Pretreatment prediction of early severe treatment-related toxicity in older patients with lung adenocarcinoma: same-center temporal validation of a risk model

Background: Older adults with lung adenocarcinoma have heterogeneous tolerance of chemotherapy-based treatment. Early severe toxicity can disrupt planned therapy, require unplanned admission, and limit treatment intensity. We developed a pretreatment risk model for severe treatment-related toxicity within the first two chemotherapy-based cycles and examined whether Fatigue, Resistance, Ambulation, Illnesses, and Loss of weight (FRAIL) category and inflammatory-nutritional markers add risk-stratification information.

Methods: This single-center retrospective cohort included patients aged ≥60 years with pathologically confirmed lung adenocarcinoma who received cytotoxic chemotherapy-based systemic treatment between September 2015 and September 2025. Among 1,106 screened patients, 1,019 formed the primary complete-case cohort; a multiple-imputation sensitivity analysis included 1,045 patients with eligible treatment exposure and adjudicable outcomes. Patients treated from September 2015 to December 2021 formed the development cohort (n=679), and those treated from January 2022 to September 2025 formed the same-center temporal validation cohort (n=340). The endpoint was Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade ≥3 treatment-related toxicity within the first two cycles. Model A contained clinical variables, Model B added FRAIL category, and Model C additionally incorporated the neutrophil-to-lymphocyte ratio (NLR) and prognostic nutritional index (PNI). Performance was assessed using discrimination, calibration, Brier score, decision curve analysis, and risk grouping.

Results: Severe treatment-related toxicity occurred in 316 of 1,019 patients (31.0%): 202 in the development cohort and 114 in the validation cohort. Toxicity rates increased across FRAIL categories: 13.5% in robust, 28.5% in pre-frail, and 51.4% in frail patients (P for trend <0.001). In Model C, frailty, higher Eastern Cooperative Oncology Group (ECOG) performance status, tumor-node-metastasis (TNM) stage IV disease, and lower PNI indicated greater risk. Model C yielded an area under the receiver operating characteristic curve (AUC) of 0.770 [95% confidence interval (CI), 0.736-0.809] in development and 0.753 (95% CI, 0.700-0.805) in validation. In the validation cohort, the calibration intercept was 0.124 (95% CI, -0.194 to 0.442) and slope was 0.986 (95% CI, 0.706 to 1.267). Model C also produced ordered low-, intermediate-, and high-risk strata with increasing observed toxicity rates.

Conclusions: A pretreatment model combining clinical variables, FRAIL category, NLR, and PNI separated older patients with lung adenocarcinoma into different levels of early severe toxicity risk. The model showed moderate discrimination, acceptable calibration, and directionally consistent sensitivity analyses. It may support closer observation and supportive-care planning, but routine use should await multicenter external validation and prospective evaluation of clinical impact.