The Risk Ratio of Immune-Related Colitis, Hepatitis, and Pancreatitis in Patients With Solid Tumors Caused by PD-1/PD-L1 Inhibitors: A Systematic Review and Meta-Analysis

Purpose: The meta-analysis was put into practice in evaluating the risk ratio of immune-related digestive system inflammation in patients with solid tumors caused by PD-1/PD-L1 inhibitors. Method: The process of the meta-analysis was performed by us according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Results: After screening and eligibility assessment, a total of 26 clinical trials involving 16,409 patients were selected for the final quantitative synthesis. Immune-related digestive system inflammations, including colitis, hepatitis, pancreatitis, were evaluated separately. Compared with chemotherapy, PD-1/PD-L1 inhibitors led to an increase in the incidence risk of all grade colitis (RR = 2.43, 95% CI: [1.23, 4.82], P = 0.01). Similar incidence trend could also be seen when PD-1/PD-L1 inhibitors were combined with chemotherapy (RR = 2.62, 95% CI: [1.25, 5.48], P = 0.01). Whether compared with Nivolumab plus Ipilimumab or Ipilimumab alone, the incidence risk of colitis in the Nivolumab group was significantly lower than that of the control group. Similar analysis results could also be seen in the incidence risk of hepatitis. We did not find a statistically significant effect on the incidence of immune-related pancreatitis after the use of PD-1/PD-L1 inhibitors. Conclusion: The use of PD-1/PD-L1 inhibitors increased the incidence risk of immune-related colitis and hepatitis, but this potential to increase the incidence risk of the disease was weaker than Ipilimumab.


INTRODUCTION
Immune-related digestive system inflammation, including colitis, hepatitis, pancreatitis, can be caused by a variety of pathogenic factors, such as genetic abnormality, autoimmune factors, immune-related drugs, viral infections, and so on (1)(2)(3)(4). PD-L1(B7-H1) is thought to be involved in the regulation of cellular and humoral immune responses through the PD-1 receptor on activated T and B cells (5,6). PD-1/PD-L1 inhibitors block the negative regulatory signal by inhibiting the binding of PD-1 and PD-L1, allowing T cells to restore their activity, enhancing immune response, and thereby exerting anti-tumor activity (7)(8)(9)(10). Satisfactory anti-tumor efficacy had been shown in plenty of clinical trials . However, with the increasing clinical application in different kinds of malignant diseases, more and more PD-1/PD-L1 related side toxicity effects had been reported, and immune-related digestive system inflammation was one of them .
Although the incidence rate of immune-related digestive system inflammation was not as high as myelosuppression, it had an important impact on the quality of patients lives and even the survival prognosis . Some of them, such as pancreatitis, might even jeopardize the life of patient if it was neglected in the process of therapy (13, 15-17, 20, 22, 26, 27, 30). Therefore, we should pay enough attention to immunerelated gastrointestinal inflammation in clinical work. However, due to the interference from other anti-tumor drugs, we were unable to clearly define the relationship between immune related digestive system inflammation and PD-1/PD-L1 inhibitors (15)(16)(17)(18)36). Furthermore, the combination of PD-1/PD-L1 inhibitors with other anti-tumor immunoassays, such as Ipilimumab, also increased the difficulty for our judgment (13,24,29,35).
To investigate the relationship between incidence risk of immune-related digestive system inflammation and PD-1/PD-L1 inhibitors, we performed this meta-analysis.

METHODS
The meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement (37).

Search Strategy
The PubMed website was used to identify clinical trials involving PD-1/PD-L1 inhibitors for solid tumor patients. Relevant Abbreviations: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand 1; HR, hazard ratios; RR, risk ratio; CI, confidence interval; RE, random effect; FE, fixed effect. randomized clinical trials (RCTs), reported from inception to July 31, 2019, were collected by using search keywords and Medical Subject Headings (MeSH) terms pertinent to the intervention of interest, such as cancer, tumor, PD-1/PD-L1, nivolumab, opdivo, pembrolizumab, immune checkpoint inhibitor, Keytruda, Imfinzi, MK-3475, atezolizumab, Tecentriq, MPDL3280A, avelumab, Bavencio, durvalumab, and BMS-963558. Furthermore, some RCTs that could not be found on the PubMed website were obtained by searching and checking references of other systematic reviews, meta-analyses, and conference proceedings of the American Society of Clinical Oncology, the European Society for Medical Oncology, the American Association for Cancer Research, and the World Conference on Cancers.
According to our analysis design, the inclusion criteria were as follows: (1) RCTs would be preferred choices, (2) PD-1/PD-L1 inhibitors were used as an anti-tumor therapy, (3) The treatment regimen of the control group included anti-tumor drugs or placebo, (4) All enrolled patients were diagnosed with solid tumors rather than hematological malignancies, (5) At least one of Immune-related Digestive System Inflammation (colitis, hepatitis, and pancreatitis) was reported, (6) The results of the clinical trials are reported in English or reported in other languages and English.

Data Extraction
Four investigators (Zewen Zhang, Xiaowei Yang, Donghua Li, Li Zhang) were designated to determine the eligibility and duplicate independently by checking titles and abstracts of enrolled studies. The data categories of enrolled studies were collected as follows: first author, the year of publication, study name and number, treatment regimen, number of evaluable cases, related drug name, phase stage, tumor type, incidence rate of immune-related digestive system inflammation.
Both all-grade and grade 3-5 immune-related digestive system inflammation were taken into account for the final comprehensive meta-analysis. The basic characteristics of all enrolled studies would be summarized in Table 1.

Statistical Analysis
Risk Ratio (RR) was used to assess the risk of developing immunological gastrointestinal inflammation. 95% confidence interval (CI) were calculated by random effect (RE). P<0.05 was regarded as statistically significance. Statistical tests were all twosided. Subgroup analysis would be performed according to the type of tumor, treatment plan, and specific drug name. Cochrane's Q and the I 2 statistic, proposed by Higgins and colleagues, were used for checking the heterogeneity among enrolled trials (37,38). I 2 values <25, 25-50, and >50% indicated low, medium  The evaluation indicators related to the quality of the included trials, named Newcastle-Ottawa scale, including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective outcome reporting, would be checked one by one and summarized in a figure (42). Review Manager 5.3, proposed by the Cochrane Collaboration, was used for the final comprehensive analysis.  Table 1  . Nivolumab (n = 10), Pembrolizumab (n = 10), Atezolizumab (n = 5), and Avelumab (n = 1), listed in Table 1, were used in corresponding clinical trials . Eight kind of tumors, including renal cell carcinoma (n = 1), NSCLC (n = 10), melanoma (n = 7), head-and-neck carcinoma (n = 2), triple-negative breast cancer (n = 1), SCLC (n = 2), gastric or gastro-esophageal junction cancer (n = 2), urothelial carcinoma (n = 1), were referred. Among these enrolled clinical trials, there were 1 phase I/II clinical trial, 1 phase II clinical trial, 1 phase II/III clinical trial, and 23 phase III clinical trials. Twentyfive clinical trials were reported to be randomized controlled trial (RCT), while the RCT information of 1 clinical trial was unavailable (29). Previous treatments could be found in 12 trials (14, 19-21, 23, 26, 28-30, 32-34). Publication bias, checked by Harbord's test (37), was shown in the form of funnel plots (Supplemental Figures 1-6).
The same grouping and subgroup approach as before were taken for evaluating the incidence risk of grade 3-5 hepatitis.

DISCUSSION
The hallmarks of cancer involves active evasion by cancer cells from attack and elimination by immune cells; this capability highlights the dichotomous roles of an immune system that both antagonizes and enhances tumor development and progression (43,44). Therefore, cancer can also be defined as an immune-related disease (43,44). In the field of antitumor therapy, immunosuppressants had been widely used as a new anti-tumor therapy in clinical practice, and had achieved gratifying clinical effects . With the development of anti-tumor immunosuppressants, a number of immunerelated side effects had been reported, and immune-related digestive system inflammation was one of them . PD-1/PD-L1 inhibitor is the most commonly used anti-tumor immunosuppressant in clinical practice, and it is also one of the most common immunosuppressive drugs for causing immune gastrointestinal inflammatory diseases among cancer patients . To investigate the relationship between incidence risk of immune-related digestive system inflammation and PD-1/PD-L1 inhibitors, we performed this meta-analysis.
After screening and eligibility assessment, a total of 26 clinical trials involving 16,409 patients were enrolled for the final metaanalysis . All enrolled clinical trials were considered to be of higher good quality, when study quality and risk of bias among enrolled studies were evaluated by Newcastle-Ottawa scale (42). The evaluation results of bias was shown in Supplemental Figure 8 (42). Therefore, the analysis results based on the data from the above included trials had a high degree of credibility. However, due to the small number of studies included in the individual groups, sufficient subgroup analysis was not performed, which is also a shortcoming of this study.
Through a comprehensive analysis, we found that the effect of PD-1/PD-L1 inhibitors on the risk of immune related hepatitis was roughly the same as that for immune related colitis (Figures 3, 4), while no significant statistical results were seen for the analysis of immune related pancreatitis (Figures 5, 6) (12, 15-17, 20, 22, 27, 30, 31, 36). This might be related to the low incidence of immune-related pancreatitis and the small number of patients included in the study (Figures 5, 6) (12, 15-17, 20, 22, 27, 30, 31, 36).
For drug-induced immune related digestive system inflammation of grade 3-5, stopping the use of the corresponding induced drug remained the primary treatment option (11-13, 15-20, 22-24, 26, 27, 29-36). However, due to the particularity of the tumor patient population, in clinical work, the discontinuation anti-tumor treatment should be carefully considered to prevent the sudden stop of all anti-tumor drugs leading to rapid tumor progression, endangering the lives of patients . Through the above analysis, we found that PD-1/PD-L1 inhibitors can increase the risk of developing colitis and hepatitis. Therefore, when we encountered the need to stop anti-tumor therapy to alleviate severe immune related digestive system inflammation, it was preferred to stop the PD-1/PD-L1 inhibitor . This had an important guiding significance for us to determine the cause of immune related digestive system inflammation and the adjustment of clinical treatment.

CONCLUSIONS
The use of PD-1/PD-L1 inhibitors increased the incidence risk of immune-related colitis and hepatitis, but this potential to increase the incidence risk of the disease was weaker than Ipilimumab.

DATA AVAILABILITY STATEMENT
All datasets analyzed for this study are included in the article/Supplementary Material.

AUTHOR CONTRIBUTIONS
YT had full access to all data in the study and all authors had final responsibility for the decision to submit for publication. ZZ, XY, DL, LZ, and YT had the full data of the paper. ZL, SZ, YM, CJ, and YZ were responsible for the collection of clinical data. ZZ helped to gather the online data and write the report.