A Systematic Review And Meta-analysis Of Immune Checkpoint Inhibitors In The Treatment Of Solid Tumors: Immune-related Pancreatic Toxicit

Background:Immunotherapy with immune checkpoint inhibitors(ICIs)has become a novel treatment for tumors when the human immune system’s ability to fight cancer is compromised.ICIs enhance the immune system’s attack on tumors by inhibiting immune checkpoint molecules,effectively suppressing tumor growth,and spread.While ICIs have shown significant therapeutic effects in some types of tumors,this treatment method can also lead to a range of adverse events(AEs),including pancreatic AEs.The pathogenesis of pancreatic AEs caused by ICIs treatment is still unclear,but some studies suggest that ICIs may trigger pancreatitis and elevated pancreatic enzymes by activating the immune system and the pancreas.Several clinical studies are currently underway to investigate potential risk factors for pancreatic AEs in ICIs treatment,such as patient age,sex,tumor type,and treatment dosage,to understand the correlation between these factors and pancreatic AEs in ICIs treatment.In addition,some studies aim to explore the pathogenesis of pancreatic AEs in ICIs treatment,such as immune cell types and activation status,pancreatic tissue structure and function,to understand the impact of ICIs treatment on the pancreas and its response mechanism.Although pancreatic AEs are not the most common side effect of ICIs treatment,their potential severity and harm have become a significant concern.Objective:This systematic review and meta-analysis aims to determine the incidence and risk of pancreatic AEs associated with ICIs therapy for solid tumors.Methods:We performed a systematic literature search in PubMed database,Embase database and Cochrane Library database from the inception to March 15,2022,for all randomized controlled trials that compared ICIs with standard treatment in solid tumors,and the studies reporting immune-related pancreatitis or elevation of serum amylase or lipase levels were included.A systematic review and meta-analysis was conducted following registration of the protocol in PROSPERO(ID:345350).For the analysis of the overall incidence of AEs,a random effect model with logit transformation was applied.All models are adapted by restricted maximum likelihood estimation with a classic continuity correction of 0.5 for zero cells and the corresponding sample sizes.The summary measures of the primary outcome were the incidence and its 95%CI.A random effects model using the Mantel-Haenszel method was used for meta-analysis,and the meta-analysis presented by pooling ORs and 95%CIs.Post-hoc analysis was performed by matching the included studies according to the mirror principle to form several mirror groups for adjusted indirect comparisons,and ORs(95%CIs)were derived from each mirror group.The statistical analyses above were all performed by R statistical software and Review Manager 5.3 software.Results:49 unique randomized controlled trials with at least one ICI-containing arm(35 089 patients)were retrieved.The incidences for all-grade pancreatitis,amylase elevation and lipase elevation were 0.93%(95%CI 0.76-1.13),2.53%(95%CI 1.74-3.65)and 2.80%(95%CI 1.78-4.39),respectively.The incidences for grade>3 pancreatitis,amylase elevation and lipase elevation were 0.68%(95%CI 0.53-0.88),1.28%(95%CI 0.90-1.83)and 1.85%(95%CI 1.24-2.73),respectively.The use of ICIs was associated with an increased risk of all-grade pancreatic irAEs including pancreatitis(OR=2.43,95%CI 1.57-3.75,P<0.0001),amylase elevation(OR=2.08,95%CI 1.50-2.88,P<0.0001)and lipase elevation(OR=1.95,95%CI 1.46-2.59,P<0.0001).The use of ICIs was associated with an increased risk of Grade>3 pancreatic irAEs including pancreatitis(OR=1.89,95%CI 1.08-3.31,P=0.03),amylase elevation(OR=2.00,95%CI 1.40-2.84,P=0.0001)and lipase elevation(OR=2.04,95%CI 1.50-2,77,P<0.0001).Subgroup analysis suggested that the risk of ICI-associated pancreatic adverse events varied in different tumor types and treatment combinations.In addition to these,the post-hoc analysis found that PD-1 inhibitors had a significant higher risk of pancreatic AEs compared with PD-L1 inhibitors and the patients undergoing dual ICI therapy were at a significantly higher risk of pancreatic AEs than the patients receiving single ICI therapy.Conclusion:The Meta-analysis in this study found that solid tumor patients undergoing treatment with ICIs may face an increased risk of pancreatic AEs such as pancreatitis,especially in the case of non-small cell lung cancer and melanoma patients.Subgroup analysis results indicate that tumor type and treatment combination also have an impact on the risk of pancreatic AEs.