Recent progress in radioactive seed implantation brachytherapy of non-small cell lung cancer: a narrative review

Introduction

Lung cancer is the malignancy with the highest mortality rate in the male population, and approximately 85% of lung cancer patients have non-small cell lung cancer (NSCLC) (1). For such patients, radiotherapy is usually used as an important alternative treatment method (2). External beam radiotherapy (EBRT), as a conventional radiation therapy, has been one of the optional therapies for the treatment of NSCLC. Although EBRT has some advantages, such as mature technology, and more convenient. However, due to the limitation of therapeutic mechanism, EBRT needs to pass the accelerated photon or electron beam through normal tissues before it can reach the tumour tissues. On the one hand, this causes additional damage to normal tissues; on the other hand, in order to achieve the therapeutic dose, EBRT needs to increase the irradiation dose, which in turn exacerbates the damage to the tissues in the irradiation path (3). However, brachytherapy has some advantages in the above problems. Since the irradiation comes from inside the tumour, the irradiation to the surrounding tissues can be effectively reduced. The efficacy of brachytherapy depends on the direct irradiation of tumours with high doses of radiation from a radiation source. Brachytherapy has a considerable dose-dependent advantage of radiation dose gradients over conventional external irradiation techniques. In fact, if the tumour moves during radiation, the radiation source also moves, because the radiation source is inside the tumour. This property differs from conventional EBRT, which requires an additional margin to account for setup and organ motion uncertainties (4-6). In this review, we describe a list based on the current literature and present promising clinical data regarding radioactive seed implantation brachytherapy (RSI-BT) in NSCLC treatment (Table 1). We present this article in accordance with the Narrative Review reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1600/rc).

Methods

The PubMed database was initially searched on March 02, 2023. Table 2 highlights the search conducted using the combination of the Medical Subject Headings (MeSH) terms: “Brachytherapy”, and “Lung Neoplasms”. And we integrated clinical studies including “radioactive seed implantation brachytherapy” to make it more accurate.

Technical background

The mechanisms of RSI-BT for cancer lesions include direct irradiation to promote apoptosis of cancer cells and inhibition of vascular growth in cancerous tissues (22-24). DNA strands are the primary target of therapeutic irradiation, and radiation-induced DNA damage can lead directly to cell death, cell cycle redistribution and microenvironmental changes without reparations. The therapeutic index of radiation reflects the differential response between tumour and normal tissues because tumour cells have a lower capacity for DNA repair than normal tissue cells. The ideal technique should be able to deliver a therapeutic dose to the tumour while minimizing the dose to the organs at risk (25).

Iridium-192 (Ir-192), cobalt-60 (Co60), iodine-125 (I-125) and palladium-103 (Pd-103) are most commonly used in modern brachytherapy (26,27). I-125, whose efficacy and safety in RSI-BT have been established, is the principal particle utilized in clinical practice (4). Especially for elderly NSCLC patients who have lost the chance for surgery and are in poor physical condition, brachytherapy can control tumour progression and improve quality of life.

The total dose can be obtained by (I) continuous low-dose-rate (LDR) irradiation; (II) repeating low-intensity pulses hourly for several days (pulsed-dose-rate irradiation); or (III) delivering several portions of a high dose at a time [high-dose-rate (HDR) irradiation] (4,26). Radioactive seed implantation brachytherapy is commonly used in LDR brachytherapy (LDR-BT), while HDR brachytherapy (HDR-BT) and pulsed-dose-rate brachytherapy (PDR-BT) have shown advantages in the treatment of internal bronchial lesions (4). As an example, Ir-192, which is commonly used as a source for HDR-BT, typically delivers at a rate of ≥12 Gy/h, compared to 0.4–2.0 Gy/h of LDR-BT. The linear quadratic (LQ) equation can be used to calculate the total biologically effective dose (BED), which can be used to assess the frequency that HDR-BT/LDR-BT is received (28). At the same time, more precise treatment planning systems (TPSs) and the use of high-resolution computed tomography (CT) have made dose control easier.

The standard treatment planning procedure for 3D volumetric image-based brachytherapy involves three main steps: (I) anatomic contouring, (II) applicator digitization, and (III) dosimetric planning and optimization, using a dedicated TPS (29). Steps (I) and (II) would be accomplished by using TPS, but step (III) usually needs more BT teams’ effort and time. Accurate delineation of the clinical target volume (CTV) and organ at risk (OAR) is a crucial step in radiotherapy treatment planning (12,30). However, it is still a labor-intensive process to manually contour the CTV and OARs in a 3D image volume with some guidelines exist to help define the contours. Deep-learning-based image processing has demonstrated tremendous potential to help this (31). Additionally, dose calculations based on the AAPM Task Group 43 formalism are currently the mainstream (32). Some model-based calculation methods are increasingly being used to improve efficiency, such as Monte Carlo simulation or solving the Boltzmann transport equation (33).

In recent years, 3D noncoplanar templates, polylactic acid templates, and automatic needles have gradually been applied in clinical treatment (34-36). They enhance RSI-BT in numerous ways, including particle selection, needle insertion, template selection and design, making brachytherapy more precise and less expensive. A study found that particle implantation using a 3D noncoplanar template requires fewer probes, less rib injury, and a higher dose in the target organ region than a conventional 3D coplanar template to achieve the same therapeutic dose, making RSI-BT for NSCLC more individualized and precise (34). Additionally, polylactic acid-based templates can reduce the cost of 3D noncoplanar templates, making RSI-BT cheaper (35). Automated probes have effectively posed a challenge to conventional manual probes in terms of probe implantation, and investigations have revealed that the average misses in probe angle and depth are 2° and 1 mm, respectively, and the average segmentation time per needle is 0.238 s, which is already useful (36).

Clinical applications

RSI-BT alone for NSCLC

Early-stage NSCLC

The location of the tumour lesion, the tumour’s clinical stage, and other factors influence the specific strategy used for RSI-BT of NSCLC. RSI-BT can be effective under a variety of circumstances.

Zhao et al. demonstrated that CT-guided brachytherapy with I-125 implantation improved local control rates, decreased side effects, and improved patient quality of life. Of the 26 patients, 11 patients had complete response (CR) and 9 patients had partial response (PR), with an overall survival (OS) of 11.7±7.6 months (7). A study including six patients also demonstrated the safety and efficacy of CT-guided I-125 implantation for BT, with only one patient progressing in the 12-month postoperative follow-up (8). For patients with early-stage NSCLC who refuse to undergo surgery, the disease can be completely controlled or even eradicated by RSI-BT (Figure 1). However, RSI-BT was not linked to a lower risk of local or distant metastases or better outcomes in patients with clinical stage I NSCLC, according to a meta-analysis by Chen et al. (37). Regardless, it may reduce local recurrence (LR) when the BED is >100 Gy. In addition, a study comparing the effectiveness of brachytherapy and external beam therapy in 543 patients with limited resection for NSCLC found that while survival rates for patients with lung cancer with T1–T4N0M0 were comparable in the groups receiving RSI-BT and EBRT (compared to EBRT, brachytherapy was associated with a decreased risk of death for both OS and disease-specific survival (DSS) [hazard ratio (HR) 0.604; 95% confidence interval (CI): 0.380–0.961 and HR 0.524; 95% CI: 0.303–0.908, respectively), patients with T1 had higher survival rates after receiving brachytherapy (38). In conclusion, RSI-BT for early-stage NSCLC has been shown to be safe and therapeutically effective.

Figure 1 A 38-year-old female with right middle lung adenocarcinoma T1bN0M0 stage IA who was treated with I-125 radioactive particle placement in the First Affiliated Hospital of Naval Medical University. (A) Before brachytherapy; (B) six months after brachytherapy; (C) two years after brachytherapy.

Advanced NSCLC

In advanced lung cancer, the therapeutic effect of RSI-BT is more limited and is more about relieving cancer symptoms and improving patients’ quality of life. The first topic covered is the function of CT-guided RSI-BT in the management of advanced NSCLC. I-125 RSI-BT alone significantly improved clinical outcomes and decreased the incidence of myelosuppression compared to chemotherapy, according to a meta-analysis by Zhang et al. (39). RSI-BT, however, might cause lung damage. To support the combined findings of complications, larger samples and higher quality randomized controlled studies are needed. The majority of studies on RSI-BT have demonstrated that the method is safe and reliable with controllable side effects and less harm to nearby organs while having the same or better local control rate, lower resource cost, and far lower overall radiation dose compared to conventional local treatment (10,13,24,40-45). However, the manageability of the difficulties associated with RSI-BT and issues with dose management have also been brought up by scholars in several studies (13,41,42). Moreover, advanced lung cancer-related airway constriction can be treated using bronchoscope-guided I-125 RSI-BT (Figure 2), and this therapy may also benefit patients with metastatic lung cancer (46,47).

Figure 2 Implantation of radioactive particles by bronchoscope for central lung cancer in the First Affiliated Hospital of Naval Medical University. (A) Before brachytherapy; (B) one month after brachytherapy; (C) three months after brachytherapy.

Radioactive stent implantation

A novel kind of radioactive particle stent implantation is being used in clinical practice in addition to the currently available BT procedure. A meta-analysis of radioactive and plain stent insertion for the treatment of malignant airway stenosis was performed by Meng et al. (48). It revealed that radioactive stent insertion was sufficient to reduce the rate of stent restenosis and extend the patient’s OS. New stents incorporating radioactive particles have also demonstrated therapeutic value in the treatment of inoperable malignant airway obstruction. Wang et al. discovered that from the second month after implantation, the group with radiographic stents had lower tracheal restenosis than the group with ordinary stents and a greater median survival (170 vs. 123 days, P<0.05). This study involved 66 patients with malignant airway obstruction (49). Moreover, radioactive stents can aid in increasing stent patency and OS and relieve superior vena cava stenosis caused by lung cancer (50). Although the safety has only been partially tested, a growing body of research points to the therapeutic potential of radioactive stents in the treatment of cavernous organs (51). However, additional reliable clinical trials are still needed.

Combining RSI-BT with other treatments

RSI-BT combined with EBRT

RSI-BT can be used not only alone in clinical treatment but also in combination with other existing therapies to improve treatment outcomes. One study found that brachytherapy can improve tissue radiosensitivity by increasing pO₂ in the tumour microenvironment, providing evidence for the combination of RSI-brachytherapy and EBRT (52). Retrospective research by Li et al. further demonstrated the efficacy of repeated I-125 seed implantation in conjunction with EBRT in the management of LR and metastasis in stage III/IV NSCLC [the overall (complete + partial) response rate was 87.4%]. The local control rates after the first, second, and third years were 94.1%, 58.8% and 41.2%, respectively (53). Dual I-125 therapy is efficient in boosting the therapeutic dose to tumour lesions following EBRT failure. With an objective response rate (ORR) of 76%, 10 patients had CR, and 9 patients had PR after I-125 implantation in a retrospective study comprising 25 patients with HNSTS who underwent surgery and experienced recurrence after EBRT from 2006 to 2018 (54).

RSI-BT combined with chemotherapy

RSI-BT has been used in combination with chemotherapy in a relatively large number of studies. Addressing the mechanism behind their combination, a study by Rong et al. found that lobaplatin (LBP) inhibits the AKT/mTOR pathway, promoting the apoptotic and antiproliferative effects of I-125 in NSCLC cells (55). I-125 particle implantation in conjunction with chemotherapy can improve the short-term local control rate [risk ratio (RR) 1.34; 95% CI: 1.09–1.65%, P=0.005] and efficiency in early-stage lung cancer, but more clinical evidence is required (56). To control the progression of advanced lung cancer with less harmful side effects, which is crucial for elderly patients, RSI-BT can also be used in combination with second-line chemotherapeutic drugs, particularly after first-line chemotherapy fails (18,19,37,57). Moreover, bronchial artery embolization chemotherapy, a particular type of chemotherapy, may be used with RSI-BT. The combination can significantly slow tumour growth and enhance NSCLC prognosis (20,58-60). In a randomized controlled trial, patients who underwent bronchial artery chemoembolization (BACE) combined with I-125 RSI-BT achieved a better disease remission rate than those who underwent BACE alone (62.75% vs. 41.18%) (58). A pilot study, however, found no discernible difference in the effects of injectable medications used alone and in combination (61). Moreover, RSI-BT coupled with chemotherapy can ease severe airway obstruction caused by NSCLC. Jiang et al. effectively combined chemotherapy with the use of conventional transbronchial needle aspiration (C-TBNA) to implant radioactive particles into a bronchial lesion in a 51-year-old patient (62). Even though the majority of the currently used regimens of RSI-BT combined with chemotherapy have produced superior outcomes, further high-quality randomized controlled studies are still required to prove the combination therapy’s safety and effectiveness.

RSI-BT combined with targeted therapy

RSI-BT combined with targeted therapy has been applied in the treatment of NSCLC (63-66). According to Feng et al., overall effectiveness in the apatinib combined with RSI-BT group was higher than that in the control group, and no fatal consequences occurred, demonstrating the therapy’s safety and effectiveness (63). The elderly cases of combined apatinib and RSI-BT described by Zhang et al. can also be used to corroborate the findings of Feng et al. (64). In addition to clinical use, according to He et al. on A549 mice, RSI-BT combined with anlotinib prevented bone loss in tumour-bearing mice, but there was no significant difference between single and multiple particle implantations at the same total dose (65).

RSI-BT combined with immunotherapy

Clinical reports of immunotherapy combined with RSI-BT in recent years are less frequent, and some studies have focused more on the mechanistic aspect. A safety investigation of oncologic therapies, which included RSI-BT, revealed no unanticipated or unmanageable adverse effects when RSI-BT was combined with immune checkpoint inhibition therapy (67). The pembrolizumab and I-125 RSI-BT combination demonstrated promising outcomes in NSCLC, and PD-L1 can be employed as a prognostic biomarker, according to a study by Wang et al. (68). Furthermore, immunotherapy can alter the shape of radioactive particles that enter tumour cells, improving the effectiveness and precision of RSI-BT (69). Although the use of immunotherapy and RSI-BT in combination has shown some positive clinical results, further research on the underlying concepts is still needed. The delivery method for RSI-BT can even be changed entirely.

Limitations

There are still several side effects that limit RSI-BT in clinical treatment, such as radiation pneumonia, pneumothorax, and haemorrhage (70). The values of the incidence of haemorrhage, pneumothorax, and radiographic lung injury have been reported in the literature to be 0.14% (95% CI: 0.07–0.21%), 0.19% (95% CI: 0.11–0.28%), and 0.00% (95% CI: 0.00–0.03%), respectively (56). Meanwhile, RSI-BT can temporarily halt the progression of the disease. The lack of a unified standard industry practice and potential complications brought on by operator technical issues may impact the effectiveness of the treatment. According to research conducted in Belgium, there is a need for advancements in RSI-BT-related education, awareness, implementation, collaboration, and cooperation (71). Consequently, additional data support and standardized training of staff are still needed.

Conclusions

As technology advances, RSI-BT is an effective local oncologic intervention. It can be used alone or in conjunction with surgery, radiation, chemotherapy, immunotherapy, and targeted therapy to play a more complex role in clinical care. Its applications are promising, and RSI-BT plays a significant role in the treatment of digestive illnesses, prostate cancer, breast cancer, and lung cancer (72,73). To ensure treatment safety and efficacy, standardization of RSI-BT is needed. Meanwhile, multicentre, randomized clinical controlled trials are needed to validate the efficacy of minimally invasive interventions for tumours, including RSI-BT.

Acknowledgments

The authors thank Shanghai Municipal Hospital Respiratory and Critical Care Medicine Specialist Alliance.

Funding: This work was supported by the Collaborative Innovation Cluster Project of Shanghai Municipal Health Commission (No. 2020CXJQ03), the Clinical Research Plan of SHDC (No. SHDC2020CR1021B-005) and the National Natural Science Foundation of China (No. 82000102).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1600/rc

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