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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 7  |  Page : 1560-1568

Comparison of I125 seed brachytherapy (radioactive seed brachytherapy) joint three-dimensional conformal radiotherapy and stereotactic ablative radiotherapy on early nonsmall cell lung cancer


1 Cancer Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
2 Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China

Date of Submission05-Apr-2020
Date of Decision28-Jul-2020
Date of Acceptance17-Sep-2020
Date of Web Publication9-Feb-2021

Correspondence Address:
Wei Sheng
Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_417_20

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 > Abstract 


Objective: The objective of the study is to compare computed tomography (CT)-based I125 radioactive seed brachytherapy (RSB) joint three-dimensional conformal radiotherapy (3D-CRT) and stereotactic ablative radiotherapy (SBRT) on early nonsmall cell lung cancer (NSCLC).
Methods: The study involved 30 Stage I and II NSCLC patients from March 2014 to June 2017. The patients were divided into two groups: 20 cases with CT-based RSB–3D-CRT (300 cGy × 10) (Group A) and 10 cases with SBRT (8 cGy × 6) (Group B). Their local control rates, 1-year survival rates, and toxic and side effects were compared.
Results: The median time of follow-up was 20 months (3–51 months). The 1-year local control rate in Groups A and B was 90% and 80%, respectively (P = 0.70). The 1-year survival rate in Groups A and B was 90% and 90%, respectively (P = 1.00). The indicator of radioactive pneumonia V20 and V30 in Groups A and B was 6.06% and 4.207%, and 11.32% and 7.111%, respectively (P = 0.000024 and 0.00090).
Conclusion: Compared with SBRT, RSB–3D-CRT was more aggressive on early NSCLC. It remarkably reduced the indicators (V20 and V30) and the incidence of radioactive pneumonia.

Keywords: I125 seeds, lung cancer, stereotactic ablative radiotherapy, three-dimensional conformal radiotherapy


How to cite this article:
Zhang Z, Mao H, Wang X, Sheng W. Comparison of I125 seed brachytherapy (radioactive seed brachytherapy) joint three-dimensional conformal radiotherapy and stereotactic ablative radiotherapy on early nonsmall cell lung cancer. J Can Res Ther 2020;16:1560-8

How to cite this URL:
Zhang Z, Mao H, Wang X, Sheng W. Comparison of I125 seed brachytherapy (radioactive seed brachytherapy) joint three-dimensional conformal radiotherapy and stereotactic ablative radiotherapy on early nonsmall cell lung cancer. J Can Res Ther [serial online] 2020 [cited 2021 Mar 4];16:1560-8. Available from: https://www.cancerjournal.net/text.asp?2020/16/7/1560/308765




 > Introduction Top


Lung cancer is a type of malignant tumor with the highest incidence and mortality rate.[1] Nonsmall cell lung cancer (NSCLC) accounts for 75%–80% of lung cancers. Surgery has been the best treatment for early NSCLC (T1-2N0M0).[2] For inoperable early NSCLC, radiotherapy is one of the optional treatments.[3] Stereotactic ablative radiotherapy (SBRT) showed high local control rate and long survival time.[4],[5],[6],[7] It is characterized by its single high-equivalent biological dose. At present, it plays a more important role in the treatment of NSCLC.[8] It uses a precise stereoscopic radiotherapy positioning system, and radiation planning is more accurate than previous radiotherapy plans in terms of location and dose as the normal tissues surrounding the target were given a low dose of radiation.[9] SBRT allows for the administration of large doses of radiotherapy to tumors, which results in obtaining ideal control effect and less toxic side effects, such as radiation reactions in normal tissues.[10],[11],[12] It can effectively achieve higher local radiation dose and lower complication probability than the conventional method and improve the therapeutic gain ratio.[13] Existing studies have shown that the local control rate of early nonoperative NSCLC stereotactic radiotherapy can be as high as 80%–97%. The overall survival rate and tumor-specific survival rate are comparable with those of surgery. The National Integrated Cancer Network (National Comprehensive Cancer Network) and the European Society for Clinical Oncology (European Society of Medical Oncology) have recommended SBRT for early peripheral NSCLC patients who cannot undergo surgery.[14],[15]

Because of limited radiation tolerance dose in normal lung tissues and surrounding important organs, and the influence of tumor irradiation volume, it is impossible to give more than the dose of 70 Gy in the traditional external radiotherapy.[16] The application of radioactive seed brachytherapy (RSB) may greatly increase the dose of local radiotherapy for lung cancer cells.[17] Radioactive I125 seed implantation is one of the methods of radiotherapy that belongs to the tissue implantation category. A therapeutic method by which sealed radioactive sources are directly implanted into tumor lesions, and radionuclides are continuously released to kill tumor cells.[18] The initial dose can reach up to the recommended prescription dose (90–160 Gy), which is a new development in clinical radionuclide therapeutics and radiotherapy. With the development of minimally invasive technology, the requirement of disease treatment has been raised. Radioactive seed implantation is more frequently applied to the treatment of rapidly developing malignant tumors. When I125 seeds are implanted into the tumor, it can continuously release low doses of gamma rays, inducing double-strand breaks while directly acting on the tumor cells. In addition, it can directly ionize water molecules in the body, produce free radicals, and promote tumor cell apoptosis. Sensitive tumor cells die quickly, whereas insensitive resting cells enter the mitotic phase.[19] Tumor cells cannot reproduce under the continuous action of gamma ray, and effective treatment can be achieved through rapid apoptosis. RSB has a good curative effect on solid tumor with high local dose (>100 cGy) and less damage to the surrounding normal tissue.[20] However, due to the close radiation distance of I125 seeds particles, there may be a risk of recurrence due to insufficient dose of clinical target volume (CTV) in the tumor subclinical focus.[21] Based on the aforementioned theory, RSB–three-dimensional conformal radiotherapy (3D-CRT) is characterized as high local dose (>100 cGy), low damage for surrounding normal tissues.[22] Using RSB to control the naked focus of tumor (gross tumor volume [GTV]) and irradiation of subclinical tumor (CTV) with 3D-CRT may be a promising strategy in the treatment of lung cancer. Through the combination of these treatment methods, both tumor GTV and subclinical focus CTV can be given a large enough dose to completely kill tumor cells, improve local control rate, reduce the radiation dose to the surrounding normal tissues, and reduce radiation damage, thus improving the early NSCLC treatment effect.[23],[24],[25] In the present study, the local control rate, 1-year survival rate, and toxic and side effects were used as parameters in comparing RSB–3D-CRT with SBRT in subtumor regions.


 > Methods Top


Clinical data

Between March 2014 and June 2017, in Shandong Provincial Hospital, 30 patients with histological or cytological confirmation of adenocarcinoma squamous lung cancer were considered as candidates in this pilot study. There were 23 males and 7 females; 17 with ages ≥60 and 13 with ages <60; and six patients were diagnosed with Stage I (T1N0M0) and 24 patients were Stage II (T2N0M0) lung cancer.

Inclusion criteria

  1. NSCLC was confirmed through histopathological and cytological examination
  2. Diagnostic imaging showed clear tumor lesions. Chest and abdomen computed tomography (CT), brain magnetic resonance imaging (MRI), and whole-body bone scan confirmed T1-2N0M0 (American Joint Committee on Cancer)
  3. Karnofsky performance score >70
  4. Estimated survival time >3 months
  5. Age >45 years old
  6. No bleeding tendency, normal coagulation function, normal blood routine examination, and no obvious abnormality in the heart, liver, and kidney functions
  7. Normal electrocardiographic results
  8. Intolerant or rejected surgery and chemotherapy
  9. No target drugs through gene detection.


The distribution of treatment group

All cases were divided into two groups: group A –20 cases with RSB–3D-CRT 300 cGy × 10 and Group B –10 cases with SBRT 800 cGy × 6.

Main instruments and equipment

Philips, Netherlands Brilliance Computed Tomography Big Bore

Under conventional conditions, the CT aperture used for diagnosis is only 70 cm; however, this is not fully satisfied in cases with special postural requirements. The Brilliance CT Big Bore has the largest 85-cm aperture in the industry. It can meet the requirements of various positions in radiotherapy localization at present and easily realize the use of mammary gland bracket and other special fixed equipment positioning and perspective requirements. Simultaneously, the Brilliance CT Big Bore can make doctors observe patients more comprehensively, help locate the target area, and calculate the dose and make plans, and the images obtained by real scanning FOV are superior to those of Extended field of view (EFOV) and High Definition field of view (HDFOV) based on imaging principles and actual image quality. Compared with the conventional CT 512 × 512 reconstruction matrix, the Brilliant CT Big Bore has a super-large reconstruction matrix of 1024 × 1024, which is four times higher than the traditional resolution information, which is very beneficial for the clinical diagnosis of minimal lesions.

Varian Trilogy Linac

The system not only can carry out conventional radiotherapy technology but also has the most advanced accurate radiotherapy technology in the world, for example, image-guided radiotherapy technology, intensity-modulated radiotherapy technology, rapid rotational volume modulation technology (RapidArc), and dynamic adaptive radiotherapy technique. Accurate and effective treatment of tumor patients at all parts of the body through high-accuracy and high-stability dose rate.

Beijing Feitian Zhaoye Technology Co., Ltd. particle therapy planning system (radioactive seed brachytherapy treatment planning system (RSBTPS))

The 3D state of the tumor can be reconstructed accurately using the treatment planning system (TPS) and the results of MRI scans. It can also accurately design the location and quantity of seed implantation, and when combined with human anatomy, it could design the implantation path and realize the conformal radiotherapy of tumor. The particle position, implant volume, profile, dose, and particle relationship can be clearly displayed, and the state of the observation and implantation needle loading can be adjusted at the right time. The 3D display provides the distribution and calculation results of implanted particles, all tissue structures with dose–volume histogram [DVH], complete prescription DVH, and boundary volume analysis and can help the operator observe the implanted state and anatomical structure.

Philips Pinnacle radiotherapy planning system

This system can provide an integrated 2D and 3D radiotherapy plan and a stereotactic radiotherapy planning system on a unified platform. Pinnacle combines the most effective software tools with the most advanced workstation technology to develop the planning process to a real-time level. Through the application of the latest computer image processing and graphics technology, the system greatly improves the calculation speed and accuracy of the patient treatment plan and realizes the image input, image registration, image fusion, 3D reconstruction, and dose calculation. Planning evaluation and other functions include achieving accurate and uniform dose exposure dose to the tumor, minimizing the amount of damage to normal surrounding tissues, and ensuring the therapeutic effect and reducing the side effects of radiation therapy to the patients, thereby bringing radiotherapy closer to the ideal state.

Treatment

Radioactive seed brachytherapy

Preoperative CT was performed with 5-mm thickness. In the TPS, the preplan was to confirm implantation guide pin number and location, particle number and location, and total activity and dose distribution of the target area (for both tumor and normal tissues) as shown in [Figure 1],[Figure 2]. Seed implantation was guided by CT. According to the dose distribution requirement, uniform distribution, or peripheral density, center sparse cloth source method was used. During particle implantation, TPS was used to optimize the dose, adjust particle location, correct unevenness, and protect important organs adjacent to the target area. CT was also used to check the results. The dose distribution of the target area and adjacent normal tissues was calculated through TPS as shown in [Figure 3],[Figure 4]. Supplementary treatment would be added if necessary. The target area was defined as the boundary of the CT lung window tumor extending 5 mm. The minimum dose covers 90% of the target volume (D90) >110 cGy. The matched peripheral dose was 110–140 cGy, and particle activity was 0.6–0.7 MIC.
Figure 1: Preoperative TPS

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Figure 2: Preoperative TPS

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Figure 3: Post-operative verification TPS

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Figure 4: Post-operative verification TPS

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Three-dimensional conformal radiotherapy

Thermoplastic film fixation was performed with patient in the supine position. Preoperative CT was performed with 5-mm thickness. The 3D TPS input consists of location reconstruction pictures. The target area was defined according to the International Commission on Radiation Units and Measurements (ICRU) 50 document. GTV indicated the primary lesion. The boundary is a lung window showing lesions on CT. The CTV was 1 cm outside the GTV. The details were double-checked by radiotherapy physicians and physical therapists. The planned target area (PTV) is 0.5 cm outside the CTV. The physiologist drew the outline of the body and the important organs. Conformal treatment was performed in three to four fields (300 cGy × 10, five times/week). TPS was optimized by DVH as shown in [Figure 5], and 90% of isodose curves covered the PTV. Spinal cord exposure was ≤30 Gy; esophageal exposure was ≤30 Gy; and heart exposure was ≤20 Gy. The 3D conformal TPS calculated and confirmed the set-up reference points that were used for radiotherapy. 3D-CRT was performed 2 weeks after RSB.
Figure 5: Dose-volume-histogram(DVH)

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Stereotactic ablative radiotherapy

Thermoplastic film fixation was performed at supine position. Preoperative CT was performed with 5-mm thickness. The 3D TPS input consists of location reconstruction pictures. The target area was defined according to the ICRU 50 document. The GTV indicated the primary lesion. The boundary is a lung window showing lesions on CT. The CTV was 1 cm outside the GTV. Radiotherapy physicians and physical therapists double-checked the details. The PTV is 1 cm outside the CTV. The physiologist drew the outline of the body and important organs. Conformal treatment was performed in three to four fields (800 cGy × 6 times, three times/week). The TPS was optimized by DVH, and 90% of isodose curves covered the PTV. Spinal cord exposure was ≤20 Gy; esophageal exposure was ≤15 Gy; and heart exposure was ≤10 Gy. The 3-D conformal TPS calculated and confirmed the set-up reference points that were used for radiotherapy.

Efficacy

Local control rate

The patients were followed up 3–51 months after treatment. CT scans were reviewed every 3 months. According to the WHO standards, complete recession (CR; tumor completely disappeared), partial recession (PR; tumor shrinkage of 50% or higher), no change (NC; tumor shrinkage <50%, smaller tumor size, or increase of <25%), and progress (tumor volume increase of 25% or higher, or the emergence of new lesions) were evaluated. Local control rate (overall response rate [ORR]) was calculated as CR + PR + NC.[26]

One-year survival rate

One-year survival rate was calculated as the number of survival cases followed up for more than 1 year/number of cases followed up ×100%.[27]

Stereotactic ablative radiotherapy group V20 and V30

The TPS was optimized by DVH, and 90% of isodose curves covered the PTV to figure out the V20 and V30.[28]

Radioactive seed brachytherapy–three-dimensional conformal radiotherapy group V20 and V30

The RSBTPS was subjected to dose optimization and real-time verification. Calculation of dose distribution in the target area and adjacent normal tissues was performed to figure out the V20 and V30. The TPS was optimized by DVH, and 90% of isodose curves covered the PTV to figure out the V20 and V30. The V20 and V30 of RSBTPS and TPS I were subjected to image fusion to obtain the V10 and V15 of the fusion image.

Safety analysis

The patient should observe and record the adverse reactions and complications of each system that may occur during the course of treatment, and the healthcare team should give treatment in a timely manner. Radiation-induced lung injury evaluation was performed according to the RTOG (Radiation Therapy Oncology Group)/EORTC (European Organization for Research on Treatment of Cancer) diagnostic grading standard,[29],[30] as shown in [Table 1].
Table 1: Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer radiation-induced lung injury evaluation

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Follow-up

The follow-up methods included outpatient service and telephone interview. The patients were followed up 3–51 months after treatment. CT scans were reviewed every 3 months. The degree of lung injury was determined using the RTOG grading standard.

Statistics analysis

The statistical analysis methods included the IBM SPSS software version 17.0 for statistical analysis, Kaplan–Meier method for survival analysis, log-rank test to compare the differences in survival between the two groups, and Cox multivariate regression analysis for independent prognostic factors. P < 0.05 was statistically significant difference.


 > Results Top


Part I The results of 20 patients who accepted radioactive seed brachytherapy–three-dimensional conformal radiotherapy

Clinical features and therapeutic evaluation

The 20 cases in this group consisted of 16 males and 4 females, with 10 cases aged ≥60 and 10 aged <60, while 4 patients were diagnosed with Stage I (T1N0M0) and 16 patients were stage II (T2N0M0) lung cancer. Local control rate (ORR) was 90%, and 16 patients were with CR, whereas two patients were with PR, and two patients were progressed (PD).

Survival outcomes

A total of four patients died and 16 patients survived, with two patients dying within a year. Overall, the 1-year survival rate was 90%.

Indicators of radioactive pneumonia (V20 and V30)

The RSB–3D-CRT group's V20 and V30 were 6.06% and 4.207%, respectively.

Part II The research results of stereotactic ablative radiotherapy

Clinical features and therapeutic evaluation

All 10 cases consisted of 7 males and 3 females, with 7 aged ≥60 and 3 aged <60, while two patients were diagnosed with Stage I (T1N0M0) and eight patients were diagnosed with Stage II (T2N0M0) lung cancer. Local control rate (ORR) was 80%, and six patients were with CR, whereas two patients were with PR, and two patients were with PD.

Survival outcomes

Three patients died and seven patients survived, with one patient dying within a year. One-year survival rate was 90%.

Indicators of radioactive pneumonia (V20 and V30)

The SBRT group's V20 and V30 were 11.32% and 7.111%, respectively.


 > Interpretation of Results Top


Local control rate (overall response rate)

The RSB–3D-CRT and the SBRT groups' ORR was 90% and 80%, respectively. There was no statistically significant difference between both groups [P = 0.76; [Table 2]].
Table 2: Local control rate (overall response rate)

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One-year survival rates

The RSB–3D-CRT and SBRT groups' 1-year survival rates were 90% and 90%, respectively. There was no statistically significant difference between both groups (P = 1.00). The mean survival time of Group A was 38.149 months and that of Group B was 49.88 months. There was no statistically significant difference between both groups [P = 0.697; [Figure 6] and [Table 3]].
Figure 6: Survival curve P = 0.697

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Table 3: One-year survival rates

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Indicators of radioactive pneumonia (V20 and V30)

The RSB–3D-CRT and SBRT groups' ORR was 6.06% and 4.207% (V20), and 11.32% and 7.111% (V30), respectively, which was statistically significant [P = 0.000024 and 0.00090, respectively; [Figure 7] and [Table 4]].
Figure 7: V20, V30 column diagram. * represents P < 0.05

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Table 4: V20 and V30 nonparametric test

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Adverse reactions and complications

Among the 20 patients in Group A, 6 cases (30%) had pneumothorax occurring in RSB, 4 of which were not treated with special treatment, whereas 2 cases were treated with closed thoracic drainage. Then, four cases (20%) were expectorated with hematopoietic phlegm. After 1–2 days of treatment with anti-inflammatory and hemostatic drugs, the symptoms disappeared. During 3D-CRT, two cases (10%) experienced degree I (cough and expectoration, and cured after treatment with anti-inflammatory drugs). No adverse reaction was above degree III. In Group B, four cases (40%) had degree III adverse reactions. Among them, three cases presented with cough and chest tightness, and one case was with chest pain that was cured after treatment [Table 5].
Table 5: Treatment-related adverse reactions

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 > Conclusion Top


  1. Local control rate (ORR) of the RSB–3D-CRT group was similar to that of the SBRT group. There was no statistically significant difference between both groups
  2. The 1-year survival rate of the RSB–3D-CRT group was similar to that of the SBRT group. There was no statistically significant difference between both groups
  3. The RSB–3D-CRT group showed significantly lower levels of radioactive pneumonia indicators (V20 and V30) than the SBRT group. There were statistically significant differences between both groups
  4. The safety of RSB–3D-CRT treatment is high, and patients reported good tolerance to the procedure. No significant adverse reactions and severe complications, as well as treatment-related deaths, were reported.


Research significance and outlook

At present, the treatment of early NSCLC (T1-2N0M0) is still mainly surgical resection.[31],[32] However, there are still some patients who cannot undergo surgical resection or targeted drug therapy because of their age, related diseases, and their own reasons.[33],[34] The treatment of these patients mainly includes SBRT, RSB, and radiofrequency microwave ablation.[35] SBRT, one of the local treatments for lung cancer, plays an important role in the comprehensive treatment of lung cancer.[36],[37],[38],[39] Conventional radiotherapy techniques tend to increase the dose to surrounding normal tissues, limiting the increase in tumor dose while increasing the incidence of complications.[40],[41] SBRT can concentrate on the high-dose area, minimize the exposure of normal tissues, and improve the local control rate of the tumor.[42],[43],[44],[45] The probability of metastasis of residual tumor cells and distant metastases can be further reduced.[46],[47] Chang et al. have shown that, for early NSCLC treatment, the local control rate of SBRT was not significantly different with surgical resection between 1 and 3 years, but the incidence of related side effects significantly decreased.[48] However, the large dose of single SBRT treatment had a significant effect on the late-reacting tissues, such as those of the lungs and trachea.[49] For adverse reactions above degree III, the incidence of radioactive pneumonia was higher than that in conventional radiotherapy.[50] Due to the influence of respiratory movement and positioning error, SBRT is prone to “cold” dosing spots in the treatment process, which affects the therapy and increases the radiation damage.[51]

The advantage of I125 seed implantation is that continuously releases low doses of irradiation to tumor cells in different proliferation cycles with uniform exposure,[52],[53] which is the equivalent of multiple hyperpartition radiotherapy.[54] On another note, it overcomes the accelerated regrowth of tumor cells. Furthermore, damage to surrounding normal lung tissues is minimal.[55] These characteristics are difficult to be achieved through external irradiation therapy. The drawbacks of I125 seed particle implantation is that due to the low dose and low penetration ability of the I125 seed particles, the tumor cells that are distant from the particle are less effective.[56] Simultaneously, there is no effect on the subclinical lesion surrounding the tumor.

3D-CRT or stereotactic radiotherapy can improve the dose to the target area to a certain extent and reduce the amount of damage to surrounding normal lung tissues.[57] However, there are also many challenges in the treatment of lung cancer due to the uncertain factors in the target area caused by respiratory movement. Based on these reasons, theoretically, combined internal and external irradiation treatment can fully gain an advantage, according to the principles of radiation physics and radiation biology, with minimal complications, being able to effectively control the tumor.[58]

Lots of studies have explored the efficacy and safety of I125 seed implantation for NSCLC, and the preliminary results are satisfactory.[59],[60],[61],[62],[63] However, there are few studies on the treatment of NSCLC by I125 seeds particle implantation.[64],[65],[66] This research applied the I125 seeds particles implantation RSB plus SBRT in early NSCLC. The local control and 1-year survival rate of two groups were similar. The group with RSB–3D-CRT showed a significantly lower level of radioactive pneumonia indicators (V20 and V30) than the SBRT group. This suggested that RSB–3D-CRT can significantly reduce the incidence of radiation pneumonia. However, due to fewer cases and shorter follow-up time, the optimal combination dose and the most appropriate interval for internal and external irradiation are still to be further studied.

The complications caused by I125 seed implantation mainly include pneumothorax, hemoptysis, chest pain, and particle migration. In this study, there were six cases with pneumothorax and four cases with sputum expectoration. Their symptoms disappeared after receiving drugs for cough and hemostasis, and no obvious clinical symptom was observed after follow-up.

External radiotherapy controlled the primary lesion and subclinical lesion. Radioactive particle implantation technique improved tumor local exposure dose, strengthened treatment, effectively improved the local control rate, decreased distant metastasis rate, and reduced the incidence of radioactive lung injury. Hence, the survival rate and quality of life of patients were improved.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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