Long-term outcomes and patterns of failure after empiric SBRT for presumed early-stage lung tumors

Background: Stereotactic body radiation therapy (SBRT) is the established standard of care for medically inoperable early-stage non-small cell lung cancer (ES-NSCLC). When a biopsy is unfeasible, it is often delivered empirically, yet long-term outcomes and failure patterns remain underreported.

Methods: A total of 56 patients with clinically staged T1–T3N0M0 lung tumors treated with empiric SBRT (2011–2022) were retrospectively analyzed. Nineteen patients with recurrence were assessed for failure patterns and survival. Overall survival (OS), progression-free survival (PFS), local failure-free survival (LFFS), regional failure-free survival (RFFS), and distant metastasis-free survival (DMFS) were estimated using the Kaplan–Meier method. Competing risk analysis was performed with death treated as a competing event.

Results: At a median follow-up of 80.4 months (95% CI: 65.2–95.6), 17 patients (30.4%) were alive. Median PFS and OS were 28.5 months (95% CI: 16.4–40.8) and 41.7 months (95% CI: 14.0–69.4), respectively. LFFS was 84.1% at 5 years and 67.3% at 10 years, RFFS was 64.7% at 5 years and 58.8% at 10 years, and DMFS was 62.4% at 5 years and 56.1% at 10 years. Pathologic confirmation of recurrence was obtained in 10 patients, identifying NSCLC in six, small cell lung cancer in three, and urothelial carcinoma in one. Local failures were infrequent and occurred early (median 8.3 months), whereas regional and distant recurrences occurred later (median 13.5 and 22.8 months). At 10 years, the estimated cumulative incidence function was 6.3% for local failure, 14.8% for regional failure, 16.6% for distant failure, and 55.8% for death.

Conclusion: Empiric SBRT provides durable local control in presumed early-stage NSCLC, but outcomes are limited by comorbid mortality and systemic progression. These findings emphasize its effectiveness as a local therapy and the need for prolonged surveillance and systemic strategies.

Introduction

Stereotactic body radiation therapy (SBRT) has become a standard treatment option for patients with inoperable early-stage non-small cell lung cancer (NSCLC), demonstrating excellent local control and survival outcomes (1–6). Emerging evidence suggests that, in selected cases, SBRT may offer outcomes comparable to those of surgical resection (7–9). However, patients with pathologically confirmed disease (pTNM staging) generally experience better outcomes than those staged clinically (cTNM), emphasizing the importance of histological confirmation (10). Histopathological examination plays a central role in guiding treatment decisions and assessing prognosis in NSCLC. Beyond confirming malignancy, it enables molecular profiling, which can identify therapeutic targets and provide important prognostic insights (11–13). Furthermore, histological subtype can influence surgical planning and determine the extent of lung resection required (14).

Guidelines recommend either surgical resection or tissue biopsy for pulmonary lesions that are highly suspicious for malignancy (15). Transbronchial biopsy offers a sensitivity ranging from 50% to 91%, depending on lesion size and location (16, 17). Transthoracic needle biopsy generally provides higher diagnostic accuracy, with sensitivity exceeding 90% regardless of tumor size (18). Despite these options, there are instances in clinical practice where biopsy results remain inconclusive or cannot be obtained due to patient frailty, comorbidities, or procedural risk. In such cases, empiric SBRT may be pursued based on clinical and radiological assessment alone. Several studies have demonstrated comparable outcomes for patients treated with or without pathologic confirmation (19–21). Nonetheless, recurrence patterns in this empirically treated population remain poorly defined, particularly in the absence of histological data that could inform on tumor behavior.

Given these diagnostic and therapeutic considerations, we conducted a retrospective single-center analysis to evaluate recurrence dynamics and clinical outcomes following empiric SBRT in patients with clinically diagnosed early-stage NSCLC. Our objective was to identify failure patterns and characterize post-treatment trajectories in this unique and understudied cohort.

Patients and methods

In a previous analysis, we reported outcomes and toxicities for 61 lung lesions treated with SBRT between 2011 and 2022. These lesions were suspected to be clinically staged T1–T3N0M0 lung tumors based on the Union for International Cancer Control (UICC) 8th edition, without histopathological confirmation. Patient inclusion and exclusion criteria, along with baseline characteristics, are described in detail in our previous publication (22). The decision to proceed with SBRT according to the Swensen criteria (23) was made by a multidisciplinary thoracic tumor board. This risk assessment primarily utilized the Solitary Pulmonary Nodule (SPN) Malignancy Risk Score (Mayo Clinic Model). This model evaluates six independent variables related to patient demographics and nodule morphology: patient age, smoking history, nodule size and spiculation, the presence of a prior extra thoracic malignancy diagnosed more than 5 years earlier, lesion location in the upper lobe, and metabolic activity on 18F-FDG PET/CT. Based on the calculated probability, patients were classi!ed into three commonly used clinical risk groups: low (<5%), intermediate (5%–60%), and high (>60%) (23).

For the current study, we extended the follow-up period through August 2025, focusing specifically on patients who experienced any form of recurrence. Unlike our previous lesion-level analysis, this study evaluated outcomes at the patient level.

A total of 19 patients developed recurrence. We analyzed the behavior and progression patterns of these tumors, with emphasis on recurrence patterns and patient outcomes following additional lines of therapy. To illustrate the course of disease and treatment, personalized patient timelines are shown using a swimmer plot (Figure 1).

Figure 1

Figure 1. Detailed history of patients with any recurrence after stereotactic body radiation therapy (SBRT). The plot depicts the clinical course of 19 patients who experienced treatment failure after SBRT. Each horizontal bar represents the timeline for a single patient, measured in months from the completion of the first radiotherapy. The length of each blue bar shows the follow-up duration for each patient, with stars indicating patients still alive at the last follow-up. Several patients experienced multiple types of failure (local, regional, and distant) and sequential interventions, such as surgery or systemic therapy.

Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (24). Local failure was defined as recurrence within the high-dose region of the irradiated field. Regional failure was defined as newly involved regional lymph nodes (hilar, mediastinal, or supraclavicular) or new pulmonary lesions in the ipsilateral lung. Distant metastasis was defined as new lesions in the contralateral lung, pleural metastases, or distant organ or lymph node involvement.

In the present report, overall survival (OS) was calculated from the completion of SBRT to death from any cause. Local failure-free survival (LFFS), regional failure-free survival (RFFS), and distant metastasis-free survival (DMFS) were measured from the completion of SBRT to the last follow-up with available staging imaging information. Progression-free survival (PFS) was defined as the time from the completion of SBRT to the first documented failure or death, whichever occurred first. All survival outcomes were estimated using the Kaplan–Meier method. The median follow-up was calculated using the reverse Kaplan–Meier method. Survival comparisons across variables, e.g., gross tumor volume (GTV) dose, were assessed using the log-rank test. To analyze recurrence patterns, competing incidence functions that account for death were used as a competing risk.

An exploratory analysis was performed to assess potential associations between biologically effective dose (BED) and relapse patterns, including local, regional, and distant failures. BED values were dichotomized using the median split. Stratified analyses were then conducted to examine possible predictors of OS, PFS, LFFS, RFFS, and DMFS based on GTV, BED, age, and tumor diameter. All comparisons were made using the log-rank test.

The BED was calculated to compare radiation impact across different fractionation schedules using the formula BED = n × d × [1 + d/(α/β)], where n is the number of fractions, d is the dose per fraction, and α/β = 10 Gy for tumor tissue. This metric enables the comparison of treatment intensity across regimens.

This retrospective analysis was conducted with approval from the institutional ethics committee (ID: 17-230). Informed consent for treatment and data use was obtained from all patients at the time of treatment. All statistical analyses were performed using IBM SPSS Statistics version 29.0.1, R version 4.4.2 (via RStudio 2024.12.1 Build 563), and GraphPad Prism version 10.5.0 (GraphPad Software, Boston, MA, USA).

Results

Patients and treatment characteristics

For all other patient characteristics, please refer to our previous results (22). Briefly, the median age at the time of SBRT was 69 years (range, 57–88), and the median Charlson Comorbidity Index (CCI) was 5 (range 2–13). Among smokers, the median tobacco consumption was 50 pack-years (py) (range, 5–120). The median forced expiratory volume in 1 second (FEV₁) was 1.4 L (range, 0.5–2.3 L), the maximum forced vital capacity (FVC_max;) was 76% of the predicted value (range, 26%–117%), and the diffusing capacity of the lung for carbon monoxide (DLCO) was 41% of the predicted value (range, 15%–109%). Prior to SBRT, biopsy procedures were attempted in 29 patients (51.8%); however, the results did not yield a definitive histological diagnosis.

The median GTV was 5.5 cc [interquartile range (IQR), 2.3–10.2 cc]. The median biologically effective dose, assuming an α/β ratio of 10 (BED₁₀), was 95.2 Gy (IQR, 95.2–105.0 Gy), and the median BED₁₀ maximum dose (D_max) was 133.3 Gy (IQR, 131.3–146.4 Gy).

Individual characteristics of all 19 patients with recurrence—including tumor size, radiation dose and fractionation, and treatment outcomes—are summarized in Tables 1A, B and Figure 1.

Table 1A

Table 1A. Individualized characteristics and outcome of all patients with any recurrence.

Table 1B

Table 1B. Individualized characteristics and outcome of patients undergoing a second course of radiation.

Clinical outcome

With a median follow-up of 80.4 months (95% CI: 65.2–95.6) as of August 2025, 17 patients (30.4%) were still alive. Recurrence was observed in 19 patients (33.9%). Regional failure occurred in 15 patients (26.8%), and distant metastases were seen in 13 patients (23.2%). Intrapulmonary recurrence involved the ipsilateral lung in six patients (10.7%) and the contralateral lung in six patients (10.7%). Median PFS was 28.5 months (95% CI: 16.4–40.8), and median OS was 41.7 months (95% CI: 14.0–69.4). LFFS was 84.1% at 5 years and 67.3% at 10 years. RFFS was 64.7% at 5 years and 58.8% at 10 years. DMFS was 62.4% at 5 years and 56.1% at 10 years (Figure 2).

Figure 2

Figure 2. Kaplan–Meier estimates of overall survival (OS), progression-free survival (PFS), local failure-free survival (LFFS), regional failure-free survival (RFFS), and distant metastasis-free survival (DMFS).

Pathology of recurrence

Pathologic confirmation of recurrence was obtained in 10 of the 19 patients with any recurrence (52.6%). Among these, three patients (15.8%) were diagnosed with small cell lung cancer (SCLC), two (10.5%) with adenocarcinoma, two (10.5%) with squamous cell carcinoma (SCC), two (10.5%) with large cell carcinoma, and one patient (5.3%) with metastatic urothelial carcinoma. The last patient had a known history of bladder cancer, diagnosed 5.5 years prior to the development of the lung lesion.

For patients with histologically confirmed recurrence, the median overall survival was 33.0 months (95% CI: 17.2–48.9). The three patients with SCLC received chemotherapy and lived for 10.2, 13.3, and 65.2 months. One patient, later confirmed to have metastases from a previously diagnosed urothelial carcinoma, developed liver and multiple bone metastases on the first follow-up CT scan after SBRT.

Pattern of first failure

Regional failure occurred in 13 patients (68.4%) as the first manifestation of recurrence, while distant metastases were observed in 11 patients (57.9%). Most regional recurrences involved intrapulmonary sites, affecting seven patients (36.8%). The most common pattern of distant metastasis was contralateral intrapulmonary spread seen in six patients (31.6%). Table 2 and Figure 3 present the distribution and frequency of first failure patterns following SBRT.

Table 2

Table 2. Pattern of first failure after empiric SBRT.

Figure 3

Figure 3. Patterns of first relapse following stereotactic body radiation therapy (SBRT). Venn diagram illustrating the distribution and overlap of recurrence sites, color-coded by frequency, with red indicating the most frequent and blue the least frequent recurrence patterns; values represent the percentage of patients within each failure category or overlapping combination.

Time to failure

Local failures after SBRT generally occurred earlier in the disease course, whereas distant metastases occurred later. The median time to local failure was 8.3 months (95% CI: 4.9–88.4), the median time to regional failure was 13.5 months (95% CI: 2.5–64.3), and the median time to distant metastases was 22.8 months (95% CI: 3.2–64.6).

Competing risk analysis

The cumulative incidence of any event increased from 28.6% at 1 year to 56.3% at 3 years, 70.2% at 5 years, and 93.2% at 10 years. Local failure remained low and plateaued early: 3.6% at 3 years (95% CI: 0.0%–8.5%) and 6.3% at 5 to 10 years (95% CI: 0.0%-13.5%). Regional failure reached 14.6% by 3 to 5 years (95% CI: 5.1%–24.1%) and then remained stable through 10 years. Distant failure continued to rise after 3 years, increasing from 10.9% at 3 years (95% CI: 2.5%–19.2%) to 16.6% at 6 years (95% CI: 5.5%–27.6%) and then remaining stable through 10 years. Death continued to accumulate across follow-up—10.7% at 1 year (95% CI: 2.5%–18.9%), 35.8% at 5 years (95% CI: 21.8%–49.8%), and 55.8% at 10 years (95% CI: 36.6%–74.9%)—and dominated late outcomes (Figure 4).

Figure 4

Figure 4. Estimated competing risk of recurrence or death over 10 years. This diagram compares the chances of different outcomes happening first during follow-up: local progression (blue), regional recurrence (green), distant recurrence (yellow), or death without recurrence (red). The risks of local, regional, and distant recurrences increased only slowly over time and reached a plateau after years. In contrast, the risk of death from other causes rose steadily and was the most common outcome in this group of patients who were mostly frail with multiple comorbidities.

The mean predicted probability of malignancy (Mayo Clinic SPN Malignancy Risk Score) for the entire cohort (n = 56) was 69.0% (SD 28.3%; range, 2.6%–97.5%). According to the established stratification criteria, three (5.4%) nodules were classified as low risk, 11 (19.6%) as intermediate risk, and 42 (75.0%) as high risk.

Predictors of patient outcomes

No statistically significant associations were observed between GTV, BED, age, or tumor diameter and any of the evaluated endpoints, including OS, PFS, LFFS, RFFS, or DMFS (all p > 0.05).

Subsequent curative-intent treatment

Seven patients received additional curative treatments. One underwent surgical resection for a solitary contralateral pulmonary metastasis, and six with solitary intrapulmonary recurrence received a second course of SBRT. Among these, two were treated for marginal recurrences (at the radiation field margin), two for new solitary ipsilateral lesions, and two for new solitary contralateral metastases. Overall survival for the five patients with solitary pulmonary nodule progression treated with curative intent was 35.6, 48.8, 80.4, 88.9, and 123.3 months, while the patient who underwent surgical resection for a new lesion had an overall survival of 92.5 months. Two patients ultimately received a third course of radiotherapy.

Discussion

Our analysis confirms that empiric SBRT offers excellent local tumor control in presumed early-stage lung cancer. Seven of 56 treated patients (12.5%) experienced an in-field (local) failure, consistent with the literature, where 3–5-year local control rates commonly exceed 90% after SBRT for stage I NSCLC (25–27). Regional failures occurred in 15 patients (26.8%) and distant metastases in 13 (23.2%). This pattern shows that although SBRT reliably sterilizes the treated tumor, occult micro metastatic disease often determines the final outcomes.

Our findings align with prior reports that regional and distant metastases are the predominant sites of failure after curative SBRT (25, 26, 28). The higher rate of regional failures in our cohort probably reflects our classification method, which considered ipsilateral lung recurrences as regional events. In contrast, other studies often treat such lesions separately or view them as new primary tumors, especially in heavy smokers, who are at increased risk of developing multiple primary malignancies (27, 28). Given the substantial smoking history in our cohort (median 50 py), this interpretation seems clinically reasonable, as patients with solitary intrapulmonary recurrence who underwent a second curative-intent treatment, either surgical resection or SBRT, achieved favorable long-term outcomes, highlighting the value of additional curative approaches in this setting.

Histology appears to influence recurrence patterns in NSCLC, with studies reporting greater microscopic extension in adenocarcinoma than in SCC (29, 30). Reinhardt et al. further suggested that some local failures may result from insufficient dose coverage of these regions (31). Despite such findings, current SBRT guidelines recommend direct GTV-expantion to Planning Target Volume (PTV) without a defined clinical target volume (CTV) (32). In our cohort, the sample size was too small to detect a significant association between histology and outcomes.

Competing risk analysis demonstrated that non-cancer-related mortality represents a major limitation to long-term survival in this medically frail cohort, with the 10-year cumulative incidence of death without prior recurrence approaching 55%. In contrast, local failures were infrequent and occurred early, with a median time to recurrence of 8.3 months, compared with 13.5 months for regional and 22.8 months for distant progression.

The competing risk analysis shows that local failures were infrequent and plateaued early (≤5 years), supporting the durability of SBRT for local control. In contrast, distant failure continued to accumulate after 3 years, reaching 16.6% by year 6, signifying a later window of systemic relapse. Death accumulated over the follow-up period, and by 10 years, it was the leading outcome, emphasizing the importance of managing long-term comorbidities alongside cancer control in this frail, elderly group.

In a study comparing surgical resection and SBRT for early-stage NSCLC, patients who underwent surgery showed superior regional control (82.9% vs. 78.1%; p = 0.912), distant control (76.1% vs. 54.0%; p = 0.152), and cancer-specific survival (81.3% vs. 75.3%; p = 0.923), although none of these differences reached statistical significance (33). Comparable findings were reported in a cohort study of 9,001 patients who underwent surgical resection for early-stage NSCLC, in which 21.5% experienced distant recurrence within 5 years of treatment. Within this surgically eligible population, older age was associated with a significantly reduced likelihood of receiving treatment after recurrence, with an odds ratio of 0.42 for patients aged ≥75 years compared with those aged <55 years. Likewise, the presence of significant comorbidities was associated with lower rates of active treatment following the development of distant metastases (34). In our cohort, 10 patients underwent biopsy confirmation after recurrence, and among the 19 patients who experienced recurrence, six did not receive any subsequent therapy for their disease.

The combination of SBRT and checkpoint inhibitors has attracted considerable attention following the demonstrated survival benefit of immunotherapy in locally advanced and metastatic NSCLC (35–37). Chang et al. conducted a phase II trial in patients with early-stage NSCLC and isolated intrapulmonary recurrence, comparing SBRT alone with SBRT combined with nivolumab. In the SBRT arm, the rates of first relapse were 13.3% local, 10.7% regional, and 16.0% distant, whereas in the SBRT plus immunotherapy (I-SABR) arm, the corresponding rates were 0%, 6.1%, and 3.0%, respectively. The addition of immunotherapy reduced the overall recurrence rate from 36.0% to 12.1% (8). However, initial results from phase III trials have yet to corroborate these findings. A study comparing SBRT alone with SBRT plus concurrent and adjuvant atezolizumab demonstrated no survival benefit. Interestingly, the combination arm showed a higher local recurrence rate (13%) compared with SBRT alone (7%) (38). Results from two additional ongoing trials, PACIFIC-4/RTOG 3515 and KEYNOTE-867, which are assessing SBRT combined with durvalumab and pembrolizumab, respectively, are expected to provide further insights into the efficacy and safety of these approaches (39, 40).

Limitations

This retrospective single-center study is subject to several limitations. First, the limited sample size, particularly the subgroup of patients who experienced recurrence, constrains the statistical robustness of subgroup analyses and limits the generalizability of the findings. Second, the absence of histopathological confirmation in all cases of recurrence restricts the ability to draw definitive conclusions regarding underlying tumor biology and recurrence patterns. The inclusion of such data would have yielded more comprehensive insights. Third, due to the frailty and comorbidities of the patient population, including chronic obstructive pulmonary disease (COPD), uniform administration of ablative radiation doses was not feasible. Consequently, heterogeneous SBRT fractionation regimens were employed, which may have influenced treatment outcomes, thereby further limiting the applicability of the results to broader clinical settings.

Conclusion

Empiric SBRT for presumed early-stage NSCLC achieved excellent and durable local control, but long-term outcomes were constrained by comorbid mortality and regional or systemic progression. Importantly, selected patients with solitary pulmonary nodule recurrence achieved durable survival with additional curative-intent therapy, emphasizing the need for individualized follow-up and treatment strategies. Overall, these findings highlight both the effectiveness of SBRT in tumor sterilization and the necessity of prolonged surveillance and tailored systemic approaches to mitigate late metastatic progression in high-risk patients.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Ethics statement

The studies involving humans were approved by Ethics committee of the University Hospital LMU Munich. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

Author contributions

KE-M: Conceptualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing. ED: Conceptualization, Data curation, Formal analysis, Writing – review & editing. LK: Formal analysis, Writing – review & editing. SK: Writing – review & editing. DK-G: Writing – review & editing. AT: Writing – review & editing. NR: Writing – review & editing. TD: Writing – review & editing. FM: Writing – review & editing. CB: Writing – review & editing. CE: Conceptualization, Funding acquisition, Writing – review & editing. SM: Writing – original draft, Writing – review & editing, Conceptualization, Data curation, Formal analysis.

Funding

The author(s) declare that no financial support was received for the research, and/or publication of this article.

Conflict of interest

Authors NR and TD were employed by the company Asklepios Kliniken GmbH.

The remaining 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.

The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Generative AI statement

The author(s) declare that Generative AI was used in the creation of this manuscript. Generative AI was used to improve readability of the manuscript. All original ideas are from the authors.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Abbreviation

BED, biologically effective dose; BED₁₀, biologically effective dose (α/β = 10 Gy); CCI, Charlson Comorbidity Index; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; CT, computed tomography; DF, distant failure; DMFS, distant metastasis-free survival; DLCO, diffusing capacity of the lung for carbon monoxide; ES, early stage; FEV₁, forced expiratory volume in 1 second; FVC_max, maximum forced vital capacity; GTV, gross tumor volume; IQR, interquartile range; LF, local failure; LFFS, local failure-free survival; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; SPN, solitary pulmonary nodule; Py, pack-years; PT, primary tumor; RECIST, Response Evaluation Criteria in Solid Tumors; RF, regional failure; RFFS, regional failure-free survival; RT, radiation therapy; SBRT, stereotactic body radiation therapy; SCC, squamous cell carcinoma; SCLC, small cell lung cancer; SCV, supraclavicular lymph node; UC, urothelial carcinoma; UICC, Union for International Cancer Control.

References

1. Ball D, Mai GT, Vinod S, Babington S, Ruben J, Kron T, et al. Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial. Lancet Oncol. (2019) 20:494–503. doi: 10.1016/S1470-2045(18)30896-9

PubMed Abstract | Crossref Full Text | Google Scholar

2. Timmerman RD, Hu C, Michalski JM, Bradley JC, Galvin J, Johnstone DW, et al. Long-term results of stereotactic body radiation therapy in medically inoperable stage I non-small cell lung cancer. JAMA Oncol. (2018) 4:1287–8. doi: 10.1001/jamaoncol.2018.1258

PubMed Abstract | Crossref Full Text | Google Scholar

3. Baumann P, Nyman J, Hoyer M, Wennberg B, Gagliardi G, Lax I, et al. Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol. (2009) 27:3290–6. doi: 10.1200/JCO.2008.21.5681

PubMed Abstract | Crossref Full Text | Google Scholar

4. Bezjak A, Paulus R, Gaspar LE, Timmerman RD, Straube WL, Ryan WF, et al. Safety and efficacy of a five-fraction stereotactic body radiotherapy schedule for centrally located non-small-cell lung cancer: NRG oncology/RTOG 0813 trial. J Clin Oncol. (2019) 37:1316–25. doi: 10.1200/JCO.18.00622

PubMed Abstract | Crossref Full Text | Google Scholar

5. Palma DA, Bahig H, Hope A, Harrow S, Debenham BJ, Louie AV, et al. Stereotactic radiation therapy in early non-small cell lung cancer and interstitial lung disease: A nonrandomized clinical trial. JAMA Oncol. (2024) 10:575–82. doi: 10.1001/jamaoncol.2023.7269

PubMed Abstract | Crossref Full Text | Google Scholar

6. Videtic GM, Paulus R, Singh AK, Chang JY, Parker W, Olivier KR, et al. Long-term follow-up on NRG oncology RTOG 0915 (NCCTG N0927): A randomized phase 2 study comparing 2 stereotactic body radiation therapy schedules for medically inoperable patients with stage I peripheral non-small cell lung cancer. Int J Radiat Oncol Biol Phys. (2019) 103:1077–84. doi: 10.1016/j.ijrobp.2018.11.051

PubMed Abstract | Crossref Full Text | Google Scholar

7. Stokes WA, Bronsert MR, Meguid RA, Blum MG, Jones BL, Koshy M, et al. Post-treatment mortality after surgery and stereotactic body radiotherapy for early-stage non-small-cell lung cancer. J Clin Oncol. (2018) 36:642–51. doi: 10.1200/JCO.2017.75.6536

PubMed Abstract | Crossref Full Text | Google Scholar

8. Chang JY, Lin SH, Dong W, Liao Z, Gandhi SJ, Gay CM, et al. Stereotactic ablative radiotherapy with or without immunotherapy for early-stage or isolated lung parenchymal recurrent node-negative non-small-cell lung cancer: an open-label, randomised, phase 2 trial. Lancet. (2023) 402:871–81. doi: 10.1016/S0140-6736(23)01384-3

PubMed Abstract | Crossref Full Text | Google Scholar

9. Chang JY, Senan S, Paul MA, Mehran RJ, Louie AV, Balter P, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol. (2015) 16:630–7. doi: 10.1016/S1470-2045(15)70168-3

PubMed Abstract | Crossref Full Text | Google Scholar

10. Chansky K, Detterbeck FC, Nicholson AG, Rusch VW, Vallieres E, Groome P, et al. The IASLC lung cancer staging project: external validation of the revision of the TNM stage groupings in the eighth edition of the TNM classification of lung cancer. J Thorac Oncol. (2017) 12:1109–21. doi: 10.1016/j.jtho.2017.04.011

PubMed Abstract | Crossref Full Text | Google Scholar

11. Gros L, Yip R, Golombeck A, Yankelevitz DF, and Henschke CI. Next-generation sequencing analysis on image-guided biopsy samples in early-stage lung cancer: feasibility study and comparison with surgical samples. JTO Clin Res Rep. (2025) 6:100777. doi: 10.1016/j.jtocrr.2024.100777

PubMed Abstract | Crossref Full Text | Google Scholar

12. Langer CJ, Besse B, Gualberto A, Brambilla E, and Soria JC. The evolving role of histology in the management of advanced non-small-cell lung cancer. J Clin Oncol. (2010) 28:5311–20. doi: 10.1200/JCO.2010.28.8126

PubMed Abstract | Crossref Full Text | Google Scholar

13. Hirsch FR, Spreafico A, Novello S, Wood MD, Simms L, and Papotti M. The prognostic and predictive role of histology in advanced non-small cell lung cancer: a literature review. J Thorac Oncol. (2008) 3:1468–81. doi: 10.1097/JTO.0b013e318189f551

PubMed Abstract | Crossref Full Text | Google Scholar

14. Veluswamy RR, Ezer N, Mhango G, Goodman E, Bonomi M, Neugut AI, et al. Limited resection versus lobectomy for older patients with early-stage lung cancer: impact of histology. J Clin Oncol. (2015) 33:3447–53. doi: 10.1200/JCO.2014.60.6624

PubMed Abstract | Crossref Full Text | Google Scholar

15. Gould MK, Donington J, Lynch WR, Mazzone PJ, Midthun DE, Naidich DP, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. (2013) 143:e93S–e120S. doi: 10.1378/chest.12-2351

PubMed Abstract | Crossref Full Text | Google Scholar

16. Steinfort DP, Khor YH, Manser RL, and Irving LB. Radial probe endobronchial ultrasound for the diagnosis of peripheral lung cancer: systematic review and meta-analysis. Eur Respir J. (2011) 37:902–10. doi: 10.1183/09031936.00075310

PubMed Abstract | Crossref Full Text | Google Scholar

17. Ost DE, Ernst A, Lei X, Kovitz KL, Benzaquen S, Diaz-Mendoza J, et al. Diagnostic yield and complications of bronchoscopy for peripheral lung lesions. Res AQuIRE Reg Am J Respir Crit Care Med. (2016) 193:68–77. doi: 10.1164/rccm.201507-1332OC

PubMed Abstract | Crossref Full Text | Google Scholar

18. Chang YY, Chen CK, Yeh YC, and Wu MH. Diagnostic feasibility and safety of CT-guided core biopsy for lung nodules less than or equal to 8 mm: A single-institution experience. Eur Radiol. (2018) 28:796–806. doi: 10.1007/s00330-017-5027-1

PubMed Abstract | Crossref Full Text | Google Scholar

19. Dautruche A, Filion E, Mathieu D, Bahig H, Roberge D, Lambert L, et al. To biopsy or not to biopsy?: A matched cohort analysis of early-stage lung cancer treated with stereotactic radiation with or without histologic confirmation. Int J Radiat Oncol Biol Phys. (2020) 107:88–97. doi: 10.1016/j.ijrobp.2020.01.018

PubMed Abstract | Crossref Full Text | Google Scholar

20. Fan S, Zhang Q, Chen J, Chen G, Zhu J, Li T, et al. Comparison of long-term outcomes of stereotactic body radiotherapy (SBRT) via Helical tomotherapy for early-stage lung cancer with or without pathological proof. Radiat Oncol. (2023) 18:49. doi: 10.1186/s13014-023-02229-0

PubMed Abstract | Crossref Full Text | Google Scholar

21. Haidar YM, Rahn DA 3rd, Nath S, Song W, Bazhenova L, Makani S, et al. Comparison of outcomes following stereotactic body radiotherapy for non-small cell lung cancer in patients with and without pathological confirmation. Ther Adv Respir Dis. (2014) 8:3–12. doi: 10.1177/1753465813512545

PubMed Abstract | Crossref Full Text | Google Scholar

22. Degerli E, El-Marouk K, Kasmann L, Khaltar K, Mansoorian S, Richlitzki C, et al. Empiric stereotactic body radiotherapy for presumed early-stage lung cancer: Pulmonary function changes, treatment-related toxicity and survival outcome. Strahlenther Onkol. (2025). doi: 10.1007/s00066-025-02434-8

PubMed Abstract | Crossref Full Text | Google Scholar

23. Swensen SJ, Silverstein MD, Ilstrup DM, Schleck CD, and Edell ES. The probability of Malignancy in solitary pulmonary nodules. Application to small radiologically indeterminate nodules. Arch Intern Med. (1997) 157:849–55. doi: 10.1001/archinte.1997.00440290031002

PubMed Abstract | Crossref Full Text | Google Scholar

24. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. (2009) 45:228–47. doi: 10.1016/j.ejca.2008.10.026

PubMed Abstract | Crossref Full Text | Google Scholar

25. Hobbs CJ, Ko SJ, Paryani NN, Accurso JM, Olivier KR, Garces YI, et al. Stereotactic body radiotherapy for medically inoperable stage I-II non-small cell lung cancer: the mayo clinic experience. Mayo Clin Proc Innov Qual Outcomes. (2018) 2:40–8. doi: 10.1016/j.mayocpiqo.2017.11.001

PubMed Abstract | Crossref Full Text | Google Scholar

26. Bradley JD, El Naqa I, Drzymala RE, Trovo M, Jones G, and Denning MD. Stereotactic body radiation therapy for early-stage non-small-cell lung cancer: the pattern of failure is distant. Int J Radiat Oncol Biol Phys. (2010) 77:1146–50. doi: 10.1016/j.ijrobp.2009.06.017

PubMed Abstract | Crossref Full Text | Google Scholar

27. Verstegen NE, Lagerwaard FJ, Haasbeek CJ, Slotman BJ, and Senan S. Outcomes of stereotactic ablative radiotherapy following a clinical diagnosis of stage I NSCLC: comparison with a contemporaneous cohort with pathologically proven disease. Radiother Oncol. (2011) 101:250–4. doi: 10.1016/j.radonc.2011.09.017

PubMed Abstract | Crossref Full Text | Google Scholar

28. Senthi S, Lagerwaard FJ, Haasbeek CJ, Slotman BJ, and Senan S. Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: a retrospective analysis. Lancet Oncol. (2012) 13:802–9. doi: 10.1016/S1470-2045(12)70242-5

PubMed Abstract | Crossref Full Text | Google Scholar

29. Gao L, Wang X, Yang X, Gu R, Zhu G, and Gao X. A clinicopathologic analysis of microscopic extension in small cell lung cancer and lung adenocarcinoma: Determination of clinical target volume with precise radiotherapy. Thorac Cancer. (2021) 12:1973–82. doi: 10.1111/1759-7714.14000

PubMed Abstract | Crossref Full Text | Google Scholar

30. Grills IS, Fitch DL, Goldstein NS, Yan D, Chmielewski GW, Welsh RJ, et al. Clinicopathologic analysis of microscopic extension in lung adenocarcinoma: defining clinical target volume for radiotherapy. Int J Radiat Oncol Biol Phys. (2007) 69:334–41. doi: 10.1016/j.ijrobp.2007.03.023

PubMed Abstract | Crossref Full Text | Google Scholar

31. Reinhardt P, Kotov I, Schmidhalter D, Correia D, Elicin O, and Schanne DH. Does omitting the clinical target volume in stereotactic radiotherapy for NSCLC affect oncologic outcomes? A retrospective analysis. Radiother Oncol. (2025) 211:111092. doi: 10.1016/j.radonc.2025.111092

PubMed Abstract | Crossref Full Text | Google Scholar

32. Guckenberger M, Andratschke N, Dieckmann K, Hoogeman MS, Hoyer M, Hurkmans C, et al. ESTRO ACROP consensus guideline on implementation and practice of stereotactic body radiotherapy for peripherally located early stage non-small cell lung cancer. Radiother Oncol. (2017) 124:11–7. doi: 10.1016/j.radonc.2017.05.012

PubMed Abstract | Crossref Full Text | Google Scholar

33. Robinson CG, DeWees TA, El Naqa IM, Creach KM, Olsen JR, Crabtree TD, et al. Patterns of failure after stereotactic body radiation therapy or lobar resection for clinical stage I non-small-cell lung cancer. J Thorac Oncol. (2013) 8:192–201. doi: 10.1097/JTO.0b013e31827ce361

PubMed Abstract | Crossref Full Text | Google Scholar

34. Wong ML, McMurry TL, Stukenborg GJ, Francescatti AB, Amato-Martz C, Schumacher JR, et al. Impact of age and comorbidity on treatment of non-small cell lung cancer recurrence following complete resection: A nationally representative cohort study. Lung Cancer. (2016) 102:108–17. doi: 10.1016/j.lungcan.2016.11.002

PubMed Abstract | Crossref Full Text | Google Scholar

35. Spigel DR, Faivre-Finn C, Gray JE, Vicente D, Planchard D, Paz-Ares L, et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. J Clin Oncol. (2022) 40:1301–11. doi: 10.1200/jco.21.01308

PubMed Abstract | Crossref Full Text | Google Scholar

36. Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. New Engl J Med. (2018) 378:2078–92. doi: 10.1056/nejmoa1801005

PubMed Abstract | Crossref Full Text | Google Scholar

37. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. New Engl J Med. (2018) 378:2288–301. doi: 10.1056/nejmoa1716948

PubMed Abstract | Crossref Full Text | Google Scholar

38. Simone CB, Daly ME, Redman MW, Hsieh M-H, Gray JE, Hesketh PJ, et al. SWOG/NRG S1914: Randomized phase III trial of induction/consolidation atezolizumab+ SBRT versus SBRT alone in high risk, early-stage NSCLC. Am Soc Clin Oncol. (2025) 43:8003. doi: 10.1200/JCO.2025.43.16_suppl.8003

Crossref Full Text | Google Scholar

39. Jabbour SK, Houghton B, Robinson AG, Quantin X, Wehler T, Kowalski D, et al. KEYNOTE-867: phase 3, randomized, placebo-controlled study of stereotactic body radiotherapy (SBRT) with or without pembrolizumab in patients with unresected stage I or II non–small-cell lung cancer (NSCLC). Int J Radiat OncolBiolPhys. (2022) 114:e376–e7. doi: 10.1016/j.ijrobp.2022.07.1516

Crossref Full Text | Google Scholar

40. Robinson C, Xing L, Tanaka H, Tasaka S, Badiyan SN, Nasrallah H, et al. 122TiP Phase III study of durvalumab with SBRT for unresected stage I/II, lymph-node negative NSCLC (PACIFIC-4/RTOG 3515). Ann Oncol. (2022) 33:S88. doi: 10.1016/j.annonc.2022.02.149

Crossref Full Text | Google Scholar