Stereotactic Radiation for Ultra-Central Non-Small Cell Lung Cancer: A Safety and Efficacy Trial (SUNSET)

Purpose/Objective(s) The use of stereotactic body radiation (SBRT) for tumors in close proximity to the central mediastinal structures has been associated with a high risk of toxicity. This prospective study (NCT03306680) aimed to determine the maximally tolerated dose (MTD) of SBRT for ultra-central (UC) non-small cell lung carcinoma (NSCLC), using a time-to-event continual reassessment methodology (TITE-CRM). Materials/Methods Eligibility criteria included age ≥ 18 years, ECOG performance status 0-2, with stage T1-3N0M0(≤ 6 cm), NSCLC, and UC tumor location, defined as planning target volume (PTV) touching or overlapping the proximal bronchial tree (PBT), esophagus, pulmonary vein (PV), or pulmonary artery (PA). The MTD was defined as the dose of radiotherapy associated with a ≤ 30% rate of grade (G) 3-5 pre-specified treatment-related toxicity occurring within 2 years of treatment. The starting dose level was 60 Gy in 8 fractions (7.5 Gy/fraction) delivered daily, with de-escalation to 60 Gy in 10 or 15 fractions if toxicity rates exceeded 30% using TITE-CRM. Estimated sample size was 30 patients. The hotspot was limited to 120% within the PTV; tumors with endobronchial invasion were excluded. Adverse event rates were assessed using CTCAE version 4.0. Secondary endpoints included overall survival (OS), progression-free survival (PFS), local control (LC), regional control (RC), and distant control (DC), calculated using Kaplan-Meier estimates, and quality of life (QOL), assessed using the Functional Assessment of Cancer Therapy (FACT) Lung questionnaire. This primary analysis occurred two years after completion of accrual. Results Between March 2018 and April 2021, enrollment completed with 30 patients at five Canadian academic institutions. The median follow-up was 36.5 months (range: 8.9-50.8). The median age was 73 years (interquartile range [IQR]: 69-78), 17 (56.7%) were female, 23 (76.7%) were T1, 6 (20.0%) T2 and 1 (3.3%) T3. Tumor was located near PBT in 18 (60.0%), esophagus 5 (16.7%), PV 1 (3.3%) and PA 14 (46.7%). All patients were assigned a dose of 60 Gy in 8 fractions. Two patients (6.7%) experienced G3-5 adverse events related to treatment: one patient with G3 dyspnea and 1 G5 pneumonia (related to interstitial lung disease [ILD]); the latter had CT findings consistent with a background of ILD identified after SBRT. Three-year actuarial outcomes were as follows: OS was 72.5% (95% confidence interval [CI]: 52.3-85.3%), PFS 66.1% (95% CI: 46.1-80.2%), LC 89.6% (95% CI: 71.2-96.5%), RC 96.4% (95% CI: 77.2-99.5%) and DC 85.9% (95% CI: 66.7-94.5%). QOL scores declined numerically over time, but the decrease were not clinically or statistically significant. Conclusion 60 Gy in 8 fractions, planned and delivered with only a moderate hotspot, has a favorable adverse event rate, within the pre-specified acceptability criteria, and results in excellent tumor control. The use of stereotactic body radiation (SBRT) for tumors in close proximity to the central mediastinal structures has been associated with a high risk of toxicity. This prospective study (NCT03306680) aimed to determine the maximally tolerated dose (MTD) of SBRT for ultra-central (UC) non-small cell lung carcinoma (NSCLC), using a time-to-event continual reassessment methodology (TITE-CRM). Eligibility criteria included age ≥ 18 years, ECOG performance status 0-2, with stage T1-3N0M0(≤ 6 cm), NSCLC, and UC tumor location, defined as planning target volume (PTV) touching or overlapping the proximal bronchial tree (PBT), esophagus, pulmonary vein (PV), or pulmonary artery (PA). The MTD was defined as the dose of radiotherapy associated with a ≤ 30% rate of grade (G) 3-5 pre-specified treatment-related toxicity occurring within 2 years of treatment. The starting dose level was 60 Gy in 8 fractions (7.5 Gy/fraction) delivered daily, with de-escalation to 60 Gy in 10 or 15 fractions if toxicity rates exceeded 30% using TITE-CRM. Estimated sample size was 30 patients. The hotspot was limited to 120% within the PTV; tumors with endobronchial invasion were excluded. Adverse event rates were assessed using CTCAE version 4.0. Secondary endpoints included overall survival (OS), progression-free survival (PFS), local control (LC), regional control (RC), and distant control (DC), calculated using Kaplan-Meier estimates, and quality of life (QOL), assessed using the Functional Assessment of Cancer Therapy (FACT) Lung questionnaire. This primary analysis occurred two years after completion of accrual. Between March 2018 and April 2021, enrollment completed with 30 patients at five Canadian academic institutions. The median follow-up was 36.5 months (range: 8.9-50.8). The median age was 73 years (interquartile range [IQR]: 69-78), 17 (56.7%) were female, 23 (76.7%) were T1, 6 (20.0%) T2 and 1 (3.3%) T3. Tumor was located near PBT in 18 (60.0%), esophagus 5 (16.7%), PV 1 (3.3%) and PA 14 (46.7%). All patients were assigned a dose of 60 Gy in 8 fractions. Two patients (6.7%) experienced G3-5 adverse events related to treatment: one patient with G3 dyspnea and 1 G5 pneumonia (related to interstitial lung disease [ILD]); the latter had CT findings consistent with a background of ILD identified after SBRT. Three-year actuarial outcomes were as follows: OS was 72.5% (95% confidence interval [CI]: 52.3-85.3%), PFS 66.1% (95% CI: 46.1-80.2%), LC 89.6% (95% CI: 71.2-96.5%), RC 96.4% (95% CI: 77.2-99.5%) and DC 85.9% (95% CI: 66.7-94.5%). QOL scores declined numerically over time, but the decrease were not clinically or statistically significant. 60 Gy in 8 fractions, planned and delivered with only a moderate hotspot, has a favorable adverse event rate, within the pre-specified acceptability criteria, and results in excellent tumor control.