Stereotactic ablative body radiation therapy for treatment of ultra-central lung tumors: a narrative review

Introduction

Stereotactic ablative radiotherapy (SABR) has emerged as the standard treatment for medically inoperable early-stage non-small cell lung cancer (NSCLC) over the past decade (1,2). The feasibility of SABR for peripheral tumors is well established (3,4). However, its application in central lung tumors remains controversial due to concerns about increased morbidity. Central lung tumors are situated in a ‘no-fly zone’ due to their association with excessive, and even fatal, toxicities following SABR (5). With advancements in radiotherapy technology and growing experience, a subset of lesions within the “no-fly zone” can now be treated with SABR, achieving safety and efficacy comparable to that of peripheral tumors. The phase I/II Radiation Therapy Oncology Group (RTOG) 0813 study demonstrated high local control (LC) rates and acceptable toxicity using 5-fraction schemes with high radiation biologically effective dose 10 (BED10) (100–132 Gy) for inoperable centrally located NSCLC (6). Other SABR regimens such as 60 Gy in eight fractions, have also shown good tolerability (7).

Ultra-central (UC) lung tumors represent a distinct subgroup of central lung tumors, which refer to lesions that lie in extreme proximity to critical mediastinal structures like the major airway, esophagus and heart. Although RTOG 0813 has established the feasibility of SABR in central lung tumors, the outcomes and side effect profile of SABR for UC lung lesions remain controversial (8-15).

In this review, we focus on the current understanding of SABR in UC lung lesions. We summarize the definitions of UC lung lesions, clinical outcome and side effect profiles (Tables 1,2) (8-13,15-27), discuss existing challenges and controversies, and explore the potential advantages of advanced radiation techniques (such as proton radiotherapy, and their combination with immunotherapy. This review aims to provide insights into optimizing the management of patients with UC lung lesions, offering an in-depth analysis of the evolving landscape in addressing these challenging cases. We present this article in accordance with the Narrative Review reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1961/rc).

Methods

We performed a thorough literature search in PubMed and clinical trial information registered on ClinicalTrials.gov from January 2006 to September 2024. Currently existing information on definitions of UC lung lesions, SABR dose regimens and treatment outcomes following SABR, SABR-related toxicities and constraints for critical organs at risk (OAR), and potential strategies to improve the application of SABR in UC lung tumors was collected and reviewed. Table 3 summarizes the search strategy.

Definitions of UC lung lesions

Central lung lesions are defined as tumors located within a 2 cm radius in all directions from the proximal bronchial tree (PBT), or immediately adjacent to mediastinal or pericardial pleura [planning tumor volume (PTV) touching the pleura]. This definition has been adopted by both the RTOG 0813 trial and European Organization for Research and Treatment of Cancer (EORTC) 22113-08113 LungTech Phase II Trial (6,28). Another definition, recommended by the International Association for the Study of Lung Cancer (IASLC), describes central lung lesions as tumors within 2 cm of any mediastinal critical structures including the trachea, bronchial tree, esophagus, heart, major vessels, spinal cord, brachial plexus, phrenic nerve, and recurrent laryngeal nerve (29,30). However, no universally recognized definition of UC lung lesions has been established yet. Table 1 (8-13,15-27) summarizes the various definitions reported in previous studies.

Chaudhuri et al. (9) were the first to introduce the concept of UC lung tumors, defining them as gross tumor volume (GTV) directly abutting the PBT or trachea. This definition has been adopted by several subsequent studies (15-20). Some of these studies also included patients with endobronchial tumors as confirmed by bronchoscopy or imaging (16,18,19,21). Tekatli et al. (21) later redefined UC lesions as tumors PTV overlaps with the trachea or main bronchi (Figure 1 presents one of our patients whose PTV overlapped with the trachea). Chang’s team (8) uniquely defined UC lesions as cases where the internal target volume (ITV) directly abuts the PBT. This definition appears reasonable, given the widespread extensive use of four-dimensional computed tomography for treatment planning. Besides affecting the main airway, radiation-induced injuries to the esophagus particularly esophageal fistula, can significantly increase patient mortality. For instance, Stephans et al. (31) reported two cases of esophageal fistula among 52 patients whose PTV fell within 2 cm of the esophagus. As a result, the category of UC lesions has been expanded to include tumors with PTV touching or overlapping the PBT or esophagus (10,22,23). Furthermore, some studies have revised the definition to include the pulmonary vein (PV), pulmonary artery (PA) (11,24-26,32,33) and other great vessels (27). This expanded definition is also utilized in the ongoing multi-center phase I dose escalation trial SUNSET (NCT03306680) (34). SABR-induced hemoptysis is generally believed to arise from bronchial circulation rather than pulmonary circulation or aorta-bronchial fistula (35). This understanding leads to a preference for using doses received by the trachea and bronchi to predict the risk of hemoptysis, rather than the great vessels (32,35). Meanwhile, a large retrospective pooled analysis found that a PTV overlapping the trachea or main stem bronchus was predictive of ≥G3 pulmonary toxicity (36). Based on these findings, we define tumors with PTV touching or overlapping the PBT, trachea, or esophagus as UC lesions in routine clinical practice. Although more evidence is needed to support its rationale, our approach reflects current clinical insights and may help manage patient risks more effectively (37).

Figure 1 Example of a patient with stage I ultra-central primary lung cancer of which its planning tumor volume overlaps with the trachea and abuts the superior vena cava. (A) Axial plane; (B) coronal plane; (C) sagittal plane. Red: gross tumor volume; purple: planning tumor volume; green: trachea; orange: esophagus.

Dose regimens of SABR for UC lung lesions

Currently, there is no consensus or guidelines for employing SABR in UC lung tumors, as existing protocols show considerable variability, making comparisons challenging. SABR regimens typically range from 4 to 12 fractions, with doses between 5 and 12.5 Gy, applied to either lung primary tumors or metastases (Table 2) (8-13,15,16,18-27). Radiation oncologists tailor contouring and dose prescription to maximize efficacy and minimize toxicity based on treatment objectives. Before the concept of UC tumors was introduced, a phase II study by Timmerman et al. (5) observed a two-year LC rate of 95% with SABR for inoperable early-stage lung cancer. However, patients with central tumors who received 60–66 Gy in three fractions experienced notably high rates of severe toxicity. Song et al. (38) later evaluated regimens with smaller doses per fraction (40 Gy/4 f, 48 Gy/4 f, 60 Gy/3 f) in patients with stage I lung cancer. While the two-year LC was favorable at 89%, the two-year overall survival (OS) was only 50%, likely due to significant central airway toxicities. These results prompted a shift toward more moderate fractionation schemes. However, Haseltine et al. (16) observed only a modest two-year LC rate of 77.4% with schemes of 45–50 Gy/4–5 f. Among 18 patients with lesions abutting the trachea or PBT, four experienced SABR-related deaths within one year—two from acute pulmonary hemorrhage and two from pneumonia—indicating a higher risk compared to patients with non-abutting tumors. In contrast, Chaudhuri et al. (9) reported a two-year LC rate of 100% in 7 patients with UC lesions treated with regimens of 50 Gy/4–5 f (BED10=100–112.5 Gy) without any grade 2+ toxicity, despite 43% of patients exceeding the maximum point dose (MPD, or Dmax) or volumetric maximum dose (Vmax) constraints established by RTOG 0813 for central airways. Farrugia et al. (13) employed similar SABR regimens (50 Gy/5 f in 44.6%, 55 Gy/5 f in 42.2%) as those used in RTOG 0813 for node-negative, non-metastatic NSCLC patients with GTVs abutting the PBT (32.6%), trachea (9.3%) or aorta (37.2%). The crude LC rate was 93% and the two-year OS rate was 53.3%. Only one case of G3 dysphagia was reported, with no G4–5 acute toxicities. These findings suggest that SABR schemes with a BED10 over 100 Gy might be feasible for patients with UC lesions, though fractionation schedules and potential risk factors must be cautiously considered.

Since 2003, risk-adapted SABR approaches with smaller fraction sizes, such as 60 Gy/8 f (BED10=87.5 Gy), have also been frequently used for central lung tumors (7,39). This regimen was subsequently validated as both safe and effective for UC lesions, with promising long-term outcomes and rare grade 3+ toxicities (11,25). The three- and five-year LC rates reached 88% and 72.7%, respectively (25). This is comparable to established SABR regimens in central lung tumors such as 50 Gy/4–5 f (6). Based on these findings, the SUNSET trial selected 60 Gy/8 f as its initial dose (34), and the LUSTRE trial applied it to the UC NSCLC subgroup (40). Breen et al. (20) presented results from the largest single-institution cohort of early-stage, unselected UC NSCLC patients treated at the Mayo Clinic. The study included 110 patients treated with three SABR regimens (50 Gy/5 f, 60 Gy/8 f, 48 Gy/4 f), reporting similar long-term LC rates across the groups. Although the PTV was trimmed in some cases to minimize overlap with normal structures, four (4%) patients died of bronchopulmonary toxicities, and two patients (1.8%) developed grade 3 esophagitis. Mihai et al. (19) also reported comparable long-term LC rates (two-year 92% and four-year 79.8%, respectively), with over 87% of patients receiving 60 Gy/8 f. Despite allowing dose painting to spare the airways, five (8.7%) patients died from fatal hemoptysis. These findings suggest that while the 60 Gy/8 fraction regimen offers high LC, it should be used with caution in UC tumors that carry a high risk of bleeding.

Loi et al. (24) presented a cohort of oligometastatic UC NSCLC patients treated with risk-adapted dose regimens (median BED10=105 Gy, ranging from 75 to 132 Gy). Multivariate analysis revealed that a BED10 greater than 75 Gy (equivalent to 50 Gy/10 f) was independently associated with a markedly superior LC [median progression-free survival (PFS): 17 vs. 6 months]. The only reported grade 5 toxicity was an esophagitis that occurred following SABR of 50 Gy/5 f to a lesion adjacent to both the left main bronchus and the esophagus. Regnery et al. (12) observed a one-year LC rate of 91% and a two-year LC rate of 73% following SABR with 50 Gy/10 f. However, one patient on oral anticoagulants developed grade 3 hemoptysis. Despite the lower BED10, the 50 Gy/10 f regimen has achieved complete remission in some patients (41). Two studies examining a 60 Gy/12 f (BED10=90 Gy) regimen reported unexpectedly high incidence of grade 3+ bronchopulmonary hemorrhage, with Tekatli et al. (21) finding that 10 patients (21.3%) experienced grade 3+ hemoptysis, and 7 (15%) of these patients died from it. This elevated bleeding rate was likely attributed to high Dmax (median 138%, 123–154%) within the PTV, as 53% of patients had endobronchial tumors and 32% had tumors larger than 7 cm, resulting in Dmax ≥60 Gy in 89% for the main bronchi and 43% for the trachea. Consequently, the two-year OS rate was only 28.7%, less favorable than most published studies. Lodeweges et al. observed favorable LC rates (1-year 98%, 2-year 85%, 3-year 78%) and a relatively longer 2-year OS of 52%, which are comparable to the aforementioned high BED regimens (20,22,25). However, despite adhering to dose restrictions for the bronchus and trachea (D0.5cc ≤45 Gy) and permitting PTV undercoverage when necessary, fatal hemorrhage occurred in 10 (14%) patients (22).

It is generally accepted that a BED10 of at least 100 Gy is required for curative intent (42), though this goal may not be essential in clinical practice, particularly for palliative cases or patients in poor health. Van Diessen et al. (43) have found that reducing the dose for involved lymph nodes from BED10 70 Gy to 60 Gy did not increase regional failure. Park et al. (44) observed that patients with early-stage central tumors had noninferior LC and OS compared to those with peripheral tumors when treated with a lower mean BED (mean 120.2 vs. 143.5 Gy). These results suggest that central or UC lesions may not require the same high BED as peripheral tumors to achieve effective control. Rim et al. (45) recommended a BED10≥85 Gy (corresponding to 55 Gy/10 f or 45 Gy/5 f) for central and UC tumors in their meta-analysis. Salvestrini et al. (23) reported favorable long-term outcomes with risk-adaptive SABR (median BED10=92 Gy, range from 83 Gy to 132 Gy) in the largest UC cohort, where only 28% of the patients received BED10 ≥100 Gy. Notably, no significant difference in outcomes was detected between patients who received BED10 ≥100 Gy and those who received a BED10<100 Gy. Cong et al. (18) treated UC lung tumors and mediastinal lymph nodes using lower BED10 regimens (median 59.5 Gy, ranging from 48 Gy to 65.6 Gy), achieving a one-year LC of 54.4% with no bronchial or esophageal toxicity, despite all tumors invading the trachea and PBT. This approach appears feasible for advanced patients with poor general health and who are unsuitable for systemic therapy. However, two cases of cardiac death possibly related to SABR were registered, despite the low radiation dose to the heart (Dmax was 39.2 and 19.0 Gy, D15cc was 14.9 and 13.1 Gy, respectively).

The phase II HILUS trial investigated a SABR regimen of 56 Gy/8 f (BED10=84 Gy) in 65 patients with primary or metastatic lung tumors located ≤1 cm from the PBT. Despite excluding tumors extending through the wall of the main bronchus, the trial unexpectedly recorded 8 cases of fatal bronchopulmonary hemorrhage (46). While the expanded trial demonstrated high long-term LC (three-year LC 84%), the authors advised against using 56 Gy/8 f for tumors within 1 cm of the main bronchi and trachea (47).

SABR-related toxicities and OAR constraints

OAR protection during SABR for UC lung tumors is crucial, as these lesions are extremely near critical structures especially the trachea, PBT, and esophagus. The constraints for these organs vary depending on the fractionation schedules, and no uniform standard currently exists. OAR constraints in clinical practice are primarily derived from previous clinical trials, such as RTOG 0813, and expert experience (6,48-52). However, few prospective studies have investigated the associations between dosimetric parameters and SABR-related toxicity. This review focuses on studies examining OAR constraints during SABR for central lung tumors, with a particular emphasis on UC lung tumors.

Trachea and PBT

Radiation-induced airway injury was the most frequently reported toxicity in central lung tumors (35), which can manifest as mucosal necrosis, cartilaginous destruction, and inflammatory infiltration in the absence of viable tumor within the radiated area (53). Fatal bronchopulmonary hemorrhage is the most prominent cause of mortality associated with lung SABR (41). The reported incidence of grade 5 hemoptysis ranged from 0% to 15%, reflecting substantial heterogeneity in outcomes (Table 2). In addition to massive hemoptysis, bronchial stenosis and atelectasis can impair pulmonary ventilation, potentially leading to secondary pneumonia and respiratory failure (36,54).

Table 4 summarizes the OAR constraints adopted in published clinical trials for SABR of UC or central lung tumors (6,34,46). However, these constraints remain controversial and are sometimes exceeded in clinical practice (9,18). Prospective data on specific SABR-related toxicities and corresponding dose parameters are limited, making it challenging to define precise dose thresholds. A systematic review identified a maximum dose of ≥180 Gy₃ (BED3, corresponding to 45 Gy in 5 fractions or 55 Gy in 8 fractions) to the PBT as a significant risk factor for SABR-related mortality (55). Additionally, several retrospective studies have reported associations between mean dose or volume-dose parameters (e.g., D0.03cc, D0.1cc, D0.5cc, D4cc) and SABR-related toxicities such as bronchial stenosis, atelectasis, fistula, and hemoptysis (13,19,20,22,56-60).

Until sufficient prospective evidence is available, SABR should be pursued with caution under the following conditions: (I) Patients with endobronchial invasion, a subgroup at higher risk of fatal bleeding (46,55). High Dmax within the PTV should be avoided, such as by limiting the hotspot to 120% of the prescription dose or less (61). (II) Peri-SABR use of anti-platelet agents, anticoagulants, anti-vascular endothelial growth factor therapies (12,16,62). In particular, antiangiogenic agents should generally be avoided within 30 days before or after SABR for UC tumors (63). (III) Patients with decreased platelet counts or coagulation dysfunction. (IV) Invasive procedures such as bronchoscopy or biopsy before, during and after SABR (53). (V) Patients with squamous cell carcinoma (64). In these cases, hypofractionated radiotherapy should be considered as an alternative to SABR.

Esophageal toxicity

Compared to acute esophagitis, which typically resolves on its own, late-onset toxicities such as perforation, fistula, bleeding and stricture are of greater concern. Wang et al. (62) reported a probability of 13% of grade 3+ esophageal toxicity in UC patients whose PTV overlapped the esophagus, with two (2%) cases of trachea-esophageal fistula. Consequently, dose constraints for the esophagus have often been prioritized over tumor dose coverage in radiotherapy planning. Because of the uncertainties regarding the esophagus tolerance, a more conservative approach is generally taken, which may, however, compromise LC rates. In some centers, tumors near the esophagus (e.g., within 2 cm) are treated with 6–7 fractions of 7–8 Gy (65,66). While certain authoritative centers in China recommend against using SABR in such cases. It is crucial to establish effective esophagus dose constraints for the to ensure that the benefits of SABR are not undermined. Dmax, D5cc, and D1cc are frequently associated with esophageal toxicity (67-71). It is noteworthy that many existing studies have limited statistical power due to the low incidence of late or severe esophageal toxicity. The variation in reported dose thresholds may be attributed to differences in study endpoints and clinical contexts. Like airway bleeding, anti-angiogenic (vascular endothelial growth factor) agents have also been linked to an increased risk of fistula formation (31,70). Additionally, the esophagus’s frequent and irregular peristalsis during treatment complicates delineation accuracy and alters radiation dose distribution, presenting a significant challenge in treatment planning.

Pneumonitis

SABR-induced pneumonitis remains the most common toxicity, though it is often asymptomatic compared to conventional fractionation radiotherapy. This may be attributed to the smaller volume of lung tissue irradiated by SABR (12,15). The incidence of grade 2+ pneumonitis is generally less than 20%, while grade 3+ pneumonitis has been reported in 0–13% of cases (Table 1). To mitigate the risk of radiation pneumonitis (RP), total lung volume receiving >20 Gy (V20) in 2 Gy dose equivalents, V5, and mean lung dose (MLD) are commonly used dose constraints (20,72,73). Other dosimetric factors, including V8, V10, and V25, have also been associated with symptomatic RP (74,75).

In addition to well-known risk factors such as older age, underlying pulmonary diseases, larger tumor volume, high doses to normal lung tissue, and treatment with immune checkpoint inhibitors (ICIs), a central tumor location has also been associated with an increased risk of symptomatic pneumonitis (8,15,62,74,76). Although rare, SABR-induced pneumonitis can be fatal (10,45), particularly in UC patients with preexisting interstitial lung disease or chronic obstructive pulmonary disease (COPD), who may experience more severe respiratory complications (11,62,77).

Cardiac toxicity

Data on SABR-related cardiovascular toxicity are limited. While the mean or maximum dose to the heart or pericardium has been linked to poorer OS (12,20), these associations are not always statistically significant (78). Rather than focusing solely on the dose received by the whole heart, specific metrics—such as the D45% of right atria, the maximum dose to bilateral ventricles or to the left atrium, the maximum and mean dose to sinoatrial node and the dose to 90% of the superior vena cava—have shown significant correlations with non-cancer-associated survival (79-82). Timmerman et al. (5) reported a case in which a patient with a tumor adjacent to the mediastinum, superior to the hilum, died of pericardial effusion following a 3-fraction SABR regimen. This highlights the vulnerability of heart or its sub-structures, including the conducting system, myocardium, coronary arteries, valves and pericardium, to radiation-induced damage.

However, the study of SABR-related cardiac toxicity is complicated by the challenge of differential diagnosis, especially in patients with preexisting cardiovascular conditions. Cong et al. (18) reported two possibly SABR-related cardiac grade 5 adverse events occurring 4- and 11-month post-treatment. Breen et al. (20) documented five (5%) cases of grade 2 cardiac toxicity. Most of these patients had a history of heart disease before SABR, indicating that preexisting cardiovascular conditions may increase vulnerability to radiation-induced injury. Moreover, patients with COPD are two to five times more likely to have coexisting cardiovascular diseases within the lung cancer population (83). Thus, special care is required when treating patients with baseline cardiac conditions, including meticulous organ protection during planning and regular follow-ups to detect SABR-related toxicity early. Given the fact that acute cardiovascular toxicity directly associated with SABR is rare, we do not include the heart as part of the UC definition categories. However, late-onset toxicities may go undetected, as patients may succumb to other causes before these effects manifest. As OS for NSCLC patients continues to improve, long-term follow-up becomes essential for identifying and managing SABR-related cardiac toxicity.

Table 5 outlines the published studies that have explored OAR constraints in SABR for UC or central lung tumor. Most of these studies are retrospective, and the heterogeneity in dosimetric parameters (e.g., the MPD, volume dose) and study endpoints limits the applicability of their findings to clinical practice. Moreover, the lack of long-term follow-up data hampers the assessment of late-onset toxicities—an increasingly critical concern as OS continues to improve in the era of targeted therapies and immunotherapy.

Future directions

Stereotactic body proton therapy (SBPT)

Proton therapy, with its unique Bragg peak effect, allows for precise energy deposition at targeted depths, minimizing damage to surrounding healthy tissues and potentially improving survival outcomes for central and UC lung tumors (84). A retrospective study by Register et al. (85) demonstrated that proton beam therapy significantly decreases radiation exposure to critical structures such as the lung, aorta, heart, pulmonary vessels and spinal cord tissues compared to photon SABR (50 Gy/4 f) for centrally located stage I NSCLC.

Loma Linda University Medical Center was a pioneer in high-dose hypofractionated proton beam therapy for centrally located NSCLC (86). In their phase II clinical trial (86), 33 patients with T1–2N0M0 central lung cancer were treated with SBPT, with doses escalating from 51 to 60 Gy and then to 70 Gy in 10 fractions. They study observed significant improvements in both LC and OS were observed with doses up to 70 Gy, with no instances of central airway strictures, significant hemoptysis, or radiation pneumonitis requiring hospitalization or steroid treatment. The researchers concluded that a SBPT regimen with 70 Gy/10 f could be a promising standard for central tumors. Additional studies (87-90) have supported the effectiveness and tolerability of hypofractionated proton beam therapy for early-stage centrally located lung cancer. However, research specifically focusing on proton therapy for UC patients is limited, primarily because of accessibility issues, high costs, and restricted insurance coverage. A randomized phase II study (NCT01511081) by MD Anderson Cancer Center aiming to compare the toxicity and efficacy of SBPT with SABR (50 Gy/4 f) for centrally located lung cancer but was terminated early due to poor accrual (91). More efforts are needed to further explore the potential benefits of proton SABR in UC lung tumors.

SABR and immunotherapy combinations

SABR has demonstrated an impressive LC rate exceeding 90% for early-stage lung cancer (1,2). However, distant metastases remain the primary pattern of treatment failure (15,18,24,38,92,93). A retrospective study reported 5-year rates of 4.9% for local, 7.8% for regional, and 14·7% for distant recurrences, with distant recurrence constituting 66% of all cases (94). Notably, patients with central lung lesions are at a significantly higher risk of developing distant metastasis compared to those with peripheral lesions (95).

Researchers are increasingly interested in strategies to safely combine ICIs with SABR (96,97). The ablative dose effect of SABR can directly release tumor antigens, potentially enhancing the tumor response to immunotherapy (98). Immunotherapy has been reported to induce an abscopal effect in metastatic NSCLC patients (99,100), significantly improving both the PFS and OS outcomes (101-103). These promising results suggest that combining SABR with immunotherapy could allow for lower radiation doses to tumor regions adjacent to critical organs while maintaining high LC rates. This approach may be particularly beneficial for UC lesions, where target coverage needs to be sacrificed to minimize toxicity. The impressive efficacy of this combination has generated significant enthusiasm among researchers, and a growing number of clinical trials (NCT04194848, NCT04520959) are focusing on central and UC NSCLC.

Conclusions

Currently, no universally accepted definition for UC lung lesions exists. Based on available evidence, we define UC tumors with PTV touching or overlapping the PBT, trachea, or esophagus. The optimal SABR dose regimens for UC lung lesions are still being developed. Current clinical practices and researches have employed various approaches, with BED10 values ranging from 59.5 to 132 Gy. Regimens such as 50 Gy/5 f and 60 Gy/8 f are frequently applied and demonstrate promising results. However, the retrospective design of these studies lacks strong evidence. Reported LC and OS outcomes are influenced by multiple factors. Additionally, the safety profiles remain incompletely characterized. We discussed SABR-related injuries to trachea, PBT, esophagus, lung and heart. Studies examining the relationship between dosimetric parameters and SABR-related toxicity are limited. Some research has found no significant associations between dosimetric variables and SABR-related toxicity, while others have identified correlations but lacked detailed data on organ-specific toxicities. This limitation may stem from small sample sizes and low incidence of adverse events. Furthermore, the linear-quadratic model used for BED calculations might not always be valid for large single doses in SABR (104). Given that SABR-related toxicity is influenced by multiple factors beyond radiation dose alone, constraints for OAR should be tailored to individual clinical scenarios rather than applied rigidly. Well-designed prospective clinical trials are urgently demanded. Meanwhile, emerging strategies are being explored to optimize SABR for treating UC lung tumors, aiming to improve both efficacy and safety. Further research into the pathophysiological mechanisms underlying radiation-induced injury could help identify predictors and preventive measures for SABR-related toxicity.

In conclusion, SABR offers curative potential for early-stage NSCLC patients and serves as an effective local palliative treatment for advanced patients with UC lesions. However, severe SABR-related toxicities, particularly massive hemoptysis and esophageal complications, currently limit its applicability in UC patients. Careful patient selection and thorough pre-treatment assessment are crucial, taking into account factors such as tumor location, size and coexisting medical conditions. To optimize the use of SABR for UC lung tumors, establishing a standardized definition of UC tumors is imperative. This will facilitate prospective studies aiming at determining optimal regimens and validating OAR constraints. Emerging strategies, including proton SABR and the combination of SABR with immunotherapy, offer promising avenues for enhancing treatment efficacy while mitigating risks. We anticipate that rigorously designed clinical trials will provide valuable insights into safe and effective treatment approaches for UC NSCLC patients, ultimately improving outcomes while minimizing risks.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1961/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1961/prf

Funding: The current study was supported by grants from the Chongqing Science and Health Joint Medical Research Project (No. 2023GGXM002 to Y.W.), National Natural Science Foundation Project (No. 82073347 to Y.W.), and Chongqing Talent Plan (No. cstc2022ycjh-bgzxm0208 to Y.W.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-1961/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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