Bronchial arterial chemoembolization/infusion combined with iodine-125 brachytherapy in advanced non-small cell lung cancer: a promising salvage therapy after standard treatment failure

Abstract

Objectives

To evaluate the efficacy, safety and optimal intervention timing of bronchial arterial chemoembolization/infusion combined with iodine-125 brachytherapy for advanced non-small cell lung cancer after standard treatment failure.

Materials and methods

From January 2019 to April 2024, the eligible patients with advanced non-small cell lung cancer after standard treatment failure received bronchial arterial chemoembolization/infusion combined with iodine-125 brachytherapy, were included in this retrospective study. Objective response rate, disease control rate, progression-free survival, overall survival and adverse events served as the main indicators of assessment. According to the intervention timing of intervention for this combination therapy, they were divided into the early intervention subgroup and the late intervention subgroup. Statistical analyses were performed using R software (version 3.5.3).

Results

A total of 45 patients with the median age 66 years (11 women) were enrolled in this study. The objective response rate of three months after the combination therapy was 71.11% and disease control rate was 95.56%. The median progression-free survival of this cohort was 12 months and the median overall survival was 20 months. The progression-free survival (15.5 vs. 9 months, P = 0.007) and overall survival (27.5 vs. 15 months, P < 0.001) in the early intervention subgroup was significantly better than that in the late intervention subgroup. No severe complications occurred.

Conclusion

For advanced non-small cell lung cancer after standard treatment failure, the combination of bronchial arterial chemoembolization/infusion and iodine-125 brachytherapy is a promising salvage therapy with good efficacy and safety.

Key points

1st Key Point: Standard treatment failure in advanced non-small cell lung cancer is an urgent problem for clinical practice.

2nd Key Point: Bronchial arterial chemoembolization/infusion combined with iodine-125 brachytherapy can provide favorable tumor response and survival benefits to advanced non-small cell lung cancer after standard treatment failure.

3rd Key Point: For advanced non-small cell lung cancer after the first-line treatment has failed, the earlier this combination therapy intervention, the more benefit may be gained.

Introduction

Lung cancer is the leading cause of cancer-related mortality globally, with non-small cell lung cancer (NSCLC) accounting for 80–85% of lung cancer cases [1,2,3]. The majority of NSCLC patients are diagnosed at the advanced stage, having surpassed the optimal window for surgical intervention. Current clinical guidelines advocate for first-line standard treatments, which encompass concurrent chemoradiotherapy, platinum-based chemotherapy regimens, and targeted therapies for individuals with genetic mutations [4, 5]. The therapeutic landscape for advanced NSCLC has been transformed by the introduction of a variety of novel agents, including tyrosine kinase inhibitors (TKIs), epidermal growth factor receptor (EGFR) antagonists, vascular endothelial growth factor (VEGF) inhibitors, monoclonal antibodies, and immune checkpoint inhibitors (ICIs), significantly enriching and diversifying the standard treatment strategy [2,3,4,5]. Despite these advancements, a significant proportion of patients experience disease progression or recurrence within the first 1–2 years after first-line treatment. The median survival for the concurrent chemoradiotherapy and sequential chemoradiotherapy was 16.5 versus 13.3 months, respectively [6]. Numerous studies have demonstrated that the efficacy of second-line or subsequent treatments for progressive NSCLC following first-line treatment was unsatisfactory [7,8,9].A randomized study reported that the median progression-free survival of two kinds of second-line chemoradiotherapy for advanced NSCLC were 2.8 and 3.1 months, respectively, and the overall survival was 11.7 and 12.2 months, respectively [9]. Therefore, standard treatment failure for advanced NSCLC is defined as an increase of at least 20% in the total diameter of the target lesion or the appearance of one or more new lesions after first-line treatment or multiple subsequent standard treatments according to NSCLC clinical guidelines [4, 5].

For patients with advanced NSCLC who have failed standard treatment, systemic therapies alone may not be sufficient; hence, some salvage local therapies can play a critical role in improving tumor response and prolonging survival time by reducing tumor burden quickly. Bronchial arterial chemoembolization/infusion (BACE/BAI) involves the infusion of cytotoxic agents directly into the tumor-feeding arteries, followed by embolization to cut off the blood supply, leading to tumor ischemia and necrosis. This approach has been demonstrated to prolong survival time by reducing tumor burden and effective local control [10]. Iodine-125 brachytherapy, a minimally invasive method, involves the implantation of iodine-125 radioactive seeds directly into the tumor tissue. The continuous low-energy gamma radiation emitted by these seeds provides a high dose of radiation into the tumor to induce cancer cell apoptosis which has been demonstrated to prolong time to tumor progression [11, 12]. However, the optimal intervention timing of these local treatments is still uncertain for advanced NSCLC after standard treatment failure.

Therefore, this study aimed to evaluate the efficacy, safety and optimal intervention timing of BACE/BAI combined with iodine-125 brachytherapy for advanced NSCLC after standard treatment failure.

Materials and methods

Study design and patients

The study was conducted in accordance with the Declaration of Helsinki and approved by our institutional review board (number: NCC 5180). Patient consent was waived due to the retrospective nature of the study. From January 2019 to April 2024, the patients of advanced NSCLC after standard treatment failure, consequently treated with BACE/BAI combined with iodine-125 brachytherapy in our institution, were included in this study.

Flowchart of patient selection was showed in Fig. 1. Inclusion criteria were as follows: (1) advanced NSCLC was confirmed based on the American Joint Committee on Cancer staging manual, 8th edition; (2) standard treatment failure was defined as an increase of at least 20% in the sum of the longest diameter of the target lesions or the appearance of one or more new lesions after standard treatments; (3) estimated survival > 3 months. Exclusion criteria: (1) multiple primary malignancies were pathologically diagnosed; (2) recurrence of NSCLC after surgical resection or ablation; (3) unable to be followed up regularly.

Fig. 1

Flowchart of patient selection. NSCLC = non-small cell lung cancer. BACE/BAI = Bronchial arterial chemoembolization/infusion

Procedure of therapy

Our therapy strategy was that BACE/BAI should be prioritized for implementation, followed by sequential treatment iodine-125 brachytherapy within the following 1 ~ 7 days after evaluating the status, as showed in Fig. 2. All procedures were performed by 1 chief physician and 3 attending physicians.

Fig. 2

A patient with advanced lung squamous carcinoma. (a) Axial scan before the combination therapy. (b) Coronal scan before the combination therapy. (c) Angiography before bronchial arterial chemoembolization. (d) Angiography after bronchial arterial chemoembolization. (e) The optimized brachytherapy plan. (f) The dose-volume histogram calculated after brachytherapy. g) Axial scan after two months of combined treatment. h) Coronal scan after two months of combined treatment

Bronchial arterial chemoembolization/infusion

Bronchial artery chemoembolization/infusion was performed after thoracic aortic angiography, which could acquire the overview layout of potential responsible arteries for target tumors. Respectively, selective catheterization and angiography of bronchial arteries and other potential tumor responsible arteries (internal thoracic arteries, intercostal arteries or inferior phrenic arteries) were performed to determine whether they were communicating with dangerous vascular branches (such as Adamkiewicz artery or anterior spinal arteries). If necessary, cone-beam computerized tomography could be used. Therefore, super-selective intubation into the main supply arteries of tumors with a coaxial microcatheter system was indispensable when dangerous vascular branches need to be bypassed to reduce the risk of serious complications. The third-generation platinum anticancer drugs (Nedaplatin or Lobaplatin, 50 ~ 80 mg) were slowly infused into the responsible arteries and more than 300 μm embolic agents (gelfoam particles or microspheres) were used to effective embolization (Fig. 2c and d). The contraindication of embolization was that the dangerous vascular branches communicating with responsible arteries of tumors could not be bypassed and avoided by microcatheters, so such patients only received artery infusion chemotherapy without embolization.

Iodine-125 brachytherapy

Before iodine-125 brachytherapy, imaging information were imported into the seed implantation treatment planning system, provided by Beijing Astro Technology LTD.CO. (Beijing, China), to define the planning treatment volume of lung tumor through outlining the gross tumor volume, risk areas and the safety margin (5 mm) by experienced interventional radiologists. The individual brachytherapy plan was optimized based on the dose covering 90% of the target volume(D90) ≥ prescription dose and the percentage of the target tumor volume covered by 100% prescription dose(V100) > 95% (Fig. 2e).

Iodine-125 radioactive seeds were provided by Atomic High-Tech Co., Ltd (Beijing, China). According to the optimized plan, the puncture operation directly inserted into the target tumor, were performed with appropriate puncture points, pathways and spacing of needles under CT guided. From deep to shallow, iodine-125 radioactive seeds were implanted intermittently while drawing back the needle and keeping adjacent seeds at a distance of 5–10 mm. After implantation, CT was applied to evaluate the coverage and the distribution of implanted seeds (Fig. 2f).

Follow-up and evaluation of efficacy and safety

Patients were followed up regularly after receiving BACE/BAI combined with iodine-125 brachytherapy in our institution (with an interval of 1–2 months) until the patient’s death or August 2024.

Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) served as the main indicators of efficacy assessment. According to the response evaluation criteria in solid tumors (RECIST 1.1), the tumor response was assessed three months after the combined therapy to evaluated the short-term efficacy: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). ORR=(CR + PR)/Total×100% and DCR=(CR + PR + SD)/Total×100%. Progression-free survival (PFS) was defined as the duration from the BACE/BAI combined with iodine-125 brachytherapy to PD or death. Overall survival (OS) was defined as the time from the first treatment to death of any cause, or to the end of the study.

Adverse events of BACE/BAI combined with iodine-125 brachytherapy were evaluated and graded according to Common Terminology Criteria for Adverse Events.

Comparative analysis between subgroups

According to the intervention timing of BACE/BAI combined with iodine-125 brachytherapy during the overall treatment process, patients who received BACE/BAI combined with iodine-125 brachytherapy after tumor progression following only first-line treatment were divided into the early intervention subgroup, while patients who received BACE/BAI combined with iodine-125 brachytherapy after tumor progression following multiple standard treatments (at least including first-line and second-line or more) were divided into the late intervention subgroup. The comparative analysis of PFS and OS between two subgroups was performed to evaluate the optimal timing of BACE/BAI combined with iodine-125 brachytherapy, served as salvage treatment in advanced NSCLC after standard treatment failure.

Statistical analysis

Statistical analyses were performed using R software (R version 3.5.3). Categorical variables were expressed as numbers and percentages (n, %), whereas continuous variables were presented as means ± standard deviations or median. The chi-square test was utilized to compare categorical variables, while the single-factor analysis of variance was employed for continuous variables. PFS and OS were illustrated by the Kaplan-Meier method and log-rank tests were performed to assess differences. The significance threshold was 0.05 with 2-sided testing.

Results

Patients

A total of eligible 45 patients (11 women and 34 men) with advanced NSCLC after standard treatment failure, receiving BACE/BAI combined with iodine-125 brachytherapy, were enrolled in this study (Fig. 1). The median age was 66 years (range:42–81 years). All patients received first-line standard treatment before the combination therapy, including targeted therapies (n = 10), chemoradiotherapy (n = 5), chemotherapy (n = 20), as well as chemotherapy and immunotherapy (n = 10). 21 patients who received BACE/BAI combined with iodine-125 brachytherapy after tumor progression following multiple standard treatments were divided into the late intervention subgroup. The baseline characteristics were summarized in Table 1.

Table 1 Baseline clinical characteristics

Bronchial arterial chemoembolization/infusion

A total of 72 cycles of BACE/BAI were performed. Twenty-eight patients received only one cycle of BACE, 14 patients underwent the second BACE, 2 patients underwent 4 cycles of BAI and 1 patient received 8 cycles of BAI. Except bronchial arteries, eleven patients had additional tumor supply arteries, which originated from the internal thoracic arteries (n = 5), intercostal arteries (n = 4) and subclavian arteries (n = 3). The tumor supply arteries of one patient were collectively involved by branches of the subclavian artery, internal mammary artery, and bronchial artery. Eight patients with active hemoptysis before BACE/BAI alleviated significantly one week after treatment.

Iodine-125 brachytherapy

A total of 57 rounds of iodine-125 brachytherapy were performed. Eight patients underwent the second round of iodine-125 brachytherapy and 2 patients underwent the third round. The median number of initial implanted iodine-125 radioactive seeds was 56 (95%CI: 45.78–67.91) and the median number of needles was 8 (95%CI: 6.92–8.73). The median postoperative D90 was 140.53 Gy (95%CI: 138.33–145.89 Gy), ranged from 101.66 to 171.23 Gy and the median V100 was 96.7% (95%CI: 96.04–97.24%), ranged from 88.2 to 99.7%.

Efficacy

The follow-up ranged from 3 months to 60 months with a median of 20 months. The tumor response was evaluated three months after initial BACE/BAI combined with iodine-125 brachytherapy. The rates of CR, PR, SD, and PD in this cohort were 6.67% (3/45), 64.44% (29/45), 24.44% (11/45), and 4.44% (2/45), respectively. Hereby, the ORR was 71.11% (32/45) and DCR was 95.56% (43/45) during this period (Table 2). As of the end of follow-up, the median PFS of the cohort was 12 months (95%CI: 11.32–17.25 months), ranged from 2 to 39 months and the median OS was 20 months (95%CI: 17.57–25.28 months), ranged from 3 to 60 months (Fig. 3a and b).

Table 2 Tumor response after 3 months of combination therapy

Fig. 3

Progression-free survival and overall survival. (A) Progression-free survival of the entire cohort. (B) Overall survival of the entire cohort. (C) Progression-free survival of the two subgroups. (D) Overall survival of the two subgroups

Safety

Treatmentrelated mortality, serious radiation pneumonia, or spinal cord artery injury was not observed in this study and some adverse events happened in 21 patients (46.67%, 21/45), as shown in Table 3. The main complications of BACE/BAI were postoperative nausea and vomiting (n = 3), and pain (n = 4), which were grade II and improved after symptomatic treatment. The main adverse events of iodine-125 brachytherapy were pneumothorax (n = 10), bleeding (n = 4) and pain (n = 4). There was only one case of pneumothorax (grade III) needed intraoperative closed thoracic drainage because of lung tissue compression more than 40%, and other 9 cases (grade I) showed no significant increase (lung tissue compression less than 10%) after intraoperative puncture and only needed to be observed. Three cases of bleeding and four cases of pain with grade II improved after symptomatic treatment. There was one case of intraoperative hemorrhage (grade III) caused by the implantation of iodine-125 seeds, who has improved significantly after immediate arterial embolization.

Table 3 Adverse events

Comparative analysis between subgroups

According to the intervention timing of BACE/BAI combined with iodine-125 brachytherapy during the overall treatment process, there were 24 patients in the early intervention subgroup and 21 patients in the late intervention subgroup. There was no significant difference in baseline characteristics between the two subgroups, as shown in Table 1. The rates of CR, PR, SD, and PD in the early intervention subgroup were 8.33% (2/24), 66.67% (16/24), 25% (6/24), and 0% (0/24) three months after initial combination therapy, while those in the late intervention subgroup were 4.76% (1/21), 61.90% (13/21), 23.81% (5/21), and 9.52% (2/21), respectively. Therefore, there was also no significant difference in the ORR (75% vs. 66.67%, P > 0.05) and DCR (100% vs. 90.48%, P > 0.05) between the two subgroups. However, there was significant difference in the PFS and OS between the two subgroups. For the PFS, the early intervention subgroup had a median of 15.5 months, which was significantly longer than that in the late intervention subgroup (9 months) (P = 0.007 < 0.05, 95%CI: 1.28–5.89), as shown in Fig. 3C. For the OS, the early intervention subgroup had a median of 27.5 months, which was significantly better than that in the late intervention subgroup (15 months) (P < 0.001, 95%CI: 1.81–11.16), as shown in Fig. 3D.

Discussion

This single-center retrospective study evaluated that the combination of BACE/BAI and iodine-125 brachytherapy was a promising salvage therapy with good efficacy and safety for advanced NSCLC after standard treatment failure (the median PFS of the cohort was 12 months and the median OS was 20 months). Standard treatment failure in advanced NSCLC, considered as tumor progression is an inevitable challenge. The patients with advanced NSCLC who received sequential multiple standard treatments tended to have more unsatisfactory outcomes with later treatment compared to the first-line treatment [9, 13, 14]. Myelosuppression, drug resistance, chronic basic pulmonary diseases, radiation pneumonitis, immunotherapy related pneumonia and other severe complications are the main reasons for unsatisfactory outcomes, as many patients cannot tolerate subsequent standard treatments, leading to tumor progression quickly in advanced NSCLC [15, 16].

BACE/BAI is an effective local therapy for NSCLC to reduce tumor burden and control hemoptysis by increasing the drug concentration of the target tumor and embolizing the blood supply arteries. A multicenter prospective study has suggested that BACE was safe and effective in treating refractory NSCLC and could significantly improve patients’ quality of life with a median OS of 11.5 months [17]. Another prospective study has reported a median OS of 17.4 months after BAI in NSCLC patients contraindicated for standard chemotherapy [18].

Iodine-125 brachytherapy, an internal radiotherapy, can provide directly a cumulative higher radiation dose for the target tumor with negligible doses for the surrounding normal tissues because of the characteristics of iodine-125 seeds [11, 12]. By emitting continuous gamma radiation, iodine-125 seeds can destroy tumor cells at the various cell cycle stages and increase the sensitivity of hypoxic tumor cells to radioactive rays to kill tumor cells with radiation-induced bystander effect, which can provide better tumor response and longer overall survival with low-risk of radiation-related adverse reaction compared to conventional external radiotherapy [19,20,21]. For advanced NSCLC, iodine-125 brachytherapy significantly improved the overall response rate (88% vs. 59%), the median time of OS (16 months vs. 10 months) and two-year survival rates (37.1% vs. 11.1%) compared with the conventional external radiotherapy [22]. Stereotactic body radiotherapy (SBRT) is a useful local therapy for unresectable stage II or III NSCLC [23]. However, the maximal radiation dosage, large tumor burden and poor status lung function (chronic basic pulmonary diseases, radiation pneumonia and immune pneumonia) mainly restrict the effectiveness and application of SBRT for advanced NSCLC after standard treatment failure [19, 22].

BACE/BAI combined with iodine-125 brachytherapy can make up and complement technological deficiencies of each other. For hypovascular or peripheral tumors in advanced NSCLC, only BACE/BAI may not achieve the satisfactory long-term efficacy and survival [18]. However, iodine-125 brachytherapy can complement this technological deficiency. For central tumors in advanced NSCLC, as the proximity of the lesion to important organs such as large blood vessels and trachea, it is difficult for iodine-125 seeds implantation to cover the entire volume of the target tumor, which may lead to unsatisfactory outcome. Nevertheless, BACE/BAI combined with iodine-125 brachytherapy can deal with this dilemma through a synergistic antitumor effect, where the potential for reduction in tumor burden and changing in the tumor microenvironment by this combined strategy following local control may further enhance the overall response and create a more favorable environment for systemic therapies, offering a promising salvage avenue for improving patient’s long-term outcome [10, 24]. The local control rate (90% vs. 59.3%), PFS (12.6 vs. 8.2 months), and OS (644 vs. 544 days) of the BACE/BAI combined with iodine-125 brachytherapy group were significantly better than those of the BACE alone group for advanced NSCLC [10].

As a promising salvage therapy of advanced NSCLC after standard treatment failure, the combination therapy will not affect further treatment options [10,11,12]. For the tumor progression after this combination therapy, BACE/BAI or (and) iodine-125 brachytherapy could be performed once more for the local recurrent or new tumor. In addition, other multiple standard treatments, including multi-line chemotherapy, molecular targeted therapy and immunotherapy, are also widely used to serve as further and subsequent treatments for the tumor progression after this salvage combination therapy or as maintenance therapies for the tumor stability [24]. In this study, most patients have received further, subsequent or maintenance treatments after BACE/BAI combined with iodine-125 brachytherapy.

BACE/BAI combined with iodine-125 brachytherapy in advanced NSCLC after standard treatment failure is safe. In this study, identification of dangerous vascular branches, super-selective intubation and the optimized individual brachytherapy plan played an important part to reduce the risk of serious complications. Besides, BACE/BAI prioritized for implementation can effectively reduce the risk of bleeding during iodine-125 seeds implantation. Preoperative respiratory training, optimized puncture path planning, adequate pleural anesthesia, and reduced puncture frequency and damage to lung tissue can effectively reduce the incidence of pneumothorax, especially severe pneumothorax (grade III).

This study evaluated that the optimal intervention timing of BACE/BAI combined with iodine-125 brachytherapy, as a promising salvage therapy for advanced NSCLC, was the time of disease progression following the first-line treatment rather than the time of disease progression following multiple standard treatments. Although the short-term efficacy (ORR and DCR) between the two subgroups was comparable, the PFS and OS in the early intervention subgroup was significantly better than that in the late intervention subgroup. Intervention at the point of treatment failure or disease progression, when the tumor burden is still relatively limited, may allow for more effective local control and potentially enhance the response to subsequent therapies [25,26,27]. Therefore, we suggested that the earlier the intervention of this combination therapy strategy, the more beneficial it is for patients with advanced NSCLC after standard treatment failure.

Several limitations should be acknowledged in this study. First, it was a retrospective analysis and the number of patients included was relatively small. Moreover, the individualized differences in standard treatments before the combination therapy and in further treatments after the combination therapy may increase the risk of bias and impact the results. Finally, there was no control group in this cohort. Therefore, the prospective research with the same standardized protocols that includes more cases should be performed in the future to validate these preliminary results and to further explore the underlying mechanisms.

Conclusion

For advanced NSCLC after standard treatment failure, the combination of BACE/BAI and iodine-125 brachytherapy is a promising salvage therapy with good efficacy and safety. Especially, the earlier the intervention of this combination therapy strategy, the more beneficial it may be for patients.