equally to the work





  Introduction Top


An increasing number of studies have shown that trans-catheter arterial chemoembolization (TACE) has positive therapeutic effects on advanced hepatocellular carcinoma (HCC).[1],[2],[3],[4] Blood supply is one of the most important factors that affect the therapeutic effect, and the growth of HCC depends on the formation of blood vessels within the tissues. Hence, an accurate and non-invasive method of locating the tumor area is crucial for diagnosis, individualized treatment, and prognosis.[5] Improved imaging modalities allow for the accurate differentiation of tumor by blood supply. It is reported that 15-16% of HCC have poor blood supply,[5],[6] and that the survival rate of patients treated with transcatheter arterial chemoembolization (TACE) is significantly low.

Therefore, it is important to select rational treatment plans according to the tumor blood supply status. As in HCC with poor blood supply, it is difficult for the drugs to permeate the fibrous tissue structure, TACE treatment is not suitable. Therefore, TACE is not the optimal therapeutic choice for this type of cancer. Topical application of intra-tumor injection of chemotherapy drugs is used to treat HCC, as it could limit the growth of cancer cells. Moreover, due to the abundant collateral blood supply and blood supply from the portal vein and arteriovenous shunt, the efficacy of TACE is limited. Therefore, embolic therapy is less effective for HCC and a combined integrative treatment should be used.

TACE has been widely applied to treat HCC with significant curative effects.125 I seed implantation guided by computed tomography (CT) has been validated as an effective method with low dose rate and persistent ionizing radiation.[7],[8],[9] Cisplatin is a well-known chemotherapeutic drug. It has been used in bladder, head and neck, lung, ovarian, and testicular cancers and is effective against various cancer types, including carcinomas, germ cell tumors, lymphomas, and sarcomas. Cisplatin gets cross-linked with DNA purine bases. By interfering with DNA repair mechanisms, it causes DNA damage and subsequently induces apoptosis in the cancer cells.

Intra-tumor injections are widely used.[10],[11],[12],[13] In the current study, the patients with HCC in control group were treated with125 I seed implantation combined with TACE and CT, whereas the patients with HCC in treatment group were treated with125 I seed implantation combined with intra-tumor injection of cisplatin. We aimed to discuss the potential feasibility and efficacy of this method and provide further references for treating HCC with poor blood supply.


  Methods Top


Patients

A total of 100 patients with non-metastatic liver cancer were enrolled from January 2010 to October 2013 in our hospital. All these patients were diagnosed with HCC and validated using ultrasonography, enhanced CT, and enhanced magnetic resonance imaging (MRI) scan. Their tumor lesions were measured and assessed, liver function was graded as Child A-B, and Karnosk scores were given >70. No abnormal functions of the heart, lung, and kidneys were detected. Therefore, all the patients received treatment for primary liver cancer without distant metastasis. The tumor grading was performed according to the standards developed by Cong et al., and Guideline Committee[14], including 39 patients in phase I and 61 in phase II. The patients were then randomly divided into the control and treatment groups.

The control group included 33 men and 17 women, of 32-68 years of age (mean 55 years). In this group, the patients were differentiated according to the tumor size: Single tumor diameter ≤3 cm or the sum of the largest diameter ≤3 cm (n = 5), diameter ≤5 cm (n = 17), diameter ≤10 cm (n = 22), and diameter >10 cm (n = 6). The treatment group (including 29 men and 21 women) had an age range of 37-65 years (mean 52 years). In the treatment group, the tumor size differed: Single tumor diameter ≤3 cm or sum of the largest diameter ≤3 cm (n = 7), diameter ≤5 cm (n = 15), diameter ≤10 cm (n = 19), and diameter >10 cm (n = 9). This study was conducted in accordance with the declaration of Helsinki. This study was conducted with approval from the Ethics Committee of the Second Hospital of Shandong University, written informed consent was obtained from all participants.

Treatment method

The patients in the control group were treated using125 I seed implantation combined with TACE and CT. After 3 weeks of TACE, brachytherapy was performed with125 I seed implantation guided by CT in the control group. Multi-point injection of cis-platinum (DDP) 10 − 30 mg in 5-20 ml saline (according to the tumor size) was administered using125 I seed (China Institute of Atomic Energy Co., Ltd) implantation with a radioactive particle treatment planning system (TPS, Zhuhai Hejia Medical Equipment Co., Ltd.). The125 I radioactive particles were supplied by. The other instruments used in this study included DSA (type: SMC-III, Beijing Chimat Image Technology Co., Ltd.), spiral CT (type: definition AS+, Siemens AG, Germany) and puncture guidance system (type: HGGR-2000 radioactive particle treatment planning system, Zhuhai Hejia Group Co., Ltd.).

Efficacy evaluation

Efficacy evaluation was performed using the objective evaluation criteria for solid tumors as recommended by the Barcelona Clinic Liver Cancer (BCLC) staging system,[15],[16] BCLC staging has been externally validated and allocates management choices to the following 5 different disease categories: Very early, early, intermediate, advanced, and terminal. The patients were followed-up at 1, 2, 6, and 12 months, postoperatively, and enhanced CT, MRI, serum alpha fetoprotein (AFP) level, T lymphocyte subpopulation (CD3, CD4, and CD8) count, blood routine, liver and kidney function indexes, and planting metastasis were performed.

Statistical analysis

The test for normal distribution and homogeneity of variance were performed to determine whether t-test could be applied. All continuous variables were described using the mean ± standard deviation. Analysis of Variance (ANOVA) was used to estimate the differences among the groups, and further comparisons were performed using q test. All statistical analyses were performed using SPSS 11.5 software (IBM SPSS Statistics, IBM Corporation, Chicago, IL), and a P value of <0.05 was considered statistically significant.


  Results Top


No significant difference was noted in the tumor gross volume, blood AFP level, and T lymphocyte subpopulation (CD3, CD4, and CD8). There was no significant difference detected in routine blood examination, liver, and kidney functions. All the cases were operated successfully. The tumor sizes were measured with enhanced CT/MRI. The averaged reduction of tumor volume was 27.4% in the control group and 38.6% in the therapy group (X2 = 3.76, P < 0.05, [Table 1]). 6 months after surgery, the percentage of CR (complete response) + PR (partial response) in the treatment group (88%) was higher than that in the control group (74%). The NC (no change) + PD (progressive disease) percentage in the treatment group (12%) was lower than that in the control group (26%).
Table 1: Comparison of clinical effects between the two groups at 6 months after surgery

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Blood routine examination including white blood cell (WBC), red blood cell (RBC), platelet (PLT), aspartate aminotransferase (AST), alanine transaminase (ALT), and total bilirubin (TBIL) showed no significant difference in myelosuppression and liver function damage between the two groups (P > 0.05, [Table 2]), while the blood AFP level was significantly reduced in the treatment group (P < 0.05). T lymphocyte subpopulation (CD3, CD4, and CD8) count indicated no significant cellular immune damage, which revealed that neither of the groups had significant myelosuppression or liver and kidney dysfunctions.
Table 2: Comparison of laboratory inspection between the two groups at 6 months after surgery

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Within 6 months of treatment, distant metastasis was found in the control group (n = 11) and treatment group (n = 3). Follow-up survival analysis showed that 2 patients died due to distant metastasis in the treatment group, and that 8 patients died in the control group (P< 0.05) [Table 3].
Table 3: Distant metastasis and overall survival occurred in follow-up cases between the two groups

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  Discussion Top


HCC is a highly malignant tumor characterized by fast tumor cell proliferation and a short patient survival rate. The liver is a radioactive-sensitive organ and 75% of the patients may develop hepatic insufficiency with external exposure to >40 Gy of radiation.[17] Permanent implantation of radioactive particles guided by percutaneous CT has shown positive curative effects. Radioactive particles can continuously generate gamma rays, which irradiate DNA double strands that could destroy the tumor nuclei and superimpose radiation effects on the tumor cells resulting in the loss of reproductive capacity of the tumor cells. There are no systemic complications associated with the local application of radioactive particles.

Iodine oils are mainly deposited in the tumor vessel, sinusoids, and nearby liver tissue after being injected through the hepatic artery. Iodine oils remaining in the local tumor can reduce the tumor blood supply which could lead to tumor cell necrosis as a result of ischemia and tissue hypoxia.[18],[19] This effect is dose-dependent, and residual active ingredients can be detected in the iodine oil-free or deficient area where the tumor is prone to relapse.[20],[21] Embolization therapy has achieved good results, but the 3-year and 5-year survival rates are still low.[22],[23] Embolization therapy is affected by multiple factors, of which blood supply is an important one. Therefore, for HCC with poor blood supply, embolization therapy is less effective and comprehensive treatment should be undertaken.

Synchronous chemoradiotherapy is a new way of comprehensive treatment. Radiation and chemotherapeutic drugs have multiplication effects to induce tumor cell apoptosis at a molecular level.[24],[25] Currently, remission rates of most of the chemotherapeutic drugs are no more than 20%.[26] Traditional systemic chemotherapy for the treatment of HCC includes hyperthermia, electro-chemotherapy, and local injection of absolute ethanol. These are rarely used, however, as sporadic case reports focusing on direct injection of chemotherapeutic drugs into tumors have noted. Cisplatin is a strong cytotoxic broad-spectrum anticancer drug that exerts anticancer effects by directly disrupting DNA replication and affecting immunity.[27] Multiple injections of cis-platinum (DDP) in the liver tumor can damage cancer micro-lesions, tumor cells, and tumor thrombus in the capillary vessels. It can also inhibit the transfer of the tumor cells to the peripheral tissues. Besides, DDP can effectively prevent tumor recurrence and intrahepatic metastasis by creating a hypertonic environment of local drugs. This further enables DDP to enter into the cell and inhibits protein synthesis, forms cross links compensated DNA strands, and inhibits the growth of tumor cells. Simultaneously, combined with continuous γ-ray consisting of radioactive particles, it can effectively reduce the rate of cancer recurrence and intrahepatic metastasis by suppressing tumor cell reproduction. Based on various indicators, our results demonstrated the treatment efficacy in the treatment group as compared to the control group. No significant adverse reaction, including liver and kidney dysfunction and immunosuppression, was detected.

Taken together, we found that intra-tumor injection of cisplatin and TACE + 125 I seed implantation have synergistic effects for the treatment of HCC. Further, the efficacy was found to be superior to single TACE+ 125 I seed implantation. Therefore, TACE + 125 I seed implantation + cisplatin intra-tumor injection may be an effective therapeutic approach in HCC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Acunas B, Rozanes I. Hepatocellular carcinoma: Treatment with transcatheter arterial chemoembolization. Eur J Radiol 1999;32:86-9.  Back to cited text no. 1
    
2.
Xiao E, Li D, Shen S, Zhou S, Tan L, Wang Y, et al. Effect of preoperative transcatheter arterial chemoembolization on apoptosis of hepatocellular carcinoma cells. Chin Med J (Engl) 2003;116:203-7.  Back to cited text no. 2
    
3.
Wu F, Wang ZB, Chen WZ, Zou JZ, Bai J, Zhu H, et al. Advanced hepatocellular carcinoma: Treatment with high-intensity focused ultrasound ablation combined with transcatheter arterial embolization. Radiology 2005;235:659-67.  Back to cited text no. 3
    
4.
Ako S, Nakamura S, Nouso K, Dohi C, Wada N, Morimoto Y, et al. Transcatheter arterial chemoembolization to reduce size of hepatocellular carcinoma before radiofrequency ablation. Acta Med Okayama 2018;72:47-52.  Back to cited text no. 4
    
5.
Sergio A, Cristofori C, Cardin R, Pivetta G, Ragazzi R, Baldan A, et al. Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): The role of angiogenesis and invasiveness. Am J Gastroenterol 2008;103:914-21.  Back to cited text no. 5
    
6.
Si Q, Mu H, Yan G, Qian X, Xu C, Wang X, et al. Individualized treatment models based on blood supply characteristics in hepatocellular carcinoma using color doppler hemodynamics. Hepatogastroenterology 2007;54:334-41.  Back to cited text no. 6
    
7.
Niu H, Zhang X, Wang B, Zhou Z, Wang J, Xu Z. The clinical utility of image-guided iodine-125 seed in patients with unresectable pancreatic cancer. Tumour Biol 2016;37:2219-23.  Back to cited text no. 7
    
8.
Shi F, Zhang X, Wu K, Gao F, Ding Y, Maharjan R, et al. Metastatic malignant melanoma: Computed tomography-guided 125I seed implantation treatment. Melanoma Res 2014;24:137-43.  Back to cited text no. 8
    
9.
Xiong J, Kwong Chian S, Li J, Liu X. Iodine-125 seed implantation for synchronous pancreatic metastases from hepatocellular carcinoma: A case report and literature review. Medicine (Baltimore) 2017;96:e8726.  Back to cited text no. 9
    
10.
Mehta HJ, Begnaud A, Penley AM, Wynne J, Malhotra P, Fernandez-Bussy S, et al. Restoration of patency to central airways occluded by malignant endobronchial tumors using intratumoral injection of cisplatin. Ann Am Thorac Soc 2015;12:1345-50.  Back to cited text no. 10
    
11.
Mehta HJ, Begnaud A, Penley AM, Wynne J, Malhotra P, Fernandez-Bussy S, et al. Treatment of isolated mediastinal and hilar recurrence of lung cancer with bronchoscopic endobronchial ultrasound guided intratumoral injection of chemotherapy with cisplatin. Lung Cancer 2015;90:542-7.  Back to cited text no. 11
    
12.
Monga SP, Wadleigh R, Sharma A, Adib H, Strader D, Singh G, et al. Intratumoral therapy of cisplatin/epinephrine injectable gel for palliation in patients with obstructive esophageal cancer. Am J Clin Oncol 2000;23:386-92.  Back to cited text no. 12
    
13.
Dasari S, Tchounwou PB. Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol 2014;740:364-78.  Back to cited text no. 13
    
14.
Cong WM, Bu H, Chen J, Dong H, Zhu YY, Feng LH, Chen J; Guideline Committee. Practice guidelines for the pathological diagnosis of primary liver cancer: 2015 update. World J Gastroenterol. 2016;22:9279-9287.  Back to cited text no. 14
    
15.
Marrero JA. Hepatocellular carcinoma. Curr Opin Gastroenterol 2006;10:339-51.  Back to cited text no. 15
    
16.
Llovet JM, Ducreux M, Lencioni R, Di Bisceglie AM, Galle PR, Dufour JF, et al. EASLEORTC clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol 2012;56:908-43.  Back to cited text no. 16
    
17.
Stryker JA. Science to practice: Why is the liver a radiosensitive organ? Radiology 2007;242:1-2.  Back to cited text no. 17
    
18.
Petrich T, Helmeke HJ, Meyer GJ, Knapp WH, Potter E. Establishment of radioactive astatine and iodine uptake in cancer cell lines expressing the human sodium/iodide symporter. Eur J Nucl Med Mol Imaging 2002;29:842-54.  Back to cited text no. 18
    
19.
Chung JK. Sodium iodide symporter: Its role in nuclear medicine. J Nucl Med 2002;43:1188-1200.  Back to cited text no. 19
    
20.
Choi BI, Kim HC, Han JK, Park JH, Kim YI, Kim ST, et al. Therapeutic effect of transcatheter oily chemoembolization therapy for encapsulated nodular hepatocellular carcinoma: CT and pathologic findings. Radiology 1992;182:709-13.  Back to cited text no. 20
    
21.
Staunton M, Dodd JD, McCormick PA, Malone DE. Finding evidence-based answers to practical questions in radiology: Which patients with inoperable hepatocellular carcinoma will survive longer after transarterial chemoembolization? Radiology 2005;237:404-13.  Back to cited text no. 21
    
22.
Hamilton SN, Tyldesley S, Hamm J, Jiang WN, Keyes M, Pickles T, et al. Incidence of second malignancies in prostate cancer patients treated with low-dose-rate brachytherapy and radical prostatectomy. Int J Radiat Oncol Biol Phys 2014;90:934-41.  Back to cited text no. 22
    
23.
Nag S, DeHaan M, Scruggs G, Mayr N, Martin EW. Long-term follow-up of patients of intrahepatic malignancies treated with iodine-125 brachytherapy. Int J Radiat Oncol Biol Phys 2006;64:736-44.  Back to cited text no. 23
    
24.
Jegannathen A, Mais K, Sykes A, Lee L, Yap B, Birzgalis A, et al. Synchronous chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck using capecitabine: A single-centre, open-label, single-group phase II study. Clin Oncol (R Coll Radiol) 2011;23:149-58.  Back to cited text no. 24
    
25.
Chenoufi N, Raoul JL, Lescoat G, Brissot P, Bourguet P.In vitro demonstration of synergy between radionuclide and chemotherapy. J Nucl Med 1998;39:900-3.  Back to cited text no. 25
    
26.
Abbott DE, Sohn VY, Hanseman D, Curley SA. Cost-effectiveness of simultaneous resection and RFA versus 2-stage hepatectomy for bilobar colorectal liver metastases. J Surg Oncol 2014;109:516-20.  Back to cited text no. 26
    
27.
Launay-Vacher V, Rey JB, Isnard-Bagnis C, Deray G, Daouphars M. Prevention of cisplatin nephrotoxicity: State of the art and recommendations from the European Society of Clinical Pharmacy Special Interest Group on Cancer Care. Cancer Chemother Pharmacol 2008;61:903-9.  Back to cited text no. 27
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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