ESTRO meets Asia 2024 Congress Report

Clinical and experimental studies support the concept of synergism between immune checkpoint blockade therapies and radiotherapy in several cancer types. Nonetheless, this therapeutic effect may be dependent on treatment sequencing, radiotherapy fractionation and cancer type. It is uncertain whether the combination of immunotherapy and radiation leads to increased risks of the occurrence of adverse events (AEs) that are related to either therapy. Currently, the common immunotherapeutic agents that are used in clinics are anti-PD1/PD-L1 and anti-CTLA4 antibodies, and these agents can cause class-specific AEs that are broadly categorised as “transient” AEs such as arthritis, colitis and reactive dermatitis, and “burnout” AEs such as hypophysitis and thyroiditis. The mechanisms that underpin the occurrence of these AEs include tumour- and host-specific risk factors, such as tumour-specific cross reactivity, tumour and host neoantigen homology, host genetics, and cytokine release.

The notion that the combination of immune checkpoint blockade therapy and radiotherapy could lead to increased occurrence of AEs stemmed partly from observations of systemic immune activation among immune responders who underwent stereotactic body radiotherapy (SBRT). Our group had reported that SBRT of metastases in patients who had responded to immunotherapy led to a proliferation of peripheral circulating CD8 and CD4 T-cells, and that this proliferation was enhanced upon resumption of immunotherapy. Such observations raise the possibility that systemic immune activation after combinatorial radio-immunotherapy could lead to the simultaneous potentiation of anti-tumour activity and of immune- or radiotherapy-related AEs.

On this note, several large, randomised phase II-III trials, such as that into combination of immune checkpoint blockade therapy with stereotactic ablative radiotherapy (iSABR) (Chang et al., 2023) and conventional chemoradiotherapy to treat locally advanced head and neck cancer (JAVELIN HN) (Lee et al. 2021), have not reported incremental increases in numbers of AEs with combinatorial treatment. This sentiment is in line with real-world experience of combining these agents with stereotactic radiosurgery of brain metastases, in which investigators have not reported higher incidences of radiation necrosis post-treatment. A meta-analysis by Sha and colleagues in 2020, which was based on a comparative analysis of 12 radio-immunotherapy studies and 35 studies on immune checkpoint blockade therapies, led to similar conclusions, although the use of immune checkpoint blockade before radiation reported the highest proportion of AEs, and irradiation of the lungs seemed to potentiate the onset of AEs such as pneumonitis. Nonetheless, the latter was not found during several trials of the application of radio-immunotherapy in advanced lung cancers, such as the PACIFIC and iSABR trials and the European Thoracic Oncology Platform’s NICOLAS study.

All things considered, it is reasonable to conclude that current data do not suggest a substantial increase in the occurrence of either immune- or radiotherapy-related AEs when immunotherapy and radiotherapy are combined, although sequencing may play a role here, especially among extreme responders to immunotherapy who may be susceptible to exacerbated AEs with the addition of radiation. Tissue microenvironment may also be a relevant factor. Admittedly, the bulk of the evidence has been generated in the era of immune checkpoint blockade therapy, and with the increasing interest in exploration of dual and triplet combinations of other immunotherapeutic classes added to an anti-PD1/PD-L1/CTLA4 backbone, it is prudent to avoid extrapolation of existing safety data to more complex radio-immunotherapy combinations.

Associate professor Melvin L.K. CHUA
Head and senior consultant, Department of Head and Neck and Thoracic Radiation Oncology
Duke-NUS Medical School
National Cancer Centre
Singapore