Characterizing First Events in LA-NSCLC Patients Treated with Chemoradiotherapy

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Definitive chemoradiotherapy (CRT) is a standard treatment for locally advanced non-small cell lung cancer (LA-NSCLC). After treatment, patients are at risk for local disease recurrence, developing new sites of disease, and death without disease recurrence. Here, we characterize the rates of these events in a modern patient cohort and explore risk factors for each event. The hypothesis is that these rates and risk factors will better inform treatment strategies for local intensification and systemic therapy. We reviewed patients who underwent staging PET/CT and were treated for LA-NSCLC with definitive CRT at our institution between 2010 and 2022. Competing risks analyses were performed to calculate rates of disease progression and death without disease progression. Competing risks analyses were repeated after dividing disease progression into in-field recurrence versus out-of-field progression and after subdividing in-field recurrences into progression of high-risk (large) tumors or lymph nodes (defined as having metabolic tumor volume [MTV] >20 cc on staging PET/CT) versus progression of low-risk (small) tumors or lymph nodes. Predictors of each event type were identified using univariate and multivariable Fine and Gray competing risks regressions. A total of 210 patients met inclusion criteria, and the median follow-up duration is 43 months. Median age was 68 (IQR 60 to 74), and 77% of patients had ECOG performance status 0-1. Median progression-free survival and overall survival durations are 13 and 40 months, respectively. The 3-year cumulative incidence rate (CIR) of disease progression was 58%, and the 3-year CIR of death without disease progression was 18%. The 3-year CIR for out-of-field disease progression was 44%, and the 3-year CIR for in-field recurrence was 14%. The 3-year CIR for in-field recurrence of high-risk lesions was 11%, and the 3-year CIR for low-risk lesions was 4%. Multivariable analyses examining predictors of out-of-field progression revealed two statistically significant factors: total disease burden on PET (SHR 1.03 per 10 cc, p = 0.013) and durvalumab receipt (SHR 0.60, p = 0.031). Multivariable analyses also revealed two predictors of death without disease progression: age (SHR 1.06 per year, p = 0.018) and ECOG performance status (SHR 1.81, p = 0.012). For LA-NSCLC patients treated with definitive CRT, we found that developing new sites of disease is the most common first event, followed by death without disease recurrence. In-field disease recurrence is relatively uncommon, particularly when treating relatively small tumors and lymph nodes. These findings may inform prioritization of strategies to improve systemic therapy, intensify local therapy, and minimize treatment-related toxicity.