News release

From: Elsevier

Thymus radiation is linked to worse outcomes in patients with non-small cell lung cancer

Until recently, the thymus was thought to be of little use beyond puberty, but new research has shown that radiation to the organ is associated with worse outcomes in patients being treated for non-small cell lung cancer (NSCLC).

In a study published today (Wednesday) in the leading cancer journal Annals of Oncology [1], researchers analysed 1,107 patients with NSCLC and found that patients whose thymus was exposed to radiation during cancer treatment had an increased risk of the cancer spreading to other parts of the body (metastasising) and of dying from their disease. This association was seen only in patients whose thymus was still relatively healthy before treatment.

The findings add to the growing evidence that the thymus may remain important in adulthood, and suggests that protecting it during medical treatments may improve outcomes.

The senior author of the paper is Hugo Aerts, professor at Harvard University and director of the Artificial Intelligence in Medicine program at Mass General Brigham, Boston, USA. He explained: “The thymus is a small immune organ located in the upper chest that helps produce and train T cells, which are essential for recognising infections and fighting cancer. It is most active early in life and gradually shrinks with age when functional tissue is replaced by fat. For many years, people interpreted this as meaning the adult thymus was essentially irrelevant.”

However, recent work by the same research team, published in two back-to-back Nature papers [2], challenged that view. They found that although the adult thymus produces fewer new T cells than it does in childhood, some adults retain substantially more functional thymic tissue than others. The amount of function that remains appears to vary considerably between adults, and that variation may still have important consequences. The researchers found that this remaining thymic health was associated with greater T-cell diversity, better longevity, less cancer and improved outcomes after immunotherapy.

In the Annals of Oncology study, the researchers used artificial intelligence (AI) to analyse routine computed tomography (CT) scans to estimate the health of the thymus by examining its size, shape, density and tissue composition. A higher thymic health score indicated well-preserved thymic tissue, while a lower score indicated a thymus that was not functioning well or was damaged.

They assessed thymic health before radiotherapy started, and they also used the patients’ radiation treatment plans to calculate how much radiation had reached the thymus. As the thymus sits in the middle of the chest, it often receives radiation during treatment for lung cancer even though it is not the intended target of therapy.

The patients included 460 from a randomised, prospective, phase III trial comparing different doses of radiotherapy (60Gy versus 74Gy) with carboplatin-paclitaxel-based chemoradiotherapy, with or without the targeted therapy, cetuximab, between November 2007 and June 2013 (RTOG-0617 trial). A further 647 patients were also included who had been treated in routine clinical practice, both before and after immunotherapy became standard of care; 422 patients were treated with platinum-based chemoradiotherapy alone (HARVARD-cohort, treated between 2003 and 2014) or followed with durvalumab (the HARVARD-durva cohort, treated between 2017 and 2023).

Prof. Aerts said: “In all three patient groups, we found that higher radiation exposure to the thymus was consistently associated with a greater risk of the cancer spreading to distant parts of the body.”

This association was observed only in patients whose thymus was functioning relatively well before treatment. These patients generally had the best outcomes overall, but they were also the group most vulnerable to higher radiation doses to the thymus. Among these patients, higher thymic radiation doses were associated with a 29% higher risk of distant metastasis in the RTOG-0617 clinical trial, a 33% higher risk in the Harvard chemoradiation cohort, and a 95% higher risk in the cohort treated with chemoradiation followed by the immunotherapy drug durvalumab.

“We also found that patients who received higher thymic radiation doses showed a greater loss in thymic health one year later, supporting the idea that radiation may directly damage this immune organ. In a smaller subgroup, they also tended to have lower lymphocyte counts, which is consistent with a possible effect on immune function,” said Prof. Aerts.

“Perhaps most encouragingly, we found that protecting the thymus would not require a new treatment or new technology. Using existing radiotherapy planning techniques, radiation exposure to the thymus could often be substantially reduced without compromising treatment of the cancer or increasing radiation to other important organs. If future studies confirm that this improves outcomes, thymus-sparing could be implemented relatively rapidly in routine cancer care.”

Professor Raymond Mak, a radiation oncologist at Mass General Brigham, professor at Harvard Medical School, and co-senior author of the study, said: “Over the past several decades, radiation oncology has become increasingly successful at protecting healthy organs in the chest like the heart and lungs, while maintaining excellent cancer control. Our findings suggest the thymus may deserve consideration alongside those organs. Importantly, this can often be achieved using existing treatment-planning techniques, meaning it could potentially be adopted relatively quickly if confirmed in prospective studies.”

Although further studies are needed before a recommendation could be made about limiting the radiation dose to the thymus during cancer treatment, the researchers believe that radiation oncologists should be made aware of the findings from this study.

“The thymus is currently not routinely treated as an important organ during radiation planning in adults,” said Prof. Aerts. “More broadly, our findings raise the possibility that preserving immune health during medical treatment may become a new principle of medicine. Modern oncology increasingly depends on the patient’s immune system, particularly as immunotherapies become part of standard treatment across many cancers. As we continue to improve cancer treatment, we may need to think not only about protecting organs such as the heart, lungs and spinal cord, but also about preserving the immune system itself. If confirmed in prospective studies, the thymus could become one of the first immune organs routinely protected during treatment planning.”

Strengths of the study include the large number of patients, with many treated in the ‘real world’. This also means that differences in treatment and patient selection may be sources of bias. The patients were predominantly white and so the findings need to be validated in ethnically diverse groups of patients. The AI models were trained on a diverse collection of scans and extensively tested and validated in other studies, but further validation with different scanners and in different institutions and countries is needed before they can be used in clinics. Another important limitation is that the analysis looked at patients treated above and below a radiation dose threshold of 35Gy; the researchers say this threshold was exploratory rather than a validated clinical cut-off and should be investigated further in prospective studies.