Risk and Outcomes of Secondary Cancer Among Lung Cancer Survivors After Definitive Treatment

Second primary cancers are an important cause of morbidity, mortality, and resource use among lung cancer survivors, yet their risk relative to recurrence and their determinants have been incompletely defined.

To quantify the competing risks of recurrence, intrathoracic new cancer (locoregional or distant recurrences confined to the thorax and/or second primary lung cancers), and non-lung secondary cancers (NLSCs) after curative-intent local therapy for non-small cell lung cancer (NSCLC) and to identify clinical factors associated with NLSC.

This cohort study included consecutive stage I to III NSCLC survivors treated with definitive local therapy and evaluated in a dedicated survivorship clinic at a single high-volume academic cancer center from January to May 2019. Follow-up was measured from completion of local therapy; eligible participants were disease-free 12 months or longer following curative-intent surgery or radiotherapy. Data were analyzed in October 2025.

Definitive local therapy (surgery or radiotherapy) for NSCLC followed by survivorship care.

The outcomes were incidence and timing of recurrence, NLSC, intrathoracic new cancer, extrathoracic cancer, or death measured using nonparametric cumulative incidence functions (CIFs), with death as a competing event, and multivariable Fine-Gray and cause-specific Cox models for NLSC. Overall survival (OS) was estimated using the Kaplan-Meier method.

Among 496 survivors (58.5% female [290]; median [IQR] age, 69.1 [62.8-74.3] years), the median (IQR) follow-up was 71.6 (57.7-84.8) months. Of these patients, 367 (74.0%) were former smokers; the index cancer was adenocarcinoma in 372 (75.0%); 337 (67.9%) had stage I disease, 72 (14.5%) had stage II, and 87 (17.5%) had stage III. Recurrence occurred in 67 of 496 patients (13.5%). Secondary cancers developed in 116 of 496 patients (23.4%), including a new primary lung cancer in 77 of 496 patients (15.5%) and NLSC in 39 of 496 patients (7.9%). Median (IQR) time to diagnosis of an NLSC was 52.3 (35.9-65.6) months, and CIFs (competing risks) at 5 years (death and other first events treated as competing risks) were 11.5% for recurrence, 5.6% for NLSC, 16.8% for intrathoracic new cancer, and 10.4% for extrathoracic cancer. In Fine-Gray models, a hereditary syndrome and/or pathogenic germline variant was associated with higher risk for NLSC (subdistribution hazard ratio [SHR], 10.76; 95% CI, 4.62-25.06; P < .001), whereas pack-years (per 10) were not associated with higher risk (SHR, 1.00; 95% CI, 0.97-1.03; P = .85). Cause-specific Cox results were concordant (HR, 8.32; 95% CI, 3.14-22.02; P < .001).

In this cohort study of NSCLC survivors, the risk of NLSC was clinically meaningful and distinct from intrathoracic new cancers. Genetic predisposition correlated with NLSC risk and should inform survivorship care pathways.