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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 2  |  Page : 426-431

Analysis of the clinical efficacy and safety of computerized tomography-guided 125 I seed implantation in the treatment of non-small cell lung cancer that relapsed after chemoradiotherapy


1 Departement of Medical Oncology; Departement of Intervention, Affiliated Zhongshan Hospital of Dalian University, Dalian, P. R. China
2 Departement of Intervention, Affiliated Zhongshan Hospital of Dalian University; The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian, P. R. China
3 Department of Interventional Therapy, Dalian University Affiliated Xinhua Hospital, Dalian, P. R. China

Date of Submission20-Sep-2021
Date of Decision24-Dec-2021
Date of Acceptance20-Jan-2022
Date of Web Publication06-May-2022

Correspondence Address:
Li Chuang
Department of Intervention, Affiliated Zhongshan Hospital of Dalian University, Dalian, Dalian 116001
P. R. China
Wencai Weng
Department of Interventional Therapy, Dalian University Affiliated Xinhua Hospital, Dalian 116001
P. R. China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_1660_21

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 > Abstract 


Purpose: The purpose is to evaluate the clinical efficacy and safety of computerized tomography (CT)-guided 125I seed implantation in the treatment of recurrent non-small cell lung cancer (NSCLC) after chemoradiotherapy.
Materials and Methods: We retrospectively analyzed the data of 30 recurrent NSCLC patients in our institute from January 2016 to June 2020. According to the preoperative Treatment planning system plan, CT was used to guide 125I seed implantation into 30 evaluable lesions in the lungs. Clinical response rate, quality of life score, and adverse reactions were observed at postoperative follow-up.
Results: The postoperative follow-up duration was 13 (1–24) months, of which the disease control rate at months one, three, and six were 96.67%, 93.1%, 85.18%, respectively and the objective response rate was 53.33%, 48.27%, and 48.14%, respectively. The postoperative 1-year and 2-year survival rates were 76.66% (23/30) and 53.33% (16/30), respectively. Median overall survival was 18 (1–24) months. The postoperative 1-year and 2-year progression-free survival (PFS) rates were 63.33% (19/30) and 40% (12/30), respectively. The median PFS was 14.5 (1–24) months. Adverse reactions include radiation-related pulmonary reactions in four patients (13.33%); skin reactions in four patients (13.33%); radiation-related esophageal reactions in two patients (6.67%), and leukopenia in three patients (10%). Other radiation-related adverse reactions did not occur.
Conclusion: We conclude that 125I seed implantation is an effective and safe treatment for recurrent NSCLC.

Keywords: 125I seed implantation, clinical efficacy, recurrence non-small cell lung cancer, safety


How to cite this article:
Wang Z, Chen S, Su M, Zhao G, Zhou J, Chuang L, Wang R, Weng W. Analysis of the clinical efficacy and safety of computerized tomography-guided 125 I seed implantation in the treatment of non-small cell lung cancer that relapsed after chemoradiotherapy. J Can Res Ther 2022;18:426-31

How to cite this URL:
Wang Z, Chen S, Su M, Zhao G, Zhou J, Chuang L, Wang R, Weng W. Analysis of the clinical efficacy and safety of computerized tomography-guided 125 I seed implantation in the treatment of non-small cell lung cancer that relapsed after chemoradiotherapy. J Can Res Ther [serial online] 2022 [cited 2022 Jul 7];18:426-31. Available from: https://www.cancerjournal.net/text.asp?2022/18/2/426/344874




 > Introduction Top


Lung cancer is one of the malignancies with the highest incidence and mortality rate. Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancers.[1] Local recurrence after chemoradiotherapy is the most challenging problem in the treatment of advanced NSCLC as the efficacy of second- and third-line treatments is low.[2] In addition, patients are sometimes unable to tolerate intensive chemotherapy,[3] the effects of cumulative radiotherapy doses, and toxic side-effects of another course of radiotherapy,[4] which limits their clinical applications. Although targeted and immunotherapy are gradually emerging, as for advanced recurrent NSCLC, its effective rate and adverse reactions limit its clinical application.[5]

Computerized tomography (CT)-guided 125I radioactive seed implantation is a new short-distance radiotherapy for lung tumors and is currently used in clinical practice. Radioactive seed implantation is a good local therapy modality[6] due to its minimally invasive, precise, and high local tumor-dose strengths.[7] As radiation from 1251 seeds decreases with the inverse square of its distance, a high radiation dose can be achieved in the tumor target region, while the dose rapidly decreases around the target area, resulting in an extremely low dose to healthy tissues and organs at risk. Currently, it is widely used in the treatment of many malignancies.[8] In this study, we retrospectively analyzed the data of 30 advanced NSCLC patients who relapsed after chemoradiotherapy and subsequently received treatment with CT-guided 1251 seed implantation from January 2016 to June 2020.


 > Materials and Methods Top


Patient information

In this study, we retrospectively analyzed patients with pathologically confirmed NSCLC that relapsed after chemoradiotherapy and were treated at our Oncology Center from January 2016 to June 2020. There were 28 male and 2 female, aged 66.46 ± 11.03 years. The tumor, node, and metastasis (TNM) stages at previous first-line treatment were III (22 cases [73.3%]) and IV (8 cases [26.6%]), respectively. Before seed implantation, the surgeon assessed the lesions to be unresectable, and these patients failed chemoradiotherapy. Patients had at least one measurable lesion. There were seven patients who received external radiotherapy alone, with a median radiotherapy dose of 55 (45–60) Gy; 15 patients who received chemotherapy alone; and eight patients who received radiotherapy plus chemotherapy, with a median radiotherapy dose of 55.2 (45–60) Gy [Table 1].
Table 1: General information of patients

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Inclusion criteria

(1) Patients with cytopathologically confirmed NSCLC. (2) Patients with Stage III or IV disease based on the 8th edition of Union for International Cancer Control TNM Classification whose cancer recurred after chemoradiotherapy and who were unable to tolerate surgery. (3) Tumor diameter >1.5 cm and <8.00 cm. (4) Karnofsky Performance Score (KPS) ≥60 score and life expectancy >6 months. (5) Subject and family members provided consent and signed the informed consent form.

Instruments and equipment

Toshiba simulation localization system, seed implantation planning system (Beijing Astro Technology Co. Ltd), Mick seed implantation gun, and seed implantation localization and navigation system.

Treatment methods

Presurgery preparation

Routine blood work, coagulation function, hepatic and renal functions, cardiopulmonary function, and enhanced CT were performed to determine tumor position and size as well as neighboring major blood vessels and nerves before surgery.

Formulation of seed implantation plan

The Treatment planning system planning system was used to determine the tumor target site dose, number of radioactive seeds for implantation, and implantation site. The tumor area shown in imaging is the gross tumor volume (GTV), and the clinical target volume (CTV) is the region that is 5 mm away from the GTV. Two doses are used for the GTV and CTV, and the plan must satisfy dual prescription dose requirements to be approved. Simultaneously, the organs at risk around the tumor are delineated. In the preoperative plan, the median dose for GTV was set as 140 Gy (110,170), and the median dose for CTV was set as 90 Gy (60,120). The median number of seeds was set to 35 (range: 15–130), and the mean dose activity was 0.6 mCi (0.56, 0.8).

Intraoperative procedure

Under routine electrocardiography monitoring, a CT scan was performed for localization. After the puncture needle was inserted into the site step-by-step and there was no backflow of blood, 125I seeds were implanted according to the preoperative plan. After treatment, a CT scan was performed again to assess radiation quality, and additional seeds could be implanted in the radiotherapy cold region to ensure that the radioactive dose requirements for the entire target region are met.

Postoperative management

Three days after seed implantation, routine symptomatic treatment was carried out. CT scans were performed 3 days after implantation to validate the median GTV dose (D90) was 126 (99,153) Gy and median CTV dose was 86 (59,113) Gy based on the plan.

Efficacy evaluation

Response Evaluation. Criteria in Solid Tumors 1.1 criteria were used to assess lesion changes. Overall survival (OS) was defined as the time from seed implantation to death from any cause or last follow-up visit. Progression-free survival (PFS) was defined as the time from seed implantation to date of progression (including local recurrence, regional metastasis, or distal metastasis) or death. Performance status was assessed based on the KPS, percentage method. The Acute Radiation Morbidity Scoring Criteria issued by the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer was used to assess treatment-related adverse reactions.[9]

Statistical processing

SPSS 17.0 software package (IBM, New York, USA) was used for analysis. The t-test was used for quantitative data, the Chi-squared test was used for qualitative data, and the paired t-test was used for inter-group comparison. Normally distributed data were expressed as mean ± standard deviation (SD), and nonnormally distributed data were expressed as median (maximum, minimum). The Kaplan–Meier method was used to plot survival curves. A difference at P < 0.05 was considered to be statistically significant.


 > Results Top


Clinical response rate

Short-term clinical response rate

After surgery, follow-ups were carried out at months 1, 3, and 6. At month 1, Disease control rate (DCR, CR ± PR ± SD) was 96.67% (29/30), and (objective response rate [ORR], CR ± PR) was 53.33% (16/30). At month 3, DCR and ORR were 93.1% and 48.27% (16/30), respectively. At month 6, DCR and ORR were 85.18% and 48.14% (16/30), respectively [Table 2].
Table 2: Clinical efficacy

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Lesion diameter

Before surgery, the mean target lesion diameter was 4.36 ± 1.99 cm. At 1, 3, and 6 months after surgery, the mean target lesion diameter was 3.42 ± 1.51 cm (t = 4.83, P < 0.01), 3.01 ± 1.28 cm (t = 2.788, P < 0.01), and 2.68 ± 1.86 cm (t = 2.65, P < 0.01), respectively, with statistically significant differences. There are differences in target lesion diameters when comparing presurgery data with data obtained 1 month after surgery, when comparing data from 1 month after surgery with data from 3 months after surgery, and when comparing data from 3 months after surgery with data obtained 6 months after surgery. Hence, radioactive 125I seeds can effectively control local lesion growth within 6 months after surgery [Table 3], [Figure 1]a and [Figure 1]b.
Table 3: Tumor size

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Figure 1: Tumor size (a) and Karnofsky Performance Score score (b) changes after 125 I seed implantation operation

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Survival

The median postoperative follow-up was 13 (1, 24) months. The postoperative 1-year and 2-year survival rates were 76.66% (23/30) and 53.33% (16/30), respectively. Median OS was 18 (1,24) months. The postoperative 1-year and 2-year PFS rate were 63.33% (19/30) and 40% (12/30), respectively. The median PFS was 14.5 (1, 24) months [Figure 2]a and [Figure 2]b.
Figure 2: Kaplan-Meier estimates of (a). Overall survival and (b). Progression free survival rates for the 30 patients

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Karnofsky performance score

Before surgery, the KPS score was 65.13 ± 4.18 points. At 1, 3, and 6 months after surgery, the KPS scores were 73.53 ± 4.51 points (t = 23.89, P < 0.01), 79.93 ± 3.33 points (t = 13.87, P < 0.01), and 83.23 ± 3.04 points (t = 6.84, P < 0.01), respectively, with statistically significant differences. There are differences in KPS scores between the following comparison groups: presurgery and 1 month after surgery, 1 month and 3 months after surgery, and 3 months and 6 months after surgery. Thus, radioactive 125I seeds can significantly improve patient survival as there were statistically significant differences in KPS scores [Figure 1]b.

Adverse reactions

Treatment-related adverse reactions include radiation-related lung adverse reactions (two patients had Grade 1 dyspnea, one patient had Grade 2 dyspnea, and one patient had Grade 3 radiation-related acute pneumonitis), skin-related adverse reactions (three patients with Grade 1 dry desquamation and one patient with Grade 2 wet desquamation), radiation-induced esophageal reactions (two patients with Grade 1 dysphagia), and three patients with Grade 1 leukopenia. Cardiotoxicity, central nervous system toxicity, mucosal bleeding, thrombocytopenia, and other radiation-related adverse reactions did not occur [Table 4].
Table 4: Adverse reactions

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 > Discussion Top


Local recurrence after chemoradiotherapy is a challenge and hotspot in the clinical treatment of advanced NSCLC. About 30%–37% of patients will experience local recurrence after radical chemoradiotherapy.[10] Although immune checkpoint inhibitors have demonstrated good efficacy in the maintenance of radical chemoradiotherapy at present local recurrence is still an important clinical problem due to the emergence of drug resistance over time. In theory, salvage surgery can be used as the preferred treatment for NSCLC that recurred after radical chemoradiotherapy. The latest meta-analysis showed that in Stage III NSCLC patients who recurred after chemoradiotherapy, the median local failure-free survival and OS after salvage surgery ranged from 10 to 22 months and 13–76 months, respectively.[11] However, after receiving high-dose radical chemoradiotherapy, particularly at doses of ≥60 Gy, the mortality rate after salvage surgery is 40%.[12] Therefore, surgery is still an indispensable method in multimodal therapy for most tumor patients. However, due to limitations in subjective and objective patient conditions, surgery in patients with NSCLC who relapsed after chemoradiotherapy is still limited.

Re-irradiation is one of the treatment modalities for NSCLC that recurred after chemoradiotherapy. Patients with localized recurrent NSCLC received salvage PBT with 2-year OS, PFS, and LC rates of 79.2%, 37.1%, and 68.2%, respectively.[13] A recent study showed that the 1-, 3-, and 5-year OS rates in NSCLC patients with intrapulmonary metastases or oligo-recurrence were 97.7%, 65.3%, and 47.7%, respectively. 1-, 3-, and 5-year local failure-free rates were 97.7%, 85.1%, and 80.1%, respectively. With regards to toxicity, 22.7% of patients developed Grades 1–2 adverse reactions, including radiation pneumonitis, fatigue, and chest pain.[14] Kennedy et al. recently reported that the median OS was 39 months in patients who recurred after radical SBRT and underwent repeated SBRT. The 2-year local failure-free rate was 81% while 2-year local failure-free rate for lymph nodes at the recurrence site was 89%. Finally, the 2-year OS was 68% after repeat SBRT. With regards to toxicity, the incidence of Grade 2 radiation pneumonitis and Grade 2 chest wall toxicity was 10% and 19%, respectively. No Grade ≥3 toxicity occurred.[15]

Second-line chemotherapy is also one of the standard treatments for recurrent NSCLC. The median local failure-free survival was only 2.7–4.5 months, and the mean 1-year OS was 24.8%–52.7% for both monotherapy and combination chemotherapy.[16] In recent years, immune checkpoint inhibitors have demonstrated promising efficacy in recurrent NSCLC. However, second or more lines of treatment only extended PFS by 2.3–4 months in NSCLC patients.[17] In multimodal therapy of NSCLC, local failure-free benefits can be converted into prolonged survival. Therefore, there is an urgent need for a treatment modality that can effectively control local lesions with low toxicity for NSCLC patients who failed chemoradiotherapy.

In recent years, short-distance treatment with radioactive seeds has demonstrated good efficacy in recurrent NSCLC. Liu et al. conducted a study on 32 NSCLC patients who recurred after first-line chemotherapy. They found that the 1- and 2-year OS rates after 125I seed implantation were 92.16% and 90.62%, respectively. The incidence of pleural effusion was 3.13%.[18] Huo et al. observed 38 patients with local recurrent NSCLC who underwent seed implantation. They found that no radiation pneumonitis and radiation injury (nGrade 4) occurred, and only mild complications occurred that resolved after symptomatic treatment. The 2-month local failure-free rate was 92%, and 2-year PFS, local failure-free, and OS rates were 39.5%, 83.5%, and 47.4%, respectively.[19] These results demonstrate that the implantation of radioactive 125I seeds has clinical efficacy as a local therapy in recurrent NSCLC to some extent. Dai et al.[20] reported that 125I seed implantation results in a good local failure-free rate and ORR and DCR were 55.4% and 98.2%, respectively. Our study found that at month 1, the DCR and ORR were 96.67% and 53.33% (16/30), respectively; at month 3, the DCR and ORR were 93.1% and 48.27% (16/30), respectively; at month 6, the DCR and ORR were 85.18% and 48.14% (16/30), respectively. This supports the notion that 125I seeds can effectively decrease tumor diameter, control local tumor lesion progression, and is ideal for short-term efficacy.

Toxicity has always been a bottleneck in the treatment of recurrent NSCLC. Ji et al.[21] found that the incidence of ≥Grade 2 radiation pneumonitis, ≥eumo 2 radiation-induced esophagitis, and radiation-related skin reactions after seed therapy in recurrent or metastatic thoracic malignancy was 3.9%, 2.6%, and 6.5%, respectively. The incidence of chest wall pain was 1.3%, and no patients developed radiation myelitis or cardiotoxicity. Similarly, in our study, no Grade 3 or higher adverse event occurred, though there were treatment-related adverse events including pneumothorax (Grade 1 [n = 10] and Grade 2 [n = 4]), bronchial hemorrhage (Grade 1, n = 3), pleural hemorrhage (Grade 1, n = 2), coughing (Grade 1, n = 3), pulmonary fibrosis (Grade 1, n = 2), and one seed displacement into the pleura in one patient. Therefore, 125I seed implantation is safe and has a low incidence of postoperative adverse reactions.

In summary, CT-guided 125I seed implantation as a treatment for NSCLC is safe and effective, involves less trauma, and has a high short-term clinical response rate. Hence, it can be used as one of the local therapies for decreasing local tumor burden and improving patients' quality of life. However, there are some limitations in this study. Sample size, follow-up duration, retrospective nature, and single-arm need further improvement. Therefore, it is worth conducting a larger and more diverse prospective study to validate the efficacy and safety of CT-guided 125I seed implantation in the treatment of NSCLC.


 > Conclusion Top


We conclude that 125I radioactive particle implantation is an effective and safety treatment for the treatment of non-small cell lung cancer that relapsed after chemoradiotherapy

Acknowledgment

This study was supported by the National Key R and D Program of China (2019YFB1311300), Science and technology innovation project of Dalian City (No: 2018J12SN063).



 
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