Incidental radiation exposure to the thymus during treatment for locally advanced non-small cell lung cancer (NSCLC) is associated with worse outcomes — raising questions about whether the thymus, long thought to be largely inactive in adults, should be protected during radiotherapy.

In a multi-cohort study of over 1100 patients who received lung cancer radiotherapy, incidental thymic irradiation was independently associated with a higher risk for distant metastasis and, in some analyses, death.

The link was specifically seen among patients who, before radiation, had preserved thymic function. That, according to researchers, hints at the possibility that the poorer outcomes are related to a loss of immune competence.

“The thymus is not currently considered a standard organ at risk in adult thoracic radiation planning,” co-senior investigator Raymond Mak, MD, a radiation oncologist at Mass General Brigham Cancer Institute in Boston, told Medscape Medical News.

“I think these findings provide a reason to start thinking differently about that,” he said.

However, prospective data are needed before any changes can be made to routine practice, stressed Hugo Aerts, PhD, the other senior researcher on the work.

“We don’t think these findings are sufficient yet to establish a formal thymic dose constraint or change the standard of care,” said Aerts, who directs the Artificial Intelligence in Medicine program at Mass General Brigham.

The study was published online in Annals of Oncology.

‘Thymic Health’ and NSCLC

The thymus plays a crucial role in T cell development early in life. Traditionally, the organ has been viewed as largely irrelevant in adulthood due to thymic involution, the progressive replacement of functional tissue with fat. Recent evidence has challenged that thinking, however.

Because the thymus may be incidentally exposed to radiation during thoracic radiotherapy, Mak, Aerts, and their colleagues hypothesized that thymic radiation dose would be related to poorer outcomes in patients undergoing treatment for lung cancer.

To investigate, they analyzed data on 1107 patients with locally advanced NSCLC: 460 from the RTOG-0617 trial comparing 60-Gy and 74-Gy thoracic radiation with carboplatin-paclitaxel-based chemoradiotherapy (CRT), with or without cetuximab; 422 from the HARVARD-CRT cohort who received platinum-based CRT alone; and 225 from the HARVARD-DURVA cohort treated with definitive CRT followed by immunotherapy with durvalumab.

The researchers used a deep learning model to analyze patients’ routine CT scans and estimate their thymic function before the start of radiotherapy (based on the size, shape, density, and tissue composition of the thymus). They also applied the model to treatment planning scans to estimate radiation exposure to the thymus and other organs at risk and calculate a mean thymic dose.

Across the three cohorts, higher mean thymic dose was associated with a greater risk for distant metastasis, after adjustment for other clinical and radiation-related factors.

The magnitude of the association varied by cohort, ranging from a 1.6% to 4.2% increase in metastatic risk for each 1-Gy increase in mean thymic dose. The association was concentrated among patients with preserved thymic function before treatment.

Expressed per SD increase in mean thymic dose, higher thymic radiation exposure was associated with a 29%-33% higher risk for distant metastasis in the two CRT cohorts, and a 95% higher risk in the cohort who received CRT plus immunotherapy.

Higher mean thymic dose was also associated with increased mortality in the RTOG-0617 CRT trial (adjusted hazard ratio [aHR], 1.25) and among patients with preserved thymic health in HARVARD-CRT (aHR, 1.23).

Biologically, this makes sense, Mak told Medscape Medical News.

“If a patient has a relatively healthy, functioning thymus, there is more functional immune tissue that could potentially be damaged by radiation,” he said. “In a patient whose thymus has already largely involuted, additional radiation may have less biological impact.”

The consistency of the pattern was “striking,” Aerts added.

“Patients with preserved thymic health generally had the best outcomes, but within that group, greater radiation exposure to the thymus was associated with worse outcomes,” he said.

Patients who received higher thymic radiation doses also showed a greater loss in thymic health 1 year later, consistent with a possible biological effect of radiation on the organ.

A Radiation Dose Threshold?

The researchers conducted exploratory analyses to identify a potential thymic dose threshold associated with patient outcomes.

They found that a mean thymic dose above 35 Gy was associated with a 40%-96% higher risk for distant metastasis, depending on the cohort (with the highest risk seen in the immunotherapy group). The investigators emphasized, however, that 35 Gy was an exploratory, population-specific threshold and should not be considered a validated clinical dose constraint.

Finally, a small replanning analysis involving 16 patients suggested that thymic-sparing may be technically feasible.

“We found that thymic radiation exposure could often be substantially reduced using existing treatment-planning techniques, while maintaining tumor coverage and other organ-at-risk constraints,” Mak said.

If prospective studies confirm a benefit from thymic protection, he added, it could be incorporated into clinical practice “relatively quickly.”

According to Aerts, the findings could have broader implications as immunotherapy becomes increasingly integrated into cancer care: Protecting immune organs during treatment may need to become a priority.

“The thymus could be one of the first immune organs to become part of that conversation,” Aerts said.

A radiation oncologist who was not involved in the study agreed.

“This is one of the first research papers that is showing, across multiple datasets, that the radiation dose to the thymus can impact the behavior of the cancer over time, particularly the chances for a lung cancer to spread outside of the lungs,” said Kristin Higgins, MD, chief clinical officer at City of Hope, Atlanta.

Like Mak, she noted that radiation oncologists do not routinely consider the thymus during lung cancer treatment planning — but she expects that could change going forward. Higgins also agreed that with currently available radiotherapy technologies, thymus-sparing “would be easily implemented.”

However, echoing the researchers, she emphasized that prospective validation is needed before any widespread adoption of such strategies.

The study was funded by multiple sources, including the National Institutes of Health and the European Union — European Research Council. Mak reported having financial relationships with AstraZeneca, ViewRay, and others. Aerts reported having financial relationships with AstraZeneca, Ambient, Onc.AI, and others. Higgins reported having no relevant disclosures.