Patients with nonsmall cell lung cancer (NSCLC) who have been exposed to thymic radiation appear to be at increased risks of metastasis and mortality, particularly those with preserved thymic function, a recent study has found.
“This study highlights the thymus as a clinically meaningful organ of interest in thoracic radiotherapy (RT),” the investigators said. “High thymic dose was associated with a higher risk of distant metastasis and death and a decline in thymic health at 1-year follow-up.”
A total of 1,107 NSCLC patients were included in this multicohort analysis, including the phase III RTOG-0617 trial (n=460) and two independent real-world cohorts of participants treated with chemoradiotherapy (CRT) alone (HARVARD-CRT; n=422) or in combination with consolidation immunotherapy (HARVARD-DURVA; n=225). [Ann Oncol 2026;37:1345-1357]
The investigators assessed thymic function using a deep learning system that assessed thymic radiographic characteristics as a proxy for thymic function and measured thymic radiation exposure using mean thymic dose (MTD).
After adjusting for confounders, an association was found between incidental thymic radiation and a higher risk of distant metastases. Specifically, an increase of 1 Gy in MTD correlated with an elevated risk of distant metastasis ranging from 1.57 percent to 4.21 percent (RTOG-0617: adjusted hazard ratio [aHR], 1.29; p=0.0028; HARVARD-CRT: aHR, 1.33; p=0.011; HARVARD-DURVA: aHR, 1.95; p=0.007).
Furthermore, stratified analysis revealed a particularly higher risk among patients with preserved thymic health prior to RT, but not for those with impaired thymic health.
At 1-year follow-up, imaging showed dose-dependent declines in thymic health and lower circulating lymphocyte counts, consistent with a potential biological association between thymic irradiation and loss of immune competence.
In an exploratory feasibility study, the investigators noted the possibility of a reoptimized RT planning for thymic sparing without compromising tumour coverage or cardiopulmonary constraints.
“Patients with preserved thymic function can be identified using deep learning-based thymic health assessments and may particularly benefit from personalized radiation strategies that minimize thymic damage,” the investigators said.
“These findings advocate for a paradigm shift in thoracic radiation planning, where immunological health is prioritized alongside traditional oncological targets and organs at risk,” they added.
Thymic degradation
The unfavourable outcomes seen in recent dose escalation and intensification trials could have been driven by thymic degradation, according to the investigators.
In the PACIFIC and ADRIATIC studies, consolidation immunotherapy resulted in improved survival after CRT, but similar approaches combining concurrent immunotherapy and thoracic RT (eg, PACIFIC-2 and NRG-LU005) showed no benefit. [N Engl J Med 2017;377:1919-1929; N Engl J Med 2024;391:1313-1327; ESMO Open 2024;9(suppl 3):102986; Int J Radiat Oncol Biol Phys 2024;120(suppl 2):S2]
“Our findings imply that concurrent thymic radiation may compromise the immune system’s antitumour response, suggesting a role for treatment sequencing and thymic preservation in improving future outcomes,” the investigators said.
Notably, the two real-world cohorts and the standard 60-Gy group of the RTOG-0617 demonstrated thymic radiation dose associations, supporting its relevance to current practice. However, no association was seen in the high-dose 74-Gy group, “possibly because very high doses induce uniform thymic injury, obscuring dose-dependent effect once a critical damage threshold is exceeded,” they said.
“We included a cohort of 225 real-world patients treated with consolidation immunotherapy, whereas the other cohorts were treated before the PACIFIC era,” the investigators said.
“Therefore, treatment heterogeneity and selection bias are potential limitations, and future work in larger contemporary cohorts is needed to investigate the potential interaction between thymic dose and consolidation immunotherapy,” they added.