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 (12–16).

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.

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 (25–27). 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 (29–31). NSCLC is mainly supplied by the bronchial artery (32), and the chemotherapeutic drug could be infused into the tumor-feeding 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). In 2017, Zhu et al. (31) analyzed 36 stage III squamous cell lung cancer patients treated with BAI and revealed a prolonged PFS or OS compared with systemic chemotherapy, with an effective rate, 1-year survival rate, and 2-year survival rate of 72.2%, 75.4%, and 52.1%, respectively.

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 months (12–16). Gemcitabine-loaded DEB-BACE was first to be applied to NSCLC in 2019 (13). Although this study included only six patients, promising results with the median PFS of 8.0 months and median OS of 16.5 months were provided (13). Then, Shang et al. (12) compared the efficacy of pirarubicin-loaded DEB-BACE and BAI alone in 60 standard treatment-ineligible/rejected NSCLC patients; among them, over 85% of NSCLC patients were in advanced stage. Higher ORR, DCR, and 6-month PFS and OS rates were found in the DEB-BACE group, which indicated a superior efficacy than BAI alone (12). Sequentially, Zeng et al. (14) analyzed 23 advanced lung cancer patients treated with DEB-BACE and revealed an ORR of 78.3% and median OS of 15.6 months despite including four patients with small cell lung cancer or lung metastases. Another study from this institution showed median PFS and OS of 6.3 months and 10.2 months, respectively, for 29 advanced NSCLC patients treated with pirarubicin-loaded DEB-BACE (15). Nevertheless, there was no consensus on the optimal chemotherapeutic drug loaded in the DEB microsphere. The predominant chemotherapeutic drug loaded in the DEB microsphere was 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). Zhong et al. (39) indicated a local recurrence rate of 20.5% in advanced NSCLC treated with MWA; of these, 81.3% of relapse occurred in tumor size ≥3 cm, while Nelson et al. (40) 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.

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

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.

SX: conceptualization, data curation, methodology, and writing—original draft. ZXB: data curation, methodology, resources, and writing—review and editing. YML: writing—review 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.

This work was funded by the Clinical and Translational Medical Research Fund, Chinese Academy of Medical Sciences (no. 2020-I2M-C&T-A-021). Funding source had no involvement in the conduct of the research and preparation of the article.

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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