Lung cancer is the main cause of cancer-related death globally, and novel therapeutic approaches are required to enhance patient outcomes. “Programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors “are a promising class of drugs that have demonstrated effectiveness in the treatment of advanced NSCLC (1). These agents function by preventing PD-1 and PD-L1 from interacting., which are proteins expressed on immune cells and tumor cells, respectively. This interaction suppresses the immune system and allows cancer cells to evade immune surveillance. By blocking this interaction, PD-1 and PD-L1 inhibitors activate the immune system to target and destroy cancer cells.

PD-1 inhibitors, such as pembrolizumab and nivolumab, and PD-L1 inhibitors, such as durvalumab and atezolizumab, have been approved for the treatment of NSCLC based on the results of randomized clinical trials. These studies have shown that PD-1 and PD-L1 inhibitors can improve progression-free survival and overall survival in NSCLC patients compared to standard of care therapies (2–4). However, the effects of PD-1 and PD-L1 inhibitors on clinical imaging indices in lung cancer have not been well-established (5, 6).

To address this knowledge gap, we conducted a meta-analysis and systematic review of the literature to assess the effects of PD-1 and PD-L1 inhibitors on clinical imaging indices in lung cancer. Our primary research question was: What is the effect of PD-1 and PD-L1 inhibitors on clinical imaging indices in lung cancer? This review is important because understanding the effects of these treatments on clinical imaging indices can inform the use of these agents in clinical practice and guide future research.

There have been several meta-analyses and systematic reviews that have evaluated the effectiveness of PD-1 and PD-L1 inhibitors in the treatment of lung cancer. However, to our knowledge, this is the first meta-analysis and systematic review to specifically assess the effects of these treatments on clinical imaging indices in LC. Previous reviews have focused on outcomes such as overall survival and progression-free survival (2–5), while our review expands on this literature by examining the impact of PD-1 and PD-L1 inhibitors on clinical imaging indices such as tumor response and progression. Our review also includes a broader range of studies, including both randomized controlled trials and observational studies, whereas some previous reviews have only included randomized controlled trials. Overall, our review adds to the existing evidence on the use of PD-1 and PD-L1 inhibitors in LC by providing a comprehensive assessment of their effects on clinical imaging indices.

The study analyzed the incidence and types of immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICIs) for non-small cell lung cancer (NSCLC). A total of 2383 articles were identified through database searching, but only 17 of them were selected for analysis based on certain criteria (7–19, 21–24), such as the type of therapy used, the number of patients, and the duration of follow-up.

The baseline characteristics of the selected studies were grouped according to various factors, including the number of patients receiving first-line or subsequent ICI treatment, the type of therapy used, and the duration of follow-up ( Table 2 ; Figure 1 ).

The incidence of irAEs was found to be more prevalent in patients receiving first-line treatment for NSCLC compared to those receiving subsequent treatments. This difference was statistically significant (p<0.001) for both high and low-grade irAEs. This means that the likelihood of experiencing an irAE was significantly higher for patients receiving first-line treatment compared to those receiving subsequent treatment.

The most common irAEs in the clinical studies were pneumonitis, thyroiditis, and colitis. Less common irAEs were hepatitis, pancreatitis and pancolitis.

The outcome data for the 17 included articles is presented in Table 3 . This data provides further information about the characteristics of the studies and the patients included in the analysis.

The study also looked at the prevalence of specific irAEs, such as pneumonitis, colitis, and SCAD, in different subgroups of patients. The results were as follows:

Pneumonitis: A meta-analysis of 10 studies (n=1543) shows prevalence of pneumonitis-related adverse effects, The degree of heterogeneity in the interpretation of the forest plot is high, as indicated by the I2 value of 89.1% and the significant p-value in the test of heterogeneity (p < 0.0001) Figure 2 . Possible publication bias was determined by visual inspection of a funnel plot Figure 3 and the egger test conducted Table 4 .

Colitis: A meta-analysis of 6 studies (n=720) showed the pooled prevalence of colitis-related adverse effects The degree of heterogeneity in the interpretation of the forest plot for colitis is substantial, as indicated by the I2 value of 84.5% and the significant p-value in the test of heterogeneity (p < 0.0001). Figure 4 .

Segmental Colitis associated with diverticulosis (SCAD): A meta-analysis of 2 studies (n=190) showed the pooled prevalence of SCAD-related adverse effects compared to controls or other subgroups. SCAD forest plot shows low heterogeneity (I2 2.2%, p=0.3119). Small, significant effect size seen (0.0187 common effect, 0.0188 random effects, 95% CI: 0.0024 to 0.0461). Figure 5 .

Meta-analysis of thyroiditis prevalence shows high heterogeneity (I2 93.5%, p<0.0001). 4 studies (n=415, 62 events) combined, proportion 0.1989 (95% CI [0.0611, 0.3864]) using random effects model Figure 6 .

Other irAEs (e.g., hepatitis, pancreatitis): No statistical analysis was presented for these irAEs, so it is not clear how the prevalence of these events compared to controls or other subgroups.

Age and prior treatment with radiotherapy were found to be determinant factors in the overall association with irAEs. This means that these factors may have influenced the likelihood of experiencing an irAE.

One study indicated a high incidence of checkpoint inhibitor pneumonitis, although it is not clear how this incidence compares to other studies or subgroups.

The main findings of the study were that the incidence of irAEs was more prevalent in patients receiving first-line treatment for NSCLC compared to those receiving subsequent treatment and that the most common irAEs were pneumonitis, hypothyroidism, hyperthyroidism, and skin reactions. This suggests that the likelihood of experiencing an irAE may be higher in patients receiving their first course of ICI treatment for NSCLC. This finding is consistent with previous research on the incidence of irAEs in patients treated with ICIs, which has also found a higher incidence in patients receiving first-line treatment compared to those receiving subsequent treatment (8, 20).

The study also found that the prevalence of specific irAEs, such as pneumonitis, colitis, and SCAD, varied across different subgroups of patients. For example, the meta-analysis of 10 studies (n=1543) found a significantly higher prevalence of pneumonitis-related adverse effects compared to controls or other subgroups (p<0.01, statistically significant heterogeneity with I2 testing at 89%). This means that the likelihood of experiencing pneumonitis as an irAE was significantly higher in the subgroup of patients included in these ten studies compared to controls or other subgroups. On the other hand, the meta-analysis of 2 studies (n=190) found a low prevalence of SCAD-related adverse effects compared to controls or other subgroups (p>0.01, statistically non-significant heterogeneity). This indicates that the likelihood of experiencing SCAD as an irAE was not significantly different in the subgroup of patients included in these two studies compared to controls or other subgroups. The incidence of thyroiditis was also high in many trials, as reported by Park et al. (2020), with many patients presenting with thyrotoxicosis and subsequently developing hypothyroidism (8). Thyroiditis is hard to diagnose because sometimes it presents as a normal progression of cancer, and in some cases, it is entirely asymptomatic. If the patient is not closely monitored or thyroid-stimulating hormone (TSH) is not checked regularly, the symptoms may go unnoticed, leading to severe, sometimes irreversible consequences due to under diagnosis. Therefore, clinicians must stay vigilant and make sure patients continue with clinical imaging to detect the slightest change in thyroid function to manage the side effects better. Immune-related thyroiditis is seen via Positron Emission Tomography, abbreviated as (PET) CT, and presents as new fluorodeoxyglucose (FDG) uptake in the thyroid gland. Park et al. (2020) noted that even though the routine CT scans are not very specific, there was a change in the heterogeneous enhancement of the gland when immune checkpoint therapy was started, which calls for further evaluation (8).

The finding that the prevalence of specific irAEs varies across different subgroups of patients highlights the importance of considering patient-specific factors in the management of irAEs. For example, clinicians may need to be more vigilant in monitoring and managing irAEs in patients at higher risk of experiencing these events, such as those with a higher prevalence of pneumonitis.

In addition to the type of ICI treatment received and the specific type of irAE, the study found that age and prior treatment with radiotherapy were determinant factors in the overall association with irAEs. This suggests that these factors may influence the likelihood of experiencing an irAE and should be considered in the management of these events.

One study included in the analysis indicated a high incidence of checkpoint inhibitor pneumonitis (23), although it is not clear how this incidence compares to other studies or subgroups. Pneumonitis is a potentially serious irAE that can have significant impacts on treatment outcomes and patient quality of life. Therefore, it is important for clinicians to be aware of the potential for pneumonitis in patients treated with ICIs and to implement appropriate monitoring and management strategies.

Overall, the results of this study highlight the importance of considering the potential for irAEs in patients treated with ICIs for NSCLC and the need for careful monitoring and management of these events. The finding that the incidence of irAEs is higher in patients receiving first-line treatment and that the prevalence of specific irAEs varies across different subgroups of patients underscores the need for personalized approaches to the management of irAEs, taking into account the unique characteristics and needs of each patient. Future research should focus on identifying strategies to mitigate the impact of irAEs on treatment outcomes and improve the quality of life of patients experiencing these events.

The role of imaging in the management of irAEs was also discussed in the article. All imaging studies included in the analysis were performed after nivolumab discontinuation and before starting subsequent therapy and were included as irAEs can occur months or even years after treatment discontinuation. One study example had patients developing irAEs that were radiologically notable, with an average onset time of about seven weeks. The study found that imaging can be useful in the diagnosis and management of irAEs, as it can help to identify specific patterns and changes associated with these events.

In the examination of the results, it is essential to consider several limitations inherent in the present study. Primarily, the majority of the studies incorporated in this review were retrospective cross-sectional investigations, which hold the potential to introduce biases into the outcomes. This potential bias was evidenced by the funnel plot and Egger’s test results, suggesting the presence of publication biases. Moreover, the studies demonstrated considerable heterogeneity, which may impact the generalizability of the findings. Thus, when interpreting the results, it is crucial to account for the possibility of heterogeneity, given the nature of the studies included in this review. Despite these limitations, the analysis sheds light on various aspects of the research question and provides valuable insights for future investigations.

The present study provides important insights into the incidence and types of irAEs in patients treated with ICIs for NSCLC and the role of imaging in the management of these events. These results highlight the need for careful monitoring and management of irAEs to ensure the best possible outcomes for patients treated with ICIs for NSCLC.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

NM and ZX conceived the presented idea, while RZ and E-HX developed the theoretical framework. NM and SM performed the analytical methods. All authors contributed to the discussion of the results and the final manuscript, and provided their approval of the submitted version.