This study revealed that the presence of pre-existing non-fibrotic ILAs was an independent risk factor of early-onset ICI-ILD induced by ICI monotherapy. To our best knowledge, this is the first study report on the relationship between a subcategory of ILAs and the onset time of ICI-ILD. In the present study, ILAs accounted for 21.6% (57/264) of study patients. Fibrotic ILAs accounted for 16.3% and non-fibrotic ILAs account for 5.3% of the study patients. Before administering ICIs to patients with ILAs, we should estimate their risk of developing ICI-ILD. Estimating the risk of ICI-ILD is especially important for patients with non-fibrotic ILAs.
Previous studies determined that the presence of GGAs, not including fibrotic area, was a risk for conventional chemotherapy and immunotherapy-related ILD (15, 16, 22). We also found that the presence of non-fibrotic ILAs was an independent risk factor for early-onset ICI-ILD. GGA reflects inflammation by lymphocytes in the interstitium, and ICIs exert antitumor effects via activation of lymphocytes (15, 16, 22). These results may explain why GGAs were involved with ICI-ILD (15, 16, 22).
This study found that the combination of an ICI and chemotherapy did not lead to early-onset ICI-ILD, even in patients with nonfibrotic disease. This is the first report on the combination of ICI and chemotherapy, as previous reports have only focused on ICI monotherapy (15, 16). The combination of ICI and chemotherapy may be less likely to result in ICI-ILD, even in patients with pre-existing ILAs, compared to ICI monotherapy alone. We previously reported that the incidence of irAEs, especially pneumonitis, during the first 3 months after the start of treatment was significantly higher in patients receiving ICI monotherapy than in the patients receiving a combination of ICI and chemotherapy (23).
The mechanism by which chemotherapy suppresses the development of ICI-ILD remains unclear. The reduced rate of ICI-ILD might be accounted for by the steroids administered during chemotherapy. Steroids are the most common basic treatment for ICI-ILD. In addition, the myelosuppression induced by chemotherapy could suppress inflammation through the regulation of soluble immune mediators.
In older individuals (> 60 years of age) the prevalence of ILAs has been reported to be 4–9% of smokers and 2–7% of nonsmokers (12). However, in patients with lung cancer, the prevalence of ILAs has been reported to be 14–22% (15, 24–27). In this study, 57 patients (21.6%) had ILAs, which is consistent with the prevalence reported in previous studies (15, 24–27). Based on the above, just as idiopathic pulmonary fibrosis and other ILDs (27–29), patients with ILAs may be prone to complications from lung cancer. Additionally, the presence of nonfibrotic ILAs was seen in 5.3% of all of our study patients (264 patients). Nonfibrotic ILAs account for 24.6% of the total ILAs. Other studies have reported that the presence of nonfibrotic ILAs accounted for 53.8–67.6% of all the patients with ILAs (15, 16), results that are much higher than observed in our study. It should be noted that lung cancer tends to be a complication of ILAs, and it includes nonfibrotic ILA, which is a risk for ICI-ILD.
The present study has some limitations. First, ICI-ILD was not diagnosed by histopathological examinations. Second, this study was a retrospective single-center study. Third, patients included in our study received heterogeneous regimens. Fourth, the number of ILA patient was small within the ICI-ILD group. Fifth, this study lacks evaluation of HRCT by a radiologist. A prospective multicenter study is warranted to validate the present findings. In conclusion, the presence of nonfibrotic ILAs was a significant risk factor for early-onset ICI-ILD in patients about to undergo ICI monotherapy. The presence of ILAs is more likely to be associated with lung cancer then the absence of ILAs, and early-onset ICI-ILD can interfere with the treatment of lung cancer and can be life-threatening. Clinicians should bear in mind the possible presence of ILAs, especially nonfibrotic ILAs, in patients with lung cancer, before they decide to administer ICIs.