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ORIGINAL ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 4  |  Page : 636-641

Bronchial artery chemoembolization combined with radioactive iodine-125 seed implantation in the treatment of advanced nonsmall cell lung cancer


1 Department of Intervention Radiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province 646000; Department of Intervention Radiology, The Second People's Hospital of Yibin, Yibin 644000, China
2 Department of Intervention Radiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province 646000, China
3 Department of Oncology, The Second People's Hospital of YiBin, YiBin 644000, China
4 Department of Intervention Radiology, The Second People's Hospital of YiBin, YiBin 644000, China

Date of Web Publication13-Sep-2017

Correspondence Address:
Yuwei Li
Department of Intervention Radiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province 646000
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_93_17

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 > Abstract 

Objective: The aim of this study was to investigate the short-term efficacy and safety of bronchial artery chemoembolization (BACE) combined with radioactive iodine-125 seed implantation in the treatment of nonsmall cell lung cancer (NSCLC).
Materials and Methods: Sixty-two Stage III–IV NSCLC patients were divided into Groups A and B. Thirty cases were treated with BACE combined with radioactive iodine-125 seed implantation in the Group A and 32 cases were treated with BACE alone in the Group B until disease progression. Efficacy, incidence rate of adverse drug reactions, and survival rate were compared between the two groups.
Results: The local control rates and effective rates of Groups A and B were 90% and 59.3% and 74% and 40.6%, respectively, with P < 0.05 for each. The progression-free survival of the study group and the control group was 12.6 and 8.2 months, respectively; the median survival time of the Groups A and B was 644 and 544 days, and the difference was statistically significant (P = 0.034).
Conclusion: BACE combined with radioactive iodine-125 seed implantation was safe and effective in the treatment of advanced NSCLC, with an efficacy superior to that of single BACE.

Keywords: Bronchial arterial chemoembolization, nonsmall cell lung cancer, radioactive iodine-125 seed implantation


How to cite this article:
Chen Y, Li Y, Jia Y, Lei K, Zhang X, Cao Y, Zhu J. Bronchial artery chemoembolization combined with radioactive iodine-125 seed implantation in the treatment of advanced nonsmall cell lung cancer. J Can Res Ther 2017;13:636-41

How to cite this URL:
Chen Y, Li Y, Jia Y, Lei K, Zhang X, Cao Y, Zhu J. Bronchial artery chemoembolization combined with radioactive iodine-125 seed implantation in the treatment of advanced nonsmall cell lung cancer. J Can Res Ther [serial online] 2017 [cited 2018 Nov 16];13:636-41. Available from: http://www.cancerjournal.net/text.asp?2017/13/4/636/214483


 > Introduction Top


Primary lung cancer is one of the most common malignant tumors and its mortality ranked first among all the malignant tumors in China.[1] Most of the patients, when definitely diagnosed, have lost their optimal chances of surgical operation, and only systemic venous chemotherapy and local external radiotherapy are remained as the main therapy options. For patients with advanced nonsmall cell lung cancer (NSCLC), platinum-based combination chemotherapy has been the first-line standard treatment.[2],[3] With the rapid development of interventional technology, techniques such as bronchial artery chemoembolization (BACE) and iodine-125 seed implantation have been widely applied in the treatment of NSCLC, achieving remarkable curative effects.[4],[5],[6],[7],[8],[9] In our study, 62 patients with primary NSCLC, who refused intravenous chemotherapy radiotherapy and other accepted interventional therapies due to their old age, infirmity, or other reasons, were collected during January 2012 and January 2016 in our hospital. These patients were divided into Groups A and B, with 30 in the Group A received BACE combined with iodine-125 seed implantation and 32 in Group B received BACE treatment alone. The results were reported as follows.


 > Materials and Methods Top


Materials

Clinical data

Sixty-two patients were pathologically diagnosed as lung adenocarcinoma or squamous cell carcinoma, including 37 males and 25 females, with a median age of 63 years (ranged from 51 to 73 years). Pathological examination results revealed 28 cases of squamous cell carcinoma and 34 cases of adenocarcinoma; 22 cases of central lung cancer and 40 cases of peripheral lung cancer. For all the patients, the Karnofsky performance status was >70, without serious organ damage, and the expected survival was >3 months. According to the TNM staging system, 30 and 32 patients were at Stage III and IV, respectively. No significant difference was observed in clinical data between the two groups before treatment, indicating the comparability of two groups [Table 1]. The baseline clinical data of the two groups are summarized in [Table 1].
Table 1: Baseline clinical data of Groups A and B

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Equipment and materials

Radioactive seed implantation planning system was provided by Beijing Astro Technology Co., Ltd., iodine-125 seeds (0.8 mCi) were provided by Seeds Biological Pharmacy Ltd. (Tianjin), and gelfoam sponge embolization agent (with the diameter of 350–560 μm) was obtained from Hangzhou Alicon Pharm SciandTec. Co., Ltd.; BACE was guided by Artis Zee ceiling-mounted system (SIEMENS, Germany) and seed implantation was conducted with 16-slice spiral computed tomography (CT) (GE, USA).

Methods

Patients in Group A received bronchial arterial infusion chemotherapy embolization (BACE). Bronchial artery angiography was performed by puncturing femoral arteries with modified Seldinger technique. It aimed to determine whether bronchial artery was cooriginated with intercostals arteries and of there was spinal artery branch and to observe tumor staining and vascular distribution. Superselective microcatheterization was performed at the distal bronchial artery, while nedaplatin and gemcitabine were perfused slowly (drug dosage was determined according to body surface area of the patient). An appropriate amount of gelfoam sponge particles (with the diameter of 350–560 μm) were injected to embolize tumor blood vessels. Reflux was prevented during operation [Figure 1].
Figure 1: (a) Bronchial arteriography revealed tumor staining, (b) microcatheter into the target artery and angiography after embolization showed that the vessel was occluded

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Biochemical and blood routine were tested 1 week after BACE. When no contraindication was observed and all the conditions were allowed, iodine-125 seeds were implanted. Specifically, pretreatment CT images of patients were imported into the seed implantation treatment planning system (TPS) through the DICOM interface, and tumor clinical target volume was outlined on the corresponding level. Prescription dose was usually 90–120 Gy. Implantation channels were designed, number of seeds was calculated, and isodose curve was plotted. Preoperative dose-volume histogram was exported to obtain parameters such as D90, D100, V90, V100, and V200, as well as the dose to organs at risk. During the operation, patients were properly positioned and conventional CT scanning was applied to identify the point, location, path, and depth of the puncture. Multineedle and multirow tumor puncture were performed with 18G Chiba needles, with the spacing of 1 cm. After needles were placed, seeds were implanted then needles were withdrawn. After surgery, CT was applied to assess the coverage and the distribution of implanted seeds, as well as if there were postoperative pneumothorax and bleeding. Meanwhile, TPS was employed in the postoperative quality verification, and target dose D90 higher than the peripheral dose was indicative of the high quality of implantation. For the dose cooling zone, seed supplement therapy could be performed on the premise of safety [Figure 2].
Figure 2: (a) Isodose curves for treatment planning, (b) the dose-volume histogram calculated for treatment planning, (c,d) 125I seeds were placed in the mass according to preoperative treatment planning system, (e) Isodose curves after implantation, (f) the dose-volume histogram calculated after implantation, (g) 2 months after treatment, cancer became smaller obviously

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Patients in Group B were treated with bronchial artery infusion chemotherapy embolization. The specific pre- and post-operative procedures and medications were identical to those of in the Group A.

Efficacy was evaluated in both groups 2 months after treatment, and a total of 2–4 times of BACE were conducted with an interval of 2 months.

Response assessment

Efficacies were assessed by CT scanning 2-month posttreatment according to the evaluation criteria (Choi standard), i.e., the characteristics of tumor were comprehensively considered in the efficacy evaluation, including the size, density, structure, and metabolic activity.[10] With the longest diameter of the tumor as the baseline, the following definitions were proposed: (1) complete remission (CR) referred to the complete disappearance of tumor without new lesions, and no tumor or only stripped image or metal artifact of particles was observed by imaging examination; (2) partial remission (PR) referred to the decreased tumor size of ≥10%, or decreased tumor density of ≥15% without new lesions, and no significant progress was observed in nontarget lesion; (3) stable disease (SD), not CR/PR, no progression of tumor-related symptoms was observed; and (4) progressive disease (PD) referred to the increased tumor sized of ≥10% and the tumor density does not reach PR, while new lesions, new nodules, or enlarged nodules were observed inside the tumor. The response rate of treatment was calculated as ([CR + PR]/total number of cases) ×100%, the local control rate was ([CR + PR + SD]/total number of cases) ×100%, and progression or death was considered as a failure. Assessment was then conducted every 2 months until disease progression or death of the patient. Patients were followed up from the day of treatment to June 30, 2016. There was no loss to follow-up cases and the median follow-up time was 24 months.

Statistical analysis

All data were statistically analyzed with SPSS 19.0 (IBM, New York, USA). Enumeration data were compared with the Chi-square test, with P < 0.05 being considered to be statistically significant. The effects of the two groups were compared with Mann–Whitney U-test. The Kaplan–Meier method was employed to calculate survival rate, and median survival time and log-rank test were applied to compare the difference of survival curves between the two groups.


 > Results Top


Efficacy

The treatment of all patients was successfully completed. The effect of Group A was better than that of in Group B, and the difference was statistically significant (z = 2.381, P = 0.017). CR + PR was effective, CR + PR + SD for local control, efficacy in Group A (73.3%, 22/30) was higher than that of in Group B (40.6%, 13/32), with statistically significant difference (x2 = 6.738, P = 0.009). Local control Group A (90.0%, 27/30) was higher than that of in Group B (59.4%, 19/32) and the difference was statistically significant (x2 = 7.585, P = 0.006). The progression-free survival time of the patients in Groups A and B was 12.6 and 8.2 months, respectively; and the median survival time of the patients in Groups A and B was 644 and 544 days, with statistically significant difference [P = 0.034, [Figure 3]].
Figure 3: Cumulative survival function curves of the Groups A and B (Kaplan–Meier method)

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[Table 2] shows comparison of the efficacy between NSCLC patients in Group A and Group B.
Table 2: Comparison of the efficacy between nonsmall cell lung cancer patients in the Groups A and B

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[Figure 3] shows cumulative survival function curves of the patients in Groups A and Group B (Kaplan–Meier method).

Complications

The main complications of BACE were postoperative nausea and vomiting, anorexia discomfort, and mild bone marrow suppression, which were improved after symptomatic treatment. No significant severe liver and renal function damage was observed, neither the spinal cord artery injury. In addition, there was no treatment-related death.

The main complication of 125I seed implantation was pneumothorax. There were two cases of lung tissue compression of >30% in our study, out of which two cases showed no significant increase after intraoperative puncture exhaust and needed to be observed, and in one case, pneumothorax was disappeared and diagnosed by CT scanning 5 days after intraoperative closed thoracic drainage. All the three patients were cured and discharged. There were four cases of intra- and post-operative hemoptysis and bloody sputum, with an average hemoptysis amount of <20 ml. These patients were treated with intramuscular injection of Agkistrodon snake venom thrombin, and all of them were improved. CT examination 2-month posttreatment has not revealed any serious radiation pneumonia, esophagitis, and particle displacement.


 > Discussion Top


BAI chemotherapy for lung cancer has been introduced almost 50 years ago. Recently, BAI has been widely applied in treating advanced NSCLC due to its repeatability and lower toxicity.[11],[12],[13],[14] BACE is on the basis of blood supply of lung cancer. Most scholars[15] believed that the bronchial artery was the main feeding artery of lung cancer, whereas the pulmonary artery was generally not involved in the blood supply. Drug concentration of target organ with artery perfusion is 2–6 times of that with intravenous administration, and drugs can enter the tumor again through blood circulation to offer the second chemotherapy on tumor. Therefore, BAI was both local and systemic chemotherapy for tumor.[16] By blocking tumor blood supply through embolism, BAI may result in tumor ischemia, necrosis, and shrink; in addition, a high concentration of drugs could be maintained in tumor tissue for a long time to effectively kill cancer cells.[17] Zhou et al.[18] reported 33 cases of bronchial artery lipiodol chemoembolization in the treatment of lung cancer. The results showed two cases of CR, two cases of PR, nine cases of SD, and one case of PD, with a response rate of 69.7% (CR + PR). Postoperative pathological examination revealed massive necrosis of tumor cells. No serious complication was observed such as spinal cord injury. Liu Jiangze et al.[19] reported that the response rate of the central-type NSCLC after BACE combined with concurrent radiotherapy and chemotherapy was 85.95%, with a median survival of 23.4 months. No serious complication was found.

The main complications of BACE are postchemotherapy and embolization syndromes, such as nausea and vomiting, gastrointestinal reactions, fever, bone marrow suppression, and chest pain. The most rare and serious one is paraplegia caused by spinal cord injury, with a high incidence of 2%–5%. Possible reasons involved were as follows: (1) the anterior spinal artery stemming from bronchial artery was mistakenly embolized when performing bronchial artery embolization and (2) hypertonic contrast agents or chemotherapy drugs entered the spinal cord. Dianbo et al.[20] analyzed the complications of chemotherapy and embolization in 135 NSCLC patients, and the incidence of complication was 5.9%, including one case of spinal cord ischemia (0.7%), five cases of intercostal artery ischemia (3.7%), and two cases of pulmonary embolism (1.5%). In the present study, no spinal cord and intercostal artery ischemia and pulmonary embolism were found in all 62 patients. Therefore, care should be taken to analyze the DSA image in angiography, so as to identify the trunk that bronchial artery and intercostal artery shared. Since the latter has spinal cord artery branches, it is better to conduct the superselective microcatheterization at the bronchial artery to keep away from the spinal cord artery. When necessary, lidocaine may be applied to induce spinal cord function.

Iodine-125 seed implantation has been accepted as an effective and minimally invasive therapy for tumors in a variety of organs.[21],[22],[23],[24],[25] Iodine-125 seed is a low-energy radioactive source, with a half-life of 59.7 days. It can provide continuous irradiation of about 200 days as well as a tissue penetrating power of 1.7 cm. Iodine-125 seeds can emit low-energy gamma rays continuously and provide sustained irradiation on tumor cells at different cell cycles, which may destroy tumor tissue to the greatest extent. The damage to normal tissues, however, remains minimal due to the short irradiation distance. Moreover, low-dose irradiation can decrease the oxygen enhancement ratio and increase the sensitivity of hypoxia tumor cells, so as to make a killing effect on tumor cells.[26],[27] In a retrospective analysis of the clinical efficacy of iodine-125 seed implantation in 247 Stage III NSCLC patients, Huo et al.[6] reported that the survival rates at 1, 3, and 5 years after treatment were 82.8%, 23.8%, and 11.5%, respectively, and local control rates at 1, 3, and 5 years were 92.2%, 63.8%, and 25.7%, respectively. Li et al.[28] reported that iodine-125 seed implantation combined with arterial chemotherapy in the treatment of advanced NSCLC significantly improved the quality of life and prolonged survival of the patients compared to single arterial chemotherapy. All the results indicated that the combined therapy has been an effective approach in the treatment of advanced NSCLC and worthy of clinical application. The common complications of iodine-125 seed implantation were mainly pneumothorax and bleeding. Therefore, CT image data must be carefully read before operation, so as to understand the relationship among tumor, heart, and peripheral vessels. The best puncture route should be chosen to reasonably arrange needles and avoid repeated punctures.

For peripheral or hypovascular tumors, embolization effects of BACE may be poor, while the complete necrosis may not be achieved even for tumors with abundant blood supply. Iodine-125 seeds could just compensate for this defect. Despite the richness of the tumor blood supply, iodine-25 seeds can destroy cancer cells persistently. For central or hemoptysis lung cancer, both of the technical difficulty and the risk of iodine-125 seed implantation have been high, and BACE would make up this deficiency in turn. Embolization of bronchial arteries may control tumor growth, as well as reducing the risk of hemoptysis. In addition, due to various causes, such as respiratory motion, rib occlusion, and the skills of operators, the dosage of iodine-125 seeds cannot reach the scheduled TPS, which can be made up through the BACE of blood vessels. He et al.[29] reported the application of tissue graft of iodine-125 seeds combined with BAI chemotherapy in the treatment of lung cancer. The total remission rates of the combined treatment group and the chemotherapy group at 1, 3, 6, and 12 months were 8.8%, 56.1%, 63.6%, and 84.0% and 2.7%, 21.4%, 41.9%, and 45.1%, respectively, and the differences between the groups were of statistical significance (P < 0.01 or P < 0.05). One-year cumulative survival rates of the combined treatment group and the chemotherapy group were 91% and 65%, respectively, with a median survival time of 533 and 422 days, with statistically significant difference (P < 0.05). In our study, for the experimental group and the control group, the effective rates were 74% and 40.6%, whereas the local control rates were 90% and 59.3%, and the median survival time was 644.0 ± 57.1 and 544.0 ± 66.4 days, respectively. Moreover, the differences were all statistically significant (P < 0.01).


 > Conclusion Top


The combination of BACE and iodine-125 seed implantation may offer a desirable overall efficacy, with less complications and good reproducibility, which has been worthy of clinical application. In the actual clinical practice, it should be properly combined with radiochemotherapy and molecule-targeted therapy.[30],[31] Meanwhile, efforts must be made to improve the reasonable distribution of seed dosage, modify the embolization materials, and enhance the operation skills.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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