In recent years, significant progress has been made regarding systemic therapies for lung cancer. For patients with advanced, epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) in particular, EGFR tyrosine kinase inhibitors are widely used as the first-line therapy and provide significantly improved overall survival (OS) (1,2). However, NSCLC frequently gains resistance to these drug therapies during the course of treatment. In such cases, immune checkpoint inhibitors (ICIs) with or without chemotherapy are alternatives for treating NSCLC that is resistant to cytotoxic chemotherapies/molecular targeted therapies or does not have any EGFR mutations.

ICIs, including inhibitors of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), are widely used in patients with advanced NSCLC. However, a variety of immune-related adverse events (irAEs) after the administration of ICIs have been reported. IrAEs occur in ~45% of patients with NSCLC. Endocrine, gastrointestinal and dermatologic toxicities are common events associated with irAE (3,4). The incidence of fatal irAEs is ~1% (5).

In palliative radiotherapy (PRT), the delivered doses are lower than the maximum tolerated doses of gastrointestinal tissues [mean PRT equivalent dose in 2 Gy fractions (EQD2), 36 Gy; maximum tolerance dose of small bowel, 50 Gy; maximum tolerance dose of large bowel, 55 Gy) (6). In PRT, the delivered doses (mean PRT EQD2, 36 Gy) are lower than the maximum tolerated dose of gastrointestinal tissue. However, there is a possibility that RT toxicity in the bowel is enhanced when RT and ICIs are combined. Regarding combination therapy of PRT and ICIs, certain studies suggested that it is well-tolerated (7-9). They reported that the incidence of colitis in patients treated with PRT involving the bowel was 5% or less and gastrointestinal toxicities did not increase. However, these studies were limited by the heterogeneity of patients and treatments. Therefore, further studies on the safety of PRT and ICI combination therapy are required.

In a study of adjuvant ICIs with durvalumab after definitive chemoradiotherapy for NSCLC (PACIFIC study), adjuvant ICI therapy appeared to slightly increase the incidence of pneumonitis (statistically not significant) (10). Patel et al (11) suggested that T- and natural killer (NK) cell infiltration are enhanced in lesions treated with low-dose radiotherapy. These results suggest that activated T- and NK cells accumulate in normal tissue damaged by RT and these accumulated T- and NK cells damage the tissue further. Based on these studies, the administration of ICIs may have the potential to enhance radiation toxicity. Despite the comparatively lower dose and small irradiation field size, administration of ICIs may also increase the toxicity of PRT. To the best of our knowledge, only a small number of studies have investigated whether gastrointestinal toxicities are associated with combination therapy of PRT and ICIs (7). Therefore, the present retrospective study aimed to investigate the occurrence of radiation-induced enterocolitis (RIE) after the administration of a combination therapy of PRT and ICIs in patients with metastatic lung cancer.

A total of 45 abdominal-pelvic metastatic lesions in 38 patients with lung cancer who were treated with PRT involving the bowel and ICIs (a PD-1/L1 inhibitor and/or a CTLA-4 inhibitor) between December 2015 and June 2021 were reviewed. Of these, patients who did not undergo follow-up computed tomography (CT) after treatment (n=12) and those in whom the interval between PRT and closest administration of ICIs was more than one year (n=4) were excluded from this study. Finally, the remaining 32 lesions in 28 patients were retrospectively evaluated. This retrospective study was approved by the institutional review board (Shikoku Cancer Center, Ehime, Japan). An opt-out form of consent was used to obtain consent for this study.

PRT doses were determined at the discretion of each physician and 30 Gy in 10 fractions was the most frequently used regimen. To compare the different dose-fraction schedules, total doses of PRT were calculated with EQD2 values using an α/β ratio of 3 for the bowel. PRT was performed using 6-10 MV linear accelerators (Varian Medical Systems, Inc.) and the doses of the target volumes were ≥90% of the PRT dose in principle. The treatment of all lesions was planned using three-dimensional conformal RT.

RIE after combination therapy of PRT and ICIs was graded using the Common Terminology Criteria for Adverse Events version 5.0(12). The definition of RIE was ‘segmental and circumferential bowel wall thickening and inflammatory stranding in the area of an irradiated field occurring within 6 months after PRT on CT images’. The diagnosis of RIE was based on the patient's symptoms, physical examination and CT imaging and/or colonoscopy. The dose-volume parameters of the large and small bowel were assessed using CT simulation images. The dose-volume parameters of the large and small bowel were analyzed to determine the absolute volume cubic centimeters (cc) receiving doses from 10 to 20 Gy (V10 and V20), as well as the maximum dose to 2 cc volume (D2cc) and D2cc per fraction (D2cc/fr).

The present study indicated that the combination of PRT involving the bowel and ICIs were well tolerated by a majority of patients. However, RIE of grade 2 or higher was observed in 6.3% (2/32) of patients. In all of these cases, the interval between the administration of ICIs and the completion of PRT was within 7 days and fraction doses were >3.6 Gy (evaluated at the isocenter), and D2cc/fr ≥3.4 Gy. A clear relationship between grade 2 or higher RIE and other dose-volume parameters of the bowel was not observed in patients who received PRT in combination with ICIs. However, it was indicated that a larger fraction dose of PRT and a shorter interval between the administration of ICIs and PRT may affect the incidence of grade 2 or higher RIE.

RIE is typically associated with progressive occlusive vasculitis. Although the role of ICIs in RIE remains elusive, PRT alone, as it involves a comparatively low dose, is unlikely to cause severe RIE (6,13). Bang et al (7) reported that mild colitis was observed in 4% of the patients who received ICIs and PRT to the bowel. The present results also suggested that the incidence of enterocolitis was not high after combination therapy with PRT and ICIs. By contrast, Bang et al (7) indicated that irAEs occurred more frequently when ICIs were administered within 14 days prior to and after PRT compared to when ICIs were administered 14 days or more after PRT (statistically not significant). In the present study, patients who experienced grade 2 or higher RIE received ICIs within 7 days after the completion of PRT. Although the optimal intervals between RT and ICIs to achieve a systemic effect of RT and ICIs remained to be determined (14), the administration of ICIs immediately after PRT may also be a potential risk factor for severe RIE.

In addition, several studies suggested that moderate hypofractionated regimens (6-8 Gy per fraction) may increase the synergistic effect of ICIs (15,16). In the present study, the fraction doses (3.6 and 4 Gy per fraction) in the two patients with RIE were lower than this fraction dose. A fraction dose of >3 Gy (D2cc/fr of large bowel ≥3.4 Gy) may be associated with the risk of severe RIE with PRT and ICI combination therapy. Thus, for combination therapy with PRT and ICIs, two factors, namely the fraction dose and interval between PRT and ICIs, may be important. Furthermore, the interaction between a higher fraction dose of PRT and the interval between PRT and administration of ICIs may be significant in the development of grade 2 or higher RIE.

In addition, elevated levels and imbalance of several cytokines generally result in various symptoms in advanced cancers (17). The RT-induced inflammatory response in the bowel involves the recruitment of activated inflammatory cells (18). These immune cells synthesize and release several different cytokines, inflammatory mediators and reactive oxygen metabolites (19). In addition to the RT-induced inflammatory response, ICIs also promote the activity of immune cells and facilitate autoimmune responses against any organ (20). The combination of these two factors may lead to RIE even when PRT is administered.

In the present study, one patient (3.1%) experienced grade 4 RIE after combination therapy with PRT and ICIs. In this patient, the interaction between PRT and ICIs may have induced severe RIE. Although RIE was initially alleviated in this patient, it worsened again and grade 4 RIE was developed after the subsequent administration of ICIs. Radiation recall phenomenon is an inflammatory reaction that manifests within a previously irradiated field after the administration of a variety of pharmacological agents (21). This grade 4 RIE may have been caused by a radiation recall phenomenon associated with the subsequent administration of ICIs.

There were certain limitations to the present study owing to its retrospective nature and small sample size. Selection bias and confounding factors must also be considered. In addition, based on symptoms alone, accurate differentiation between RIE and irAE is difficult in numerous cases, as RIE and irAE enterocolitis exhibit similar symptoms. Therefore, the present study focused on the importance of CT images in addition to the symptoms of enterocolitis. Although the incidence of mild irAEs in the bowel, such as diarrhea, abdominal pain and nausea, is 12.1-13.7% for anti-PD-1 and 30.2-35.4% for anti-CTLA-4, the incidence of severe irAEs of the bowel (enterocolitis) is 0.7-1.6% for anti-PD-1, 5.7-9.1% for anti-CTLA-4 and 13.6% for the combination of both therapies (22,23). In the present study, the incidence of RIE was similar to the incidence of irAEs of the bowel. However, as the CT images of RIE (grade 2 and 4) were consistent with the irradiated fields and the histology of grade 4 RIE was not typical for an irAE of the bowel, these two cases were diagnosed as RIE. Although irAE enterocolitis and RIE may not be completely separated, the results of the present study suggested that RIE may appear even after administering PRT in combination with ICIs.

Severe RIE may at times be induced by PRT involving the bowel and ICI administration. Although further studies are required, administration of ICIs immediately after PRT with a higher fraction dose (at the isocenter) was indicated to be a risk factor for severe RIE. However, a relationship between dose-volume parameters other than D2cc/fr and RIE was not observed in the present study.