Safety and Efficacy of Moderate-Intensity Stereotactic Body Radiation Therapy for Ultra-Central Lung Tumor

Background and Objectives: Ultra-central (UC) lung tumors are defined as those abutting the proximal bronchial tree. Stereotactic body radiation therapy (SBRT) for UC tumors is difficult because of concerns about severe toxicities. Therefore, we report the safety and efficacy of moderate-intensity SBRT for UC tumors at our institution. Materials and Methods: From January 2017 to May 2021, we treated 20 patients with UC tumors with SBRT at a dose of 45–60 Gy in 10 fractions. The primary endpoints were local control (LC) and overall survival (OS). Results: The median follow-up time was 15.8 months (range: 2.7–53.8 months). Ten of the 20 patients (50.0%) showed a complete response, five (25.0%) had a partial response, two (10.0%) had stable disease, and three (15.0%) showed progressive disease (PD). The response and disease control rates were 75.0% and 85.0%, respectively. Patients with PD showed local progression at median 8.3 months (range: 6.8–19.1 months) after SBRT. One-year and 2-year OS rates were 79.4% and 62.4%, respectively. One-year and 2-year LC rates are 87.1% and 76.2%, respectively. Eight patients died due to a non-radiation therapy related cause. One patient experienced grade 5 massive hemoptysis 6 months after SBRT, resulting in death. One patient experienced grade 2 esophageal pain and two experienced grade 2 radiation pneumonitis. Otherwise, no grade 3 or higher toxicities were reported. Conclusions: Moderate-intensity SBRT offers effective control of UC tumors and is a well-tolerated treatment for such tumors.


Introduction
Stereotactic body radiotherapy (SBRT) is a radiotherapy modality that precisely focuses and irradiates high-dose radiation on tumors in a short period of time [1].It is a noninvasive method for the radical treatment of localized lung cancer [2].SBRT is commonly performed in patients who are difficult to operate on owing to comorbidities, providing similar results to surgical resection in terms of local control (LC) [3].SBRT has high feasibility when the tumor is located in the peripheral lung parenchyma.However, when performing SBRT on a centrally located tumor, concerns exist regarding complications due to bystander irradiation on adjacent major organs [4].In particular, tumors adjacent to the proximal bronchial tree (PBT) have been contraindicated due to the possibility of bronchial bleeding after SBRT [5].However, several researchers have obtained favorable results by using the protracted SBRT regimen, which is biologically less toxic, and identifying and avoiding high-risk groups of such complications (e.g., anticoagulants, bevacizumab, and large tumors) [6].Since ultra-central (UC) tumors adjacent to the PBT may require a burdensome operation, such as pneumonectomy, non-invasive curative attempts through SBRT have significant therapeutic benefits [7,8].
Moderate-intensity SBRT can provide therapeutic benefits by reducing toxicities through enhanced normal tissue repair mechanisms, in contrast to conventional SBRT, which is usually irradiated within 3-4 times [9].At our institution, moderate-intensity SBRT was prescribed, with 45-60 Gy divided into 10 fractions, when patients with UC The simulation and target volume delineation were identical to those used in our previous study [8].Briefly, four-dimensional CT (4DCT) was acquired in the axial cine mode with a slice thickness of 2-3 mm using a Philips Brilliance Big Bore CT (Philips Healthcare, Cleveland, OH, USA), with patients in the supine position and their arms above their heads.The 4DCT data were sorted into 10 phases of CT images, with 0% and 50% representing the maximum inhalation and exhalation of the breathing cycle, respectively.The Body Pro-Lok™ (Body Pro-Lok, CIVCO, Kalona, IA, USA) system was used, with the compression belt positioned at the mid-abdomen.The patients were immobilized by Vac-Lok (Kikwang Medical, Hanam-si, Gyeonggi-do, Korea) and wing board (CIVCO, USA).To analyze the patients' respiratory data, a real-time position management system was used.All CT scan data were transferred to an Eclipse V.8.9 Treatment Planning System (Varian Medical Systems, Palo Alto, CA, USA).A total dose of 45-60 Gy was prescribed in 10 fractions, with the D max (the maximum point of dose in the target volume) in the target volume not exceeding 110% of the prescribed dose.The setup for treatment was verified by a physician; the bony structures and gross tumor volume were matched by an onboard con-beam CT image.

Patient Characteristics
Between January 2017 and May 2021, 21 patients were treated with SBRT for UC tumors.Among them, one patient received 50 Gy in 10 fractions for a 2.5 cm tumor obstructing the left upper lobe (LUL) main bronchus.The tumor completely regressed at 7 months, and the patient refused further follow-up.However, the tumor relapsed during follow-up at another hospital where the patient received an additional SBRT with an unknown dose.The patient revisited our hospital at 27 months due to hemoptysis but expired during hospitalization.Consequently, this patient was excluded from this study due to protocol violation.Therefore, 20 patients were included in the present study.All patients received 45-60 Gy of SBRT in 10 fractions, with a median dose of 55 Gy in 10 fractions.Only one patient received 45 Gy and the others received 50-60 Gy in 10 fractions.The longest diameter of the tumors was 3.6-9.2cm (median: 3.5 cm) and the volume was 3.6-87.4cm 3 (median: 22.2 cm 3 ).The median planned D max was 106.7% (range, 102.1-108.5%).Six patients (30%) received SBRT as a definitive aim and 13 (65%) received SBRT as a salvage treatment for recurrent disease.Two patients who had undergone salvage SBRT had a history of definitive concurrent chemoradiotherapy (patient no.7 and 11).One patient received SBRT for the consolidation of small cell lung cancer (SCLC) after chemotherapy.
Most patients were male (87.5%), with a median age of 65 years (range, 48-77 years) at treatment.Eighteen patients (90%) had non-small cell lung cancer (NSCLC), of which eight had squamous cell cancer (SqCC), eight had adenocarcinoma, and two had large cell neuroendocrine carcinoma.Additionally, one patient had SCLC and one was radiologically diagnosed with lung cancer, which was not pathologically confirmed.Regarding underlying lung disease, five patients had chronic obstructive lung disease and one had interstitial lung disease.Two patients had a history of old tuberculosis without deterioration of lung function.The characteristics of patients are summarized in Table 1.

Local Control, OS, and Toxicities
The median follow-up period in the study was 15.8 months (range: 2.7-53.8months).During follow-up, 10 of the 20 patients (50.0%) showed a complete response (CR), five (25.0%) showed a partial response (PR), two (10.0%) had stable disease (SD), and three (15.0%)had progressive disease (PD).Overall, the response rate during follow-up was 75%.Fourteen patients were alive with no evidence of disease or with controlled disease until the last follow-up.One-year and 2-year OS rates were 79.4% and 62.4%, respectively, and the corresponding LC rates were 87.1% and 76.2%, respectively (Figures 1 and 2).Eight patients died due to a non-radiation therapy cause, including six who died due to disease progression.One patient died of a treatment-related grade 5 hemoptysis 6 months after radiotherapy (patient no.19).No grade 3 or higher complications were observed in any patient except in patient no.19; therefore, the rate of grade ≥3 complication was 5%.Two patients experienced grade 2 esophageal pain 3 months after the completion of radiotherapy, but they recovered well after the administration of pain medication.Two patients had grade 2 radiation pneumonitis, which occurred 3 and 8 months after the completion of SBRT, respectively.Both patients showed improvement after the administration of oral steroids (Table 2).The remaining patients safely completed SBRT and did not experience any significant RT-related toxicities.One patient died of a treatment-related grade 5 hemoptysis 6 months after radiotherapy (patient no.19).No grade 3 or higher complications were observed in any patient except in patient no.19; therefore, the rate of grade ≥3 complication was 5%.Two patients experienced grade 2 esophageal pain 3 months after the completion of radiotherapy, but they recovered well after the administration of pain medication.Two patients had grade 2 radiation pneumonitis, which occurred 3 and 8 months after the completion of SBRT, respectively.Both patients showed improvement after the administration of oral steroids (Table 2).The remaining patients safely completed SBRT and did not experience any significant RT-related toxicities.

Complete Response
Among the patients with CR, 5 patients were treated with a definitive aim, 4 patients were treated with a salvage aim, and the remaining 1 patient received consolidation SBRT for SCLC.Among the patients with CR, patient no.20 was a 64-year-old male with severe dyspnea due to underlying emphysema, and surgery was not easy because he was also taking an anticoagulant after percutaneous intervention (PCI) with non-ST-segment-elevation myocardial infarction (NSTEMI).He achieved CR at 6 months after 55 Gy in 10 fractions of SBRT.Patient no.6, the only SCLC patient in this study, initially had extensive disease (ED) with brain, left subaortic and hilar lymph node metastases.Chemotherapy (etoposide/cisplatin regimen) was initiated first, but treatment was discontinued due to grade 4 neutropenia.Therefore, 30 Gy in 10 fractions of whole brain RT (WBRT) was given to the brain, and SBRT of 55 Gy in Medicina 2024, 60, 538 6 of 13 10 fractions was given to the lung lesions.He showed CR at 6 months after the completion of lung SBRT, and CR in brain at 3 months after WBRT.However, 2 years and 10 months after the end of WBRT, a 6 mm sized mass recurred in the left cerebellum, so re-RT of 40 Gy in 10 fractions was performed on the brain lesion, and 6 cycles of second-line irinotecan/cisplatin palliative chemotherapy were additionally administered.Currently, both lung and brain are no evidence of disease (NED) status until 50.3 months of follow-up period after the end of first SBRT.All 10 patients with CR had no toxicity of grade 3 or higher, 5 patients with grade 1 radiation pneumonitis, 2 patients with grade 1 cough, and 2 patients with grade 2 radiation pneumonitis, and all recovered well after treatment.

Partial Response
Among the 5 patients with PR, 3 received SBRT for salvage aim and 2 were definitive aim.Patient no. 13 was a 65-year-old male with biopsy-proven squamous cell of lung cancer, cT2N1M0.He was a 60 pack-year ex-smoker.The 2.7 cm enhancing mass was located in the left upper lobe and interlobar lymph node areas, with endobronchial involvement.Therefore, he was recommended left pneumonectomy, but the patient refused surgery.SBRT of 60 Gy in 10 fractions was performed, and PR was shown at 3 months after the end of SBRT.After the SBRT, the patient underwent 4 cycles of chemotherapy (vinorelbine/cisplatin regimen) and maintained PR status.He had no toxicity after SBRT.Among the patients who received SBRT with salvage aim, patient no.14 was a stage IV NSCLC patient with initial bone and liver metastases.This patient was a 69-year-old woman who was previously healthy and had never smoked.She initially showed a good response after palliative chemotherapy (pemetrexed) for cT3N3M1c of NSCLC, but she had left lower lobe endobronchial-involving mass causing obstructive pneumonitis and atelectasis.This mass was a conglomerated mass at left hilar/interlobar/subcarinal area.She underwent 45 Gy in 10 fractions of SBRT and PR was achieved.She had no toxicities other than grade 1 radiation pneumonitis at 3 months after treatment.Patient no. 3 also showed PR after receiving salvage SBRT.This patient was a 53-year-old male with no specific medical history other than hypertension (HTN).He initially underwent right upper lobectomy due to right upper lobe single mass, and was observed without additional treatment.Surgical pathology revealed NSCLC, adenocarcinoma, and pT2aN0M0.However, one year postsurgery, recurrence of the abutting mass in the right main bronchus was observed with bone metastasis, indicating rcT2N0M1.Therefore, after 60 Gy in 10 fractions of SBRT, PR was shown at 2.7 months after RT, but acute respiratory distress syndrome (ARDS) due to disease progression occurred, resulting in multiple organ failure and death at 2.73 months after the completion of SBRT.Among all 5 patients with PR, one patient (no.19) had grade 5 hemoptysis (will be described in detail in the next section).In the remaining patients, one experienced grade 1 radiation pneumonitis and 3 patients did not experience any toxicities.

PD and a Case of Fatal Hemoptysis
Among the 20 patients, three (15.0%)exhibited progressive disease (PD), and all of them underwent salvage treatment.Patient no.7 was a 62-year-old man, a non-smoker with underlying emphysema, who was initially diagnosed with NSCLC of stage cT3N3M0.He underwent definitive concurrent chemoradiotherapy (CCRT) [taxol/cisplatin regimen] at 60 Gy in 30 fractions as the first treatment; 2 years and 3 months after completion of the first RT, the UC tumor recurred in the left perivascular and hilar areas.Re-RT with SBRT at 55 Gy in 10 fractions was implemented, resulting in SD at 3 months after SBRT.However, PD occurred at 1 year 7 months after SBRT (Figure 3).Palliative chemotherapy (nivolumab) and palliative RT were performed to manage spine and brain metastasis developed 1 year after the completion of SBRT.Despite continued treatment, the patient died 19.1 months after SBRT due to the pneumonia and respiratory acidosis caused by disease progression.Patient no.11 was a 62-year-old male patient with underlying chronic obstructive pulmonary disease (COPD).He was initially diagnosed with NSCLC of stage cT4N3M0, with a right lower-lobe primary mass, and was treated with definitive CCRT (placlitaxel/cisplatin regimen) at 64.5 Gy in 30 fractions.However, 1 year and 3 months after the first RT, re-RT with SBRT at 55 Gy in 10 fractions was performed due to the recurrence of a UC tumor in the right middle lobe/right lower lobe.However, signs of progressive disease (PD) were evident on follow-up imaging 8.3 months after completion of SBRT.Thereafter, he was treated with atezolizumab; however, because of lymph node metastasis, the treatment approach was changed to gemcitabine/carboplatin chemotherapy.Since then, he has been receiving navelbine treatment until the last follow-up due to left upper lobe recurrences.Patient no. 15 was a 58-year-old man, non-smoker, who was initially diagnosed with NSCLC of stage pT2bN0M0 (stage IIA) after left lower lobectomy.He underwent four cycles of adjuvant chemotherapy (taxol/cisplatin regimen).Ten months after the first surgery, video-assisted thoracic surgery (VATS) wedge resection (WR) was performed due to LUL recurrence.Six months after WR, he was treated with SBRT at 50 Gy in 10 fractions due to UC lung tumor recurrence at the LLL postoperation site (left subaortic area) (Figure 4).At 6.8 months post-completion of SBRT, evidence of progressive disease (PD) was observed in the SBRT treatment area as well as in the lung, bone, pleura, muscle, and brain.Conservative treatment with brigatinib was started.However, the patient died of multiple organ failure due to disease progression at 9.1 months after SBRT.One of the two patients with PD had grade 2 radiation pneumonitis, while the other had grade 1 radiation pneumonitis.No grade 3 or higher toxicity was observed in any patient with PD.One patient died of treatment-related grade 5 hemoptysis 6 months after radiotherapy (patient no.19) (Figure 5).He was a 68-year-old man who had underlying pneumoconiosis, COPD, and history of old pulmonary tuberculosis 30 years ago.A left upper lobe mass obstructed the left upper lobe segmental bronchus, and the patient was recommended to undergo pneumonectomy.Before SBRT, he also had pseudoaneurysm with dilated pulmonary artery inside the consolidation in the left upper lobe.On bronchoscopic biopsy, the tumor was confirmed to be SqCC.However, the patient had underlying lung disease, making it difficult to perform surgery.He underwent SBRT at 55 Gy in 10 fractions and achieved PR 2 months after SBRT.Massive hemoptysis was observed 6.3 months after SBRT with aggravated pseudoaneurysm.Hemoptysis was estimated to be approximately 2-4 cups, along with a cough, sputum production, and shortness of breath.The patient showed loss of consciousness when admitted to the emergency department.After intubation, bronchial artery embolization was performed twice.However, he expired due to respiratory arrest.One patient died of treatment-related grade 5 hemoptysis 6 months after radiotherapy (patient no.19) (Figure 5).He was a 68-year-old man who had underlying pneumoconiosis, COPD, and history of old pulmonary tuberculosis 30 years ago.A left upper lobe mass obstructed the left upper lobe segmental bronchus, and the patient was recommended to undergo pneumonectomy.Before SBRT, he also had pseudoaneurysm with dilated pulmonary artery inside the consolidation in the left upper lobe.On bronchoscopic biopsy, the tumor was confirmed to be SqCC.However, the patient had underlying lung disease, making it difficult to perform surgery.He underwent SBRT at 55 Gy in 10 fractions and achieved PR 2 months after SBRT.Massive hemoptysis was observed 6.3 months after SBRT with aggravated pseudoaneurysm.Hemoptysis was estimated to be approximately 2-4 cups, along with a cough, sputum production, and shortness of breath.The patient showed loss of consciousness when admitted to the emergency department.After intubation, bronchial artery embolization was performed twice.However, he expired due to respiratory arrest.One patient died of treatment-related grade 5 hemoptysis 6 months after radio apy (patient no.19) (Figure 5).He was a 68-year-old man who had underlying pne coniosis, COPD, and history of old pulmonary tuberculosis 30 years ago.A left upper mass obstructed the left upper lobe segmental bronchus, and the patient was re mended to undergo pneumonectomy.Before SBRT, he also had pseudoaneurysm dilated pulmonary artery inside the consolidation in the left upper lobe.On bronchos biopsy, the tumor was confirmed to be SqCC.However, the patient had underlying disease, making it difficult to perform surgery.He underwent SBRT at 55 Gy in 10 tions and achieved PR 2 months after SBRT.Massive hemoptysis was observed 6.3 mo after SBRT with aggravated pseudoaneurysm.Hemoptysis was estimated to be app mately 2-4 cups, along with a cough, sputum production, and shortness of breath patient showed loss of consciousness when admitted to the emergency department.intubation, bronchial artery embolization was performed twice.However, he expired to respiratory arrest.

Discussion
SBRT has shown similar levels of LC and survival outcomes as those observed surgical resection for localized tumors [2].SBRT is widely acknowledged as the altern option for inoperable cases with localized lung cancers.As tumors abutting the main b chus (i.e., UC tumors) commonly require extensive surgery, including pneumonec or sleeve lobectomy, non-invasive and possibly curative SBRT may confer a signifi therapeutic benefit.However, SBRT was not recommended for UC tumors previously to the risk of fatal hemorrhage [5].Early studies reported a non-negligible occurren treatment-related toxicities.Tekatli et al. [14] reported a grade 5 complication rate of 2 (14.9% due to hemorrhage) after SBRT for treating UC tumors, and Haseltine et al also reported four cases of fatal hemorrhage (22.2%) among 18 treated cases.In the s by Tekatli et al.[14], 60% of the tumors were larger than 5 cm, and planning target vo (PTV) Dmax was greater than 123% in all treatment plans.Haseltine et al. [15] claimed two of the four cases were due to infectious pneumonia, and two cases might have related to the use of bevacizumab.Recent studies have reported a much lower rate of toxicities.Recent large-scale studies have reported grade 5 toxicity rates between 2 5% [16][17][18].In the updated meta-analysis by Rim et al. [6], the pooled rate of grade 3 plications was 9% and that of fatal toxicity was 5.7%.Pooled rates of LC and OS 90.4% and 66.4% at 2 years, respectively, and showed the clinical significance of SBR the treatment of UC tumors.Updated 2023 National Comprehensive Cancer Net (NCCN) guidelines stated that centrally located and even UC tumors could be effect and safely treated with protracted SBRT [3].
In the present study, LC and OS rates at 2 years were 76.2% and 62.4%, respecti Although the survival outcome was similar to that reported in previous studies, th rate was lower than that reported in recent studies (>90% at 2 years) [6,[16][17][18].We hyp esized that the prescribed dose (median: 55 Gy in 10 fractions, 82.5 Gy10 in biologi equivalent dose [BED]) was relatively lower than that used in recent studies.Meng [17] reported a 2-year LC rate of 92%, with a prescribed median dose of BED 120 Chang et al. [18].reported a 2-year LC rate of 96.6% after prescribing a median do BED >100 Gy10 in 92% of the included patients.However, dose escalation should be cautiously because high-dose SBRT, when treating UC tumors, may result in

Discussion
SBRT has shown similar levels of LC and survival outcomes as those observed with surgical resection for localized tumors [2].SBRT is widely acknowledged as the alternative option for inoperable cases with localized lung cancers.As tumors abutting the main bronchus (i.e., UC tumors) commonly require extensive surgery, including pneumonectomy or sleeve lobectomy, non-invasive and possibly curative SBRT may confer a significant therapeutic benefit.However, SBRT was not recommended for UC tumors previously due to the risk of fatal hemorrhage [5].Early studies reported a non-negligible occurrence of treatment-related toxicities.Tekatli et al. [14] reported a grade 5 complication rate of 21.2% (14.9% due to hemorrhage) after SBRT for treating UC tumors, and Haseltine et al. [15] also reported four cases of fatal hemorrhage (22.2%) among 18 treated cases.In the study by Tekatli et al. [14], 60% of the tumors were larger than 5 cm, and planning target volume (PTV) D max was greater than 123% in all treatment plans.Haseltine et al. [15] claimed that two of the four cases were due to infectious pneumonia, and two cases might have been related to the use of bevacizumab.Recent studies have reported a much lower rate of fatal toxicities.Recent large-scale studies have reported grade 5 toxicity rates between 2 and 5% [16][17][18].In the updated meta-analysis by Rim et al. [6], the pooled rate of grade 3 complications was 9% and that of fatal toxicity was 5.7%.Pooled rates of LC and OS were 90.4% and 66.4% at 2 years, respectively, and showed the clinical significance of SBRT for the treatment of UC tumors.Updated 2023 National Comprehensive Cancer Network (NCCN) guidelines stated that centrally located and even UC tumors could be effectively and safely treated with protracted SBRT [3].
In the present study, LC and OS rates at 2 years were 76.2% and 62.4%, respectively.Although the survival outcome was similar to that reported in previous studies, the LC rate was lower than that reported in recent studies (>90% at 2 years) [6,[16][17][18].We hypothesized that the prescribed dose (median: 55 Gy in 10 fractions, 82.5 Gy 10 in biologically equivalent dose [BED]) was relatively lower than that used in recent studies.Meng et al. [17] reported a 2-year LC rate of 92%, with a prescribed median dose of BED 120 Gy 10 .Chang et al. [18].reported a 2-year LC rate of 96.6% after prescribing a median dose of BED >100 Gy 10 in 92% of the included patients.However, dose escalation should be done cautiously because high-dose SBRT, when treating UC tumors, may result in fatal toxicities.Tekatli et al. [14].prescribed a median dose of BED 132 Gy 10 , with median D max of 138%, resulting in 21.2% of grade 5 toxicities.Although one case of fatal hemoptysis was reported in our study (5%), no other grade 3 complication was reported, and only three patients experienced grade 2 complications.Employing moderate-dose radiation therapy and implementing constraints on excessive dosages (with D max <110% in all protocols) during planning could influence the toxicities observed in the study.Considering that two-thirds (65%) of the patients included in our study received SBRT for salvage purposes aiming to address recurrent disease, it is presumed that this may have influenced toxicity outcomes.Additionally, among these patients, two individuals underwent re-RT following CCRT, which further suggests a potential impact on toxicity.
Unfortunately, we encountered one case of a fatal hemorrhage.The 5% grade 5 complication rate (1 of 20) correlated with that reported in a recent meta-analysis (5.7%) [6].The patient had pseudoaneurysm of the pulmonary artery before SBRT, which was encased in the tumor.It was temporally resolved after 1 month of SBRT and recurred at 5 months thereafter with cancer progression.Considering the pre-existing presence of a pseudoaneurysm prior to treatment, the occurrence of a hemorrhage presents a nuanced aspect where causality directly related to the treatment or otherwise remains uncertain.Pseudoaneurysm of the pulmonary artery due to lung cancer is rare but can cause fatal hemoptysis [19].Squamous histology and treatment-induced tumor necrosis are presumed to be the main causes associated with hemoptysis [19,20].Conventional radiotherapy to treat centrally located lung cancer can yield fatal hemorrhage at a rate of 13-17% [21][22][23].While various factors such as radiation dose, fractionation scheme, endobronchial involvement, and the use of bevacizumab could contribute to fatal hemorrhagic toxicity, it also suggests that a pseudoaneurysm may also contribute to toxicity.Although hemorrhagic toxicity is the most concerned complication of SBRT for central tumors, any modality of local treatment cannot fully avoid the risk of hemorrhage for cases with pulmonary artery pseudoaneurysm.Therefore, frequent follow-up with imaging studies is necessary, and administration of medications with bleeding tendency should be minimized.
Especially since the advent of new drugs such as durvalumab and pembrolizumab in 2021, there has been a tendency to prioritize chemotherapy/immunotherapy over SBRT for UC, which may carry a bleeding risk.Therefore, there is significance in demonstrating the safety and efficacy of SBRT for UC tumors through our study, and there is a need to evaluate the utility of SBRT in the era of immunotherapeutic agents.Cong et al. [24] and Lodeweges et al. [25] mentioned that 3.9% and 2.8% of patients, respectively, received immunotherapy before undergoing SBRT.In our study, out of 20 patients, seven received immunotherapy after SBRT for adjuvant or palliative purposes, and none received it concurrently.Future research should concentrate on examining the synergistic potential of immunotherapy in conjunction with SBRT, evaluating its influence on clinical outcomes and risk profiles, specifically in patients diagnosed with UC.
Our study had some limitations.Due to the small number of patients, we could not achieve statistically significant results to investigate factors affecting clinical outcomes or toxicities.Nevertheless, there is clinical significance in reporting the outcomes of patients with UC tumors who underwent moderate-dose SBRT, particularly regarding long-term complications such as bleeding risk.Our study, being a retrospective single-center study, indeed has a limitation in lacking a comparator group.Given the scarcity of patients who underwent SBRT for UC tumors, we compare our data with that from other historical studies (Table 3).When compared to other historical studies, our study demonstrated comparable results in terms of LC and OS, and showed lower or similar rates of grade 3 or higher toxicity after moderate-dose SBRT.Another limitation is the clinical heterogeneity of the patients owing to the diversity of cancer types and the aim of the treatment (salvage and primary).At our institution, we could not prescribe treatment primarily at diagnosis but recommended SBRT for patients who were deemed not amenable for, or those who refused, other treatments, including upfront surgery or palliative chemotherapy.

Conclusions
In conclusion, moderate-intensity SBRT is a feasible and effective curative modality, without excessive toxicity, for treating patients with UC lung tumors.Future studies with a larger sample size should be performed to identify factors affecting clinical outcomes and toxicities, thereby optimizing the patient selection criteria for SBRT.

Medicina 2024 ,Figure 3 .
Figure 3. Case 1 (patient no. 7).(a) A 62-year-old man, a non-smoker with underlying emphysema, was initially diagnosed with NSCLC of stage cT3N3M0.He underwent definitive CCRT (taxol/cisplatin regimen) of 60 Gy in 30 fractions as the first treatment.Two years and 3 months after CCRT, recurrence at the left prevascular and hilar lymph nodal area occurred.He was recommended to

Figure 4 .
Figure 4. Case 2 (patient no.15).(a) A 58-year-old man was initially diagnosed with NSCLC of stage pT2bN0M0 (stage IIA) after left lower lobectomy.A recurrent tumor at the LLL operation site (left subaortic area) was noted.He underwent SBRT at 50 Gy in 10 fractions.(b) Follow-up imaging at 6.8 months showing PD after SBRT.NSCLC, non-small cell lung cancer; SBRT, stereotactic body radiotherapy; PD, progressive disease; LLL, left lower lobe.

Medicina 2024 ,Figure 4 .
Figure 4. Case 2 (patient no.15).(a) A 58-year-old man was initially diagnosed with NSCLC o stage pT2bN0M0 (stage IIA) after left lower lobectomy.A recurrent tumor at the LLL operatio site (left subaortic area) was noted.He underwent SBRT at 50 Gy in 10 fractions.(b) Follow-u imaging at 6.8 months showing PD after SBRT.NSCLC, non-small cell lung cancer; SBRT, ste tactic body radiotherapy; PD, progressive disease; LLL, left lower lobe.

Figure 5 .
Figure 5. Case 3 (patient no.19).(a) A 68-year-old man with obstructive pneumonitis had a left upper lobe mass obstructing the left upper lobe segmental bronchus.He also had pseudoaneurysm of the pulmonary artery.He was recommended to undergo pneumonectomy.He underwent SBRT at 55 Gy in 10 fractions because of underlying pneumoconiosis and COPD.(b) Follow-up imaging at 2 months showing PR after SBRT.(c) Chest CT 4 months after SBRT showing tumor necrosis with progression of radiation pneumonitis/tracheobronchitis or combined infection, with diffuse wall thickening of the trachea and left main bronchus, accompanied by pericardial effusion.(d) Follow-up imaging 6 months after SBRT showing improved pneumonitis and aggravation of the dilated pulmonary artery inside the consolidation in the left upper lobe.However, massive hemoptysis was observed 6.3 months after SBRT, which resulted in death.CT, computed tomography; SBRT, stereotactic body radiotherapy; PR, partial response; COPD, chronic obstructive pulmonary disease.

Table 2 .
Patient and treatment risk factors and complications (n = 20).

Table 3 .
Published reports of the SBRT for UC lung tumors.