Background
Phase 1/2 dose escalation study. 120 patients with biopsy-proven stage I/II NSCLC located within 2 cm of the proximal bronchial tree, mediastinum, pericardium, brachial plexus, or major vessels (centrally located tumors), medically inoperable. Sequential cohorts enrolled at escalating dose levels. Conducted at 43 institutions.
Interventions and follow up
Arm A: SBRT in 5 fractions over 1.5–2 weeks; dose escalated from 10.0 Gy/fraction to 12.5 Gy/fraction (50–62.5 Gy total) in sequential cohort
Primary endpoint: Maximum tolerated dose (MTD, defined as dose-limiting toxicity rate ≤20%), local control, OS
mFollow up: Median 37.9 month
Primary endpoint: Maximum tolerated dose (MTD, defined as dose-limiting toxicity rate ≤20%), local control, OS
mFollow up: Median 37.9 month
Results
MTD: 12.0 Gy × 5 fractions = 60 Gy (12.5 Gy × 5 had DLT rate 7.2%, exceeding threshold at upper boundary)
2-yr local control: 88.8%
2-yr OS: 72.7%
Dose-limiting toxicity (all levels): 6/120 (5%)
2-yr local control: 88.8%
2-yr OS: 72.7%
Dose-limiting toxicity (all levels): 6/120 (5%)
Adverse events
Main adverse events: Grade ≥3 toxicity: 9.2% across all dose levels. DLTs included grade ≥3 events within 1 year. Grade 5 events: 3 patients (1 fatal hemoptysis, 2 other possibly treatment-related). Pulmonary and esophageal toxicities most common. Ultra-central tumors (touching proximal bronchial tree) had highest toxicity rates.
Conclusions
60 Gy in 5 fractions (12 Gy/fraction) was established as the recommended SBRT dose for centrally located NSCLC, with acceptable toxicity and high local control (88.8% at 2 years). This regimen became a standard framework for central NSCLC SBRT.
Key Limitations
Key Limitations: No control arm; phase 1/2 — not powered for definitive efficacy endpoints. Three grade 5 events raise concern about true MTD accuracy in ultra-central subgroup. Ultra-central tumors (abutting proximal bronchial tree) carry highest risk — some centers use lower doses (e.g., 50 Gy/5 fx) for these lesions. Long-term outcomes beyond 3 years not mature. Definition of "centrally located" varied between centers.
Clinical Context
RTOG 0813 defines safe dosing for central NSCLC SBRT, complementing RTOG 0236 (peripheral 54 Gy/3 fx). The 5-fraction central regimen (60 Gy/5 fx) is now widely adopted. Ultra-central tumors may warrant further dose reduction or conventionally fractionated SABR. Institutional protocols vary; some centers use 50 Gy/5 fx for ultra-central lesions. Ongoing controversy about optimal dose fractionation for bronchially adjacent tumors.
References
References: Bezjak A et al, J Clin Oncol 2019 (RTOG 0813)