Safety and potential increased risk of toxicity of radiotherapy combined immunotherapy strategy
Authors: Guan Hui , Zhou Ziqi , Hou Xiaorong , Zhang Fuquan , Zhao Jing , Hu Ke 
Published: May 2022

Accumulating interest has emerged in exploring the toxicity profiles of the combination strategy of radiotherapy (RT) and immune checkpoint inhibitors (ICIs). Much remains unknown regarding safety and the potential increased risk of toxicity of a combined treatment. ICI prolongs survival but can induce immune‐related adverse events as well. To increase awareness of adverse effect and support immediate and successful management, we go over the literature on the safety of RT combined immunotherapy strategy. Representative evidence relevant to RT combined with ICI in the brain, lung, head and neck, and pelvic malignance was reviewed respectively. Given radiation doses and fractionation, the irradiated volume, the timing of RT, and ICI would significantly affect the safety and efficiency of ICI+RT combination therapy, and no consensus had been reached about how to arrange RT delivery in the combined contexture, we went over the available literature and tried to address these challenges including the timing of RT, optimal dose and fractionations, RT target and target volume, and potential biomarkers to predict toxicity. We found even though RT+ICI combination therapy might augment toxicities, the majority of patients experienced grade 4 or 5 AE are relatively rare and no significant difference could be found between combination group and monotherapy group. Sometimes the acute toxicity with ICI is much less predictable and often life threatening and in some can give rise to permanent effects. Clinicians across disciplines should be aware of these uncommon lethal complications induced by ICI+RT. Early recognition is the key to successful treatment, reversibility of organ dysfunction, and in some cases even prevention of fatal outcome. If recognized early, managed properly, and no fatal AE occurs, the development of irAE indicates a good prognosis. It should be noted that nothing is known about potential late effects because very few studies have 5‐year follow‐up.

The nature of irAE is the attack of activated immune cells on normal tissues. The nature of RT‐induced AE is the DNA damage on normal tissue, which is related with the dose delivered and volume irradiated and the tolerance of surrounding normal tissues. The immune‐modulating effect of SBRT may augment the damage on normal tissues. To maximize the antitumor immune response, 8–12 Gy/fraction is preferred when conducting RT. The available clinical evidence suggest RT of this dose/fractionated strategy combined with ICI have a tolerable AE profile, which need further validation by more clinical trials in the future. The combination strategy of RT with anti‐PD1/PDL1 anti‐body is supposed to be concurrent or RT followed by anti‐PD1/PDL1 antibody. Although RT and ipilimumab combination sequence is controversial, ipilimumab prior to or concurrent with RT might be proper, which need more clinical validation. Under the concept of immunological dose painting, SBRT work as a trigger of immune response. It has been observed that SBRT of partially radiated tumors combined with ICI could induce similar tumor control compared with total tumor irradiation. The side effects of RT may be mitigated potentially due to the reduction of irradiated volume. The antitumor efficiency and safety profile of immunological RT dose painting+ICI deserve further investigation. Clinical predictive factors for irAE risk remain unclear, and more investigation deserves to be conducted about the irAE prediction.