SBRT for Ultra-Central NonSmall Cell Lung Cancer

• SBRT (Radiation): 50 Grays (Gy) delivered in 5 fractions, delivered using Cyberknife with Synchrony motion tracking, every other day over 2 weeks.

Primary outcomes

• Cumulative incidence of grade 3 or higher toxicity following SBRT with CyberKnife regimen with real-time motion tracking for ultra-central NSCLC. [Patients will be assessed for toxicity throughout treatment with radiation therapy (RT). Following RT, all participants will be evaluated through 12 months for the primary safety endpoint and will continue protocol safety follow-up through 5 years.]: The primary safety endpoint is the cumulative incidence of acute or late grade ≥3 AEs occurring within 12 months and assessed as possibly, probably, or definitely related to protocol treatment. AEs will be graded using the NCI CTCAE version 6.0. Prespecified thoracic AEs include dyspnea, cough, pneumonitis, lung infection, atelectasis, bronchial stenosis or obstruction, bronchopulmonary hemorrhage or hemoptysis, fistula, dysphagia or esophagitis, pleural or pericardial effusion, and chest pain.

Secondary outcomes

• Local control (LC) [Until Trial Completed (up to 5 years)]: LC will be calculated using the cumulative incidence method and reported along with a 95% exact binomial confidence interval (CI).
• Regional nodal progression [Until Trial Completed (up to 5 years)]: The regional nodal progression is defined as the length of time from radiation completion of the first documented presence of enlarged lymph nodes >1 cm \[short axis\] in the hilum or mediastinum and biopsy confirmed. The Kaplan-Meier method will be used for the analyses, and the median regional nodal progression free time with 95% CI will be reported, respectively, if available.
• Distant metastasis-free survival (DMFS) [Until trial completed (up to 5 years)]: DMFS is defined as the length of time, from radiation completion to the first evidence of clinical distant metastatic spread of NSCLC outside of the lung cavity or death, whichever occurs first. Patients who are alive and free from clinical distant metastasis will be censored at the date of last follow-up for DMFS. The Kaplan-Meier method will be used for the analyses, and the median DMFS with 95% CI will be reported, respectively, if available.
• Progression-free survival (PFS) [From baseline through the follow up period at 3, 6, 9, 12, 18, 24 months followed annually thereafter up to 5 years.]: PFS is defined as the length of time, from radiation completion to the first evidence of clinical/radiographic progression, biopsy confirmation when feasible, distant metastasis, or death, whichever comes first. Patients who are alive and free from disease progression will be censored at the date of last follow-up or date of death, whichever occurs first. SOC PET/CT imaging results will be reviewed and collected. The Kaplan-Meier method will be used for the analyses, and the median PFS with 95% CI will be reported, respectively, if available.
• Overall survival (OS) [Up to 5 years]: OS is defined as the length of time, from radiation completion, a patient lives until death. Patients who are alive will be censored at either the date of last follow-up or date of death, whichever occurs first. The Kaplan-Meier method will be used for the analyses, and the median survival time with 95% CI will be reported, respectively, if available.
• Incidence of treatment related acute and late grade 2 or higher toxicity and late grade ≥3 toxicity [From the start of radiation treatment throught 12 months and 24 months.]: The incidence of treatment related acute and late grade ≥2 and late grade ≥3 AEs (AESI) will be assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 6.0 or severity grade when CTCAE grading does not exist. Grade 1 to 5 will be used to characterize the severity of the AE. If CTCAE grading does not exist for an AE, the severity of mild, moderate, severe, life-threatening and death due to the AE, corresponding respectively to Grades 1 - 5, will be used.
• Patient-Reported Quality of Life Outcomes (QoL) [Pre-radiation/baseline, 3, 6, 9, 12, 18, 24 months post-radiation and then annually thereafter until 5 years.]: Patient-reported QoL outcomes through designated questionnaires. The EORTC QoL questionnaire (QLQ)-C30 is a 30-item form for lung cancer patients that incorporates five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea/vomiting), a global health status/ QoL scale, and several single items assessing additional symptoms commonly experienced by cancer patients. The EORTC QLQ-LC13 is a clinically validated tool to assess disease and treatment specific symptoms in lung cancer patients that will participate in clinical trials. Quality of life outcomes will be summarized over time using descriptive statistics and graphical displays. The Wilcoxon signed-rank test will be used for comparisons of QoL between follow-up time points and baseline. Repeated measure models may be employed to assess changes in QoL outcomes over time if deemed necessary.
• Pulmonary Function Testing - Forced Expiratory Volume in One Second (FEV1) [Pre-radiation/baseline to post-radiation follow-up at 6 months, 12 months, 24 months and annually thereafter until 5 years.]: The pulmonary function testing changes will be evaluated including serial PFT, FEV1, FVC (forced vital capacity), DLCO and TLC (total lung capacity) to assess the impact of precision SBRT on respiratory function.
• Pulmonary Function Testing - FVC (Forced Vital Capacity) [Pre-radiation/baseline to post-radiation follow-up at 6 months, 12 months, 24 months and annually thereafter until 5 years.]: The pulmonary function testing changes will be evaluated including serial PFT, FEV1, FVC (forced vital capacity), DLCO and TLC (total lung capacity) to assess the impact of precision SBRT on respiratory function.
• Pulmonary Function Testing - Diffusing Capacity for Carbon Monoxide (DLCO) [Pre-radiation/baseline to post-radiation follow-up at 6 months, 12 months, 24 months and annually thereafter until 5 years.]: The pulmonary function testing changes will be evaluated including serial PFT, FEV1, FVC (forced vital capacity), DLCO and TLC (total lung capacity) to assess the impact of precision SBRT on respiratory function.
• Pulmonary Function Testing - TLC (total lung capacity) [Pre-radiation/baseline to post-radiation follow-up at 6 months, 12 months, 24 months and annually thereafter until 5 years.]: The pulmonary function testing (PFT) changes will be evaluated including serial PFT, FEV1, FVC (forced vital capacity), DLCO and TLC (total lung capacity) to assess the impact of precision SBRT on respiratory function.
• Correlation of Dose-volume histogram (DVH) parameters for organs-at-risk (OARs) with observed toxicities and local control [through 12 months post-radiation]: DVH parameters for OARs will be analyzed with their correlation with observed toxicities and local control. Descriptive statistics will be presented for DVH parameters for organs-at-risk (OARs). Two-sided t-test or Mann-Whitney test, ANOVA or Kruskal-Wallis test will be utilized for continuous DHV parameters and Chi-square test or Fisher's exact test will be used for categorical DHV parameters to assess associations between DVH parameters and toxicity and LC, respectively.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Patients aged 18 or older.
2. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
3. Patients with confirmed tumor location using advanced imaging to ensure accurate classification of ultra-central NSCLC.
4. Ability to undergo bronchoscopy and Endobronchial ultrasound (EBUS) with adequate fiducial placement
5. Histologically or cytologically confirmed clinical stage T1-T2 N0 M0 NSCLC (AJCC 9th edition), with maximum tumor diameter ≤5 cm.
6. Absence of overt radiological or bronchoscopy assessed gross endobronchial invasion, invasion of the trachea, esophagus, major blood vessels, or other mediastinal structures.
7. 4D-CT (computed tomography) scans will be required to evaluate tumor motion and verification at time of simulation:

   ○ Screening for ultra-central tumor deformation between inhalation and exhalation extremities will be performed via 4D-CT to avoid inappropriate margins for significant tumor motion or deformation.
8. Ultra-central tumors must include:

   o Gross Tumor Volume (GTV) or Planning Target Volume (PTV) located within 1 cm (centimeter) of the Proximal Bronchial Tree (PBT) and/or at least one of the following: (1) GTV or protocol PTV within 1 cm of the PBT; or (2) GTV within 5 mm of or abutting/overlapping the esophagus, heart/pericardium, aorta, pulmonary artery, or pulmonary vein.
9. Patients are eligible to receive SBRT:

   * Patients deemed suitable for SBRT based on multidisciplinary evaluation;
   * Medically inoperable, decline surgery or high surgical risk as determined by a thoracic surgeon or multidisciplinary tumor board;
   * No prior overlapping thoracic radiation exceeding dose constraints for critical structures;
   * Adequate pulmonary function to tolerate procedure;
   * A minimum of two gold fiducials will be placed in or adjacent to the tumor via bronchoscopy and will be tracked/evaluated by the treating radiation oncologist and/or physicist/dosimetrist to determine quality of fiducial placement for trial inclusion.
10. Patients are eligible to receive radiation therapy:

    * Candidate for CyberKnife radiosurgery using Synchrony motion management;
    * 4D-CT is required to evaluate tumor motion. Patients with >1.5 cm excursion in any dimension will require a 5 mm PTV margin and remain eligible only if all mandatory Organs-at-risk (OAR) dosimetric and planning constraints can be met; otherwise, they are ineligible for protocol treatment.
    * OAR constraints will be prioritized over target coverage. Patients who cannot meet mandatory airway, esophagus, great vessel, heart, spinal cord, and lung constraints are not eligible for protocol treatment.
11. Female patients of childbearing potential must have a negative pregnancy test prior to treatment and agree to contraception during and for a defined period after treatment.
12. Patients who can comply with follow-up visits and treatment plans.
13. Patients who can provide written informed consent prior to study procedures.

Exclusion Criteria:

1. Patients with evidence of nodal involvement (N1-N3) or distant metastases (M1).
2. Patients with previous radiation therapy to the thorax that would result in overlap with the planned treatment field.
3. Patients with tumor-associated bronchial compression, defined as visible deformation or narrowing of the trachea, mainstem bronchus, or bronchus intermedius on diagnostic CT, simulation CT, or bronchoscopy.
4. Patients receiving concurrent chemotherapy, immunotherapy, or targeted therapy during SBRT.
5. Patients with active connective tissue disease (e.g., lupus, scleroderma, polymyositis, rheumatoid arthritis).
6. Patients with interstitial lung disease of any etiology.
7. Patients on Vascular Endothelial Growth Factor (VEGF) inhibitors.
8. Patients with tumor invasion of any major airways, esophagus, or major blood vessels.
9. Patients with evidence of endobronchial disease.
10. Patients who fail to place fiducial markers for Synchrony tracking.
11. Patients who require alternate fractionation scheduling.
12. Patients who are pregnant or are breastfeeding.
13. Patients who are unable to lie flat for the duration of treatment (approximately 45-60 minutes per fraction).
14. Patients with psychiatric illness or social situation that would limit compliance with study requirements.
15. Patients who are unable to or unwilling to give informed consent.

• Jonathan Lischalk, MD, Principal investigator, Georgetown University