Drug-Eluting Bead Bronchial Arterial Chemoembolization With and Without Microwave Ablation for the Treatment of Advanced and Standard Treatment-Refractory/Ineligible Non-Small Cell Lung Cancer: A Comparative Study

Purpose To compare the outcomes of drug-eluting bead bronchial arterial chemoembolization (DEB-BACE) with and without microwave ablation (MWA) for the treatment of advanced and standard treatment-refractory/ineligible non-small cell lung cancer (ASTRI-NSCLC). Materials and Methods A total of 77 ASTRI-NSCLC patients who received DEB-BACE combined with MWA (group A; n = 28) or DEB-BACE alone (group B; n = 49) were included. Clinical outcomes were compared between groups A and B. Kaplan–Meier methods were used to compare the median progression-free survival (PFS) or overall survival (OS) between the two groups. Univariate and multivariate Cox proportional hazards analyses were used to investigate the predictors of OS for ASTRI-NSCLC treated with DEB-BACE. Results No severe adverse event was found in both groups. Pneumothorax was the predominant MWA-related complication in group A, with an incidence rate of 32.1% (9/28). Meanwhile, no significant difference was found in DEB-BACE-related complications between groups A and B. The overall disease control rate (DCR) was 61.0% (47/77), with a significantly higher DCR in group A (85.7% vs. 46.9%, P = 0.002). The median PFS in groups A and B was 7.0 and 4.0 months, respectively, with a significant difference (P = 0.037). The median OS in groups A and B was both 8.0 months, with no significant difference (P = 0.318). The 6-month PFS and OS rates in groups A and B were 75.0% and 78.6%, 22.4% and 59.2%, respectively, while the 12-month PFS and OS rates in groups A and B were 17.9% and 28.6%, 14.3% and 22.4%, respectively. Of these, a significantly higher 6-month PFS rate was found in group A (75.0% vs. 22.4%; P < 0.001). The cycles of DEB-BACE/bronchial artery infusion chemotherapy [hazard ratio (HR): 0.363; 95% confidence interval (CI): 0.202–0.655; P = 0.001] and postoperative immunotherapy (HR: 0.219; 95% CI: 0.085–0.561; P = 0.002) were identified as the predictors of OS in ASTRI-NSCLC treated with DEB-BACE. Conclusion MWA sequentially combined with DEB-BACE was superior to DEB-BACE alone in the local control of ASTRI-NSCLC. Although the combination therapy reveals a trend of prolonging the OS, long-term prognosis warrants an investigation with a longer follow-up.


INTRODUCTION
Primary lung cancer has an incidence and mortality of over 2.2 million and 1.79 million, respectively, estimated globally in 2020 (1). In China, non-small cell lung cancer (NSCLC) has a percentage over 85% in the diagnoses of lung cancer, and most of the patients are advanced when diagnosed (2,3). The standard treatments for unresectable advanced NSCLC include chemoradiotherapy, molecular targeted therapy [such as tyrosine kinase inhibitors (TKIs)], and immunotherapy. However, it often develops refractoriness and almost 59% of unresectable stage III NSCLC patients are ineligible for chemoradiotherapy owing to the severe adverse events (4). In addition, TKIs are not available for a large proportion of patients without gene mutations. The prognosis of advanced NSCLC remains dismal, with a 5-year survival rate of 15% for stage III and that of less than 10% for stage IV (5). Furthermore, 30%-50% of NSCLC patients are diagnosed with poor performance status owing to cardiovascular and pulmonary diseases and are ineligible for systemic therapy (6). The therapeutic strategy for advanced and standard treatment-refractory/ineligible NSCLC (ASTRI-NSCLC) patients remains limited.
In recent decades, computed tomography (CT)-guided microwave ablation (MWA) has been recommended as a primary treatment option by several guidelines (7,8), especially for early-stage NSCLC that is contraindicated to undergo surgery or radiotherapy, and has been presented as a part of combination therapy for advanced-stage NSCLC (9). Moreover, bronchial arterial chemoembolization (BACE) has been increasingly applied in NSCLC, which aims to embolize the tumor-feeding arteries, extend the action time of chemotherapeutic drugs, and increase drug concentration at tumor tissues (10). As a novel drug delivery and embolization system in transarterial chemoembolization (TACE), drug-eluting bead (DEB) microsphere can release the loaded chemotherapeutic drugs slowly, improve local drug concentration, and permanently embolize the tumor-feeding arteries (11). DEB-BACE was identified as an effective and safe approach for advanced standard treatment-ineligible/rejected NSCLC (12)(13)(14)(15)(16).
The optimal cutoff value of tumor diameter in predicting local recurrence after MWA was 3 cm, with the potential mechanisms for incomplete ablation in large tumors including the limited size and homogeneity of tumor necrosis achieved by MWA and the heat-sink effect caused by the blood vessels in ablated tumor (17). In theory, BACE could block the arterial blood flow and increase drug concentration at tumor sites, which may improve the prognosis of MWA. Similar effectiveness has already been shown and recommended in liver cancers treated with TACE and thermal ablation (18,19). Liu et al. (20) indicate that combined treatment with DEB-TACE has advantages in improving the prognosis of early-stage liver cancer compared to MWA alone. However, few studies have focused on the outcomes of MWA combined with DEB-BACE for ASTRI-NSCLC. Therefore, a retrospective study was conducted to compare the outcomes of DEB-BACE with and without MWA in the treatment of ASTRI-NSCLC.

Patient Criteria
This single-center case-control study included all ASTRI-NSCLC patients who underwent DEB-BACE at this institution. The institutional ethics review board approved this study. The study protocol was conducted per the Declaration of Helsinki. Informed consent was waived due to the retrospective nature of this study. ASTRI-NSCLC patients who received DEB-BACE between May 2017 and April 2021 were allocated to the combination therapy group (MWA+DEB-BACE, group A) and DEB-BACE alone group (group B). Informed consent of MWA or/and DEB-BACE was obtained before these procedures. Patient inclusion criteria were as follows: (a) age of 18-85 years; (b) advanced NSCLC that is ineligible for or is refractory to standard treatments; and (c) Eastern Cooperation Oncology Group score of 0-2. Patient exclusion criteria were as follows: (a) concomitant radioactive seed implantation was performed during MWA procedure; (b) incomplete data; (c) lost to followup; (d) MWA combined with bronchial artery infusion chemotherapy (BAI); and (e) period between MWA and DEB-BACE longer than 1.5 months.
The histopathological subtypes were confirmed via previous percutaneous needle aspiration biopsy or surgery or fiberoptic bronchoscopy. Positron emission tomography or CT was performed to evaluate the tumor location, quantity, size, and local and distant metastases. The clinical TNM staging system of the Union for International Cancer Control (8th edition) was applied in identifying the tumor stage (5).

Microwave Ablation Procedure
The MWA indications and procedures followed the Society of Interventional Radiology (SIR) guidelines (21). As described previously (22), an MTC-3C MWA system (Vison Medical Inc., China) or an ECO-100A1 MWA system (ECO, China) was used, with a microwave emission frequency of 2,450 ± 50 MHz and an adjustable continuous wave output power of 20-80 W. The MWA antenna (Vison or ECO) was 15-18 cm in effective length and 15-17 G in outside diameter according to the tumor location and distance to the pleura, with a 15-mm active tip. Preprocedural CT was performed to inform the treatment plan and to clarify the suitable position, puncture site location, optimal puncture trajectory, and the number of MWA antennas. Local anesthesia was used for most patients, while intravenous anesthesia was used for selected patients requiring more pain control. Antennas were introduced into the planned site, and MWA was performed at the planned power and duration, with adjustments of suitable power and duration being carried out according to the intraprocedural location of MWA antennas as needed. The procedure was terminated when the tumor tissues were ablated and inactivated as much as possible. Finally, chest CT was repeated to evaluate the distribution of ablation zone and detect the potential complications.

DEB-BACE Procedure
As described previously (16), DEB-BACE procedures were performed under local anesthesia via a femoral artery approach. A 5-French pigtail catheter (PIG Impress; Merit Medical Systems, Inc., USA) was initially used for aortic arch angiography to detect the origins of tumor-feeding arteries. Then, a 5-French cobra (CB 1 Impress; Merit Medical Systems, Inc., USA) or left gastric catheter (Radifocus; Terumo Corporation, Japan) was used to select the bronchial arteries or non-bronchial systemic arteries. Super-selective catheterization with a 1.98-French microcatheter (Masters PARKWAY SOFT; Asahi Intec Co., Japan) was inserted coaxially. The chemotherapeutic regimen of paclitaxel (100-200 mg; Keaili, CSPC Pharmaceutical Group Co., China) was administered during BAI for patients who had already received systemic platinum-based chemotherapy, while nedaplatin (80-100 mg; Lubei, Qilu Pharmaceutical Co., China) was administered for patients who had not received systemic platinum-based chemotherapy. Gemcitabine (200-1,000 mg; Zefei, Hansoh Pharmaceutical Group Co., China) or endostatin (60-120 mg; Endu, Simcere Pharmaceutical Group, China) was infused on demand. BAI was followed by DEB-BACE, which was performed using 100-300 mm or 300-500 mm or 500-700 mm CalliSpheres microspheres (Jiangsu Hengrui Medical Co., China) loaded with gemcitabine (800 mg; Hansoh, China) or pirarubicin (30 mg; Adriamycin, Shenzhen Main Luck Pharmaceutical Inc., China). The CalliSpheres microspheres were first mixed with gemcitabine or pirarubicin at a temperature of 23°C-28°C for 30 min and vibrated every 5 min. Then, iodixanol (100 ml:65.2 g/ 32 g iodine; Hengrui, China) was added at a 1:1 ratio. The DEB-BACE was performed slowly and carefully in tumor-feeding arteries under fluoroscopic monitoring to avoid reflux into nontarget vessels. The technical endpoint of embolization was the absence of additional tumor staining or stasis/near stasis of the tumor-feeding arteries. For patients who received combination therapy, DEB-BACE was performed 2-45 days after MWA, followed by repeated DEB-BACE/BAI on demand. For the patients who received a repeated DEB-BACE/BAI, DEB-BACE was performed if abundant tumor staining was revealed in angiography, while BAI alone was performed for those patients without.

Follow-Up and Assessments
Short-term follow-up with CT was conducted 1-5 days after MWA during hospitalization and 3-4 weeks after MWA at an outpatient visit to detect postprocedural complications, including pneumothorax and pleural effusion. Chest tube placement was performed for patients with moderate and severe pneumothorax or pleural effusion (17). Immunotherapy was performed for patients who have not received and can tolerate programmed cell death ligand 1 (PD-L1) blockade and programmed cell death 1 (PD-1) blockade. PD-L1 blockade was administered for patients with high PD-L1 expression according to the previous testing.
MWA-or DEB-BACE-related complications were evaluated according to criteria from the SIR (21,23). Enhanced CT was routinely performed every 3 months. Based on the Response Evaluation Criteria in Solid Tumors version 1.1 (24), treatment response was evaluated and classified as a complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). The disease control rate (DCR) was defined as CR or PR or SD. Overall survival (OS) was defined as the interval from the start of MWA in group A or the first DEB-BACE in group B to death or the last follow-up (October 31, 2021). For patients who died during the follow-up period, OS was calculated as the interval from the MWA or DEB-BACE procedures to death. For patients who survived but were lost to follow-up, OS was calculated as the interval from the MWA or DEB-BACE procedures to the last follow-up. Progression-free survival (PFS) was defined as the interval from the MWA or DEB-BACE procedures to the time of objective progression, including local progression and/or distant metastases. For patients who did not die or progress, the censoring date was defined as the last clinical assessment date.

Statistical Analysis
Categorical variables are described as frequencies and percentages, and continuous variables are described as the mean ± SD. Statistical analyses were performed using SPSS 25.0 for Windows (IBM, Somers, New York). The clinical characteristics, complications, and prognostic data were compared by Student's t-test or Mann-Whitney U test for continuous variables and by chi-square test for categorical variables. Of these, Kaplan-Meier methods were used to compare the median PFS or OS between the two groups. The OS for ASTRI-NSCLC treated with DEB-BACE was estimated using the Kaplan-Meier method. The possible predictors of OS included 21 parameters on demographics, treatment history, MWA or/and DEB-BACE factors, and radiological features. Variables with a P-value <0.05 in the univariate analyses were entered as candidate variables into a stepwise Cox proportional hazards analyses. The results of the multivariate analyses indicated the predictors for the OS. A P-value <0.05 was considered to indicate statistical significance in the univariate and multivariate Cox proportional hazards analyses.

Patient Characteristics
A total of 77 NSCLC patients (28 in group A and 49 in group B; Figure 1) were included. Of these, 41 patients (53.2%) were squamous cell carcinoma and 45 patients (58.4%) were stage III NSCLC. Detailed demographic characteristics are presented in Table 1; a significant difference was found in the incidence of hypertension (P = 0.021), whereas other variables revealed no differences. There were 21 patients (27.3%) who received immunotherapy after DEB-BACE, with PD-L1 blockade administered in six patients (7.8%) and PD-1 blockade administered in 15 patients (19.5%).

Complications
No severe adverse event was found in both groups. Detailed MWA-related complications in group A are presented in Table 2; pneumothorax was the predominant MWA-related complication, with an incidence rate of 32.1% (9/28). Detailed DEB-BACE-related complications between groups A and B are presented in Table 3, with no significant difference.

Clinical Outcomes
Detailed clinical outcomes between the two groups are presented in Table 4. In a mean follow-up of 21.7 ± 14.1 months, the median PFS in groups A and B was 7.0 and 4.0 months, respectively, with a significant difference (P = 0.037; Figure 2A). The median OS in groups A and B was both 8.0 months, with no significant difference (P = 0.318; Figure 2B). The 6-month PFS and OS rates in groups A and B were 75.0% and 78.6%, 22.4% and 59.2%, respectively, while the 12-month PFS and OS rates in groups A and B were 17.9% and 28.6%, 14.3% and 22.4%, respectively. Of these, a significantly higher 6month PFS rate was found in group A (75.0% vs. 22.4%; P < 0.001). There were nine patients (11.7%) who achieved PR at 3 months after MWA or/and DEB-BACE ( Figure 3). The overall DCR was 61.0% (47/77) at 3 months after MWA or DEB-BACE; of these, a significantly higher DCR was found in group A (85.7% vs. 46.9%, P = 0.002).

DISCUSSION
The first-line therapeutic strategy for unresectable advanced NSCLC is chemoradiotherapy, which can provide an objective response rate (ORR) of 23%-34% and a median OS of 11.6 months after systemic platinum-based chemotherapy, or an ORR of 51.5%, a median OS of 22.0 months, and a median PFS of 17.0 months after chemoradiotherapy (25)(26)(27). The incidence rate of adverse events was 62% as reported (26). Second-line systemic chemotherapy or TKIs were considered when the patients fail to respond to chemoradiotherapy and can provide a median OS of 12.2 months and a median PFS of 3.1 months for stage III NSCLC patients (28).  In recent decades, BACE/BAI has been reported as an effective and safe approach for advanced NSCLC, especially for chemoradiotherapy-ineligible/rejected patients, with a median PFS of 6.5-14.0 months and a median OS of 13.1-25.0 months (29)(30)(31). NSCLC is mainly supplied by the bronchial artery (32), and the chemotherapeutic drug could be infused into the tumorfeeding arteries directly during BAI, which can improve the bioavailability of the drug without leading to severe adverse events (33). BAI has a local drug concentration 2-6 times higher than that of systemic chemotherapy and also has effects on lymph node metastases (34). Both local and systemic chemotherapy could be achieved in BACE/BAI, which attributes to the drugs entering the tumor again through the blood circulation, and tumor ischemia, necrosis, or shrinking caused by the embolization (35). In 2012, Nakanishi et al. (29) attempted BAI in 25 advanced chemotherapy-refractory/ ineligible NSCLC patients and presented an ORR of 52% and a median PFS and OS of 6.5 months and 17.4 months, respectively. Similarly, another study performed 142 cycles of BAI in 40 advanced chemoradiotherapy-ineligible/rejected NSCLC patients and found an ORR of 32.5%, a DCR of 92.5%, and a median OS of 13.1 months (30 DEB microspheres can provide a higher local drug concentration while reducing the systemic drug concentration and toxicity (11). Several studies have identified the efficacy and safety of DEB-BACE in advanced lung cancer and found a median PFS of 6.3-11.0 months and a median OS of 8.0-16.5     gemcitabine in this study. Although pirarubicin showed moderate anticancer activity, mild toxicity, and a high response rate for advanced NSCLC as reported (34), no superior efficacy of pirarubicin over gemcitabine was found in this study. The median PFS and OS of advanced NSCLC treated with DEB-BACE in this study were 5.0 and 8.0 months, which seem to be less than the reported results. Potential mechanisms were (a) over 40% of the patients were stage IV and over 50% of the patients were standard treatment-refractory, and (b) 35.1% of the patients survived until the last follow-up. In addition, the immune checkpoint inhibitors were identified as the second-line treatment for advanced NSCLC, and PD-1 blockade combined with systemic chemotherapy has been revealed as a promising approach (36). Identically, this study revealed that postoperative immunotherapy was one of the predictors to prolong the OS of ASTRI-NSCLC treated with DEB-BACE, which is per the additional immunotherapy that may improve the survival of advanced NSCLC after BAI/DEB-BACE, as reported (16).
The mechanisms of MWA are that microwaves can induce the oscillation of the water molecules that flip back and forth at a speed of 2-5 billion times a second depending on the frequency of the wave itself, allowing for a superior convection profile and causing coagulative necrosis conforming to the target sites (37). The optimal indication for thermal ablation is NSCLC with tumor <3 cm in diameter (8). Tumor diameter is a critical risk factor of local recurrence and OS after MWA in NSCLC as reported, especially for the tumor ≥3 cm in diameter (17,38).   summarized a local recurrence rate of 5%-19% after MWA in NSCLC with tumor <4 cm in a systemic review. It has been reported that thermal ablation combined with TACE can decrease the recurrence rate and may improve the prognosis compared to ablation monotherapy for early-stage liver cancer (18,19). Identical results were demonstrated in the combination therapy of DEB-TACE and MWA compared to MWA monotherapy for early-stage liver cancer (20). A study from China reviewed 138 advanced NSCLC patients and found that the 1-, 2-, and 3-year survival rates of the combination therapy group (BACE and radiofrequency ablation) were 90.7%, 58.1%, and 20.9%, respectively, which revealed a better prognosis than that of BACE or ablation monotherapy groups (41). In this study, the combination therapy of MWA and DEB-BACE revealed a superior local control, with a higher 6-month PFS rate and a longer PFS than DEB-BACE alone. The potential mechanisms were inactivating the majority of tumor tissues that can be achieved directly by MWA, and DEB-BACE leads to the continuous delivery of loaded chemotherapeutic drugs and the embolization of tumor-feeding arteries, thereby reducing the collateral circulation and enhancing the synergistic anticancer effects on residual tumor tissue. Although the combination therapy reveals a trend of prolonging the OS, no significant difference was found. The leading causes were that 42.9% of the patients in group A survived until the last follow-up and the limited mean follow-up of 21.7 ± 14.1 months in this study. This study has several limitations. First, it was a retrospective study; patient selection bias may exist. Second, the sample size was still limited for patients treated with combination therapy. Third, this study consists of advanced patients who are ineligible for or are refractory to standard treatments, and heterogeneity may exist. Fourth, the sequence of MWA and DEB-BACE is required to be further investigated. Fifth, the follow-up period was still limited, and the long-term evaluation of OS for combination therapy should be further explored.
In conclusion, the combination therapy of MWA and DEB-BACE is an effective and safe approach for ASTRI-NSCLC. MWA sequentially combined with DEB-BACE was superior to DEB-BACE alone in the local control of ASTRI-NSCLC. Although the combination therapy reveals a trend of prolonging OS, long-term prognosis warrants an investigation with a longer follow-up.

DATA AVAILABILITY STATEMENT
The data used to support the findings of this study are available from the corresponding author upon request.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences. The ethics committee waived the requirement of written informed consent for participation. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

AUTHOR CONTRIBUTIONS
SX: conceptualization, data curation, methodology, and writing-original draft. ZXB: data curation, methodology, resources, and writing-review and editing. YML: writingreview and editing. BL: resources and writing-review and editing. FLK: writing-review and editing. JZP: writing-review and editing. XGL: validation, supervision, and writing-review and editing. All authors contributed to the article and approved the submitted version. Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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