Primary Tumor Failure After Definitive Chemoradiation in Locally Advanced Non-Small Cell Lung Cancer: A Brief Report on the Implications for NRG LU-008.

Purpose: Locoregional failure (LRF) after definitive chemoradiation for locally advanced non-small cell cancer is suboptimal. LU-008 aims to improve local control through an stereotactic body radiation therapy boost. We quantified first-failure patterns after modern chemoradiation and determined whether patients with LRF had LU-008 eligibility.

Methods and materials: Consecutive adults treated with definitive chemoradiation (>60 Gy, 1.8-2 Gy/fraction ± immunotherapy) from 2011 to 2021 at a single institution were reviewed. First progression was classified as isolated LRF, isolated distant failure (DF), or synchronous LRF + DF; LRF was subclassified as primary tumor failure (PTF), regional failure (RF), or PTF + RF. PTF was defined radiographically within the 90% isodose of the primary tumor gross tumor volume. LU-008 eligibility (tumor <7 cm, ≥1 node, primary >2 cm from nodal clinical tumor volume) was applied retrospectively. Cumulative incidence functions used Fine-Gray models with death as a competing risk.

Results: Among 786 patients (median follow-up 66.9 months), 484 first failures occurred: 109 isolated LRF, 122 synchronous LRF + DF, and 253 isolated DF. Isolated PTF occurred in 40 patients (5.1%); PTF + RF in 29 (3.7%). Five-year cumulative incidence was 52% for any DF, 42% for any LRF, 25% for any isolated LRF (DF-free), 17% for any PTF (PTF + RF, DF-free), and 10% for isolated PTF. Only 28 of 69 PTF-containing LRFs (41%) met LU-008 criteria. Failure patterns were similar for patients who received immunotherapy consolidation. Overall, 129 of 231 patients with any LRF (56%) were LU-008-ineligible, commonly due to central or ultracentral primaries, and experienced earlier PTF (median, 12.1 vs 22.4 months; P = .002). PTF risk increased steeply with primary tumor gross tumor volume up to ∼200 cm².

Conclusions: Although DF is the most common site of failure, LRF remains a problem. Many PTFs after chemoradiation occur in patients who would be excluded from LU-008, mainly because of central-tumor location. This high-risk subset of central primaries may require alternative escalation or combined modality strategies beyond the proposed LU-008 paradigm.