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Journal of Immunology Research
Volume 2018, Article ID 1027323, 9 pages
https://doi.org/10.1155/2018/1027323
Review Article

Risk of Immune-Related Pancreatitis in Patients with Solid Tumors Treated with Immune Checkpoint Inhibitors: Systematic Assessment with Meta-Analysis

1Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
2Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, China
3Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
4Department of Ophthalmology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
5Department of Digestive Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, China

Correspondence should be addressed to Yan-li Hou; moc.621@0370_lyh, Yu-xia Yao; moc.361@25610671731, and Bang-wei Cao; nc.ude.umcc@ygolocno

Received 17 December 2017; Revised 5 April 2018; Accepted 12 April 2018; Published 3 June 2018

Academic Editor: Takami Sato

Copyright © 2018 Qiang Su et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

We performed a systematic review and meta-analysis to determine the risk of immune-related pancreatitis associated with the treatment by immune checkpoint inhibitors (ICIs) for solid tumors. Eligible studies were selected from multiple databases including phase II/III randomized controlled trials (RCTs) with ICIs in solid tumor patients. The data were analyzed with Stata version 12.0 software. After excluding ineligible studies, a total of 15 clinical trials were considered eligible for the meta-analysis, which included 9099 patients. Compared with chemotherapy or placebo, the risk ratio (RR) for all-grade lipase elevation after CTLA-4 inhibitor treatment was 1.05 (95% confidence interval (CI): 1.01–2.24, ). However, the risk for pancreatitis after ICI treatment in any subgroup was not significantly higher than that after control therapy. In addition, compared with ipilimumab/nivolumab alone, the RR for all-grade and high-grade lipase elevation under combination treatment of nivolumab and ipilimumab was 6.43 (95% CI: 1.43–28.99, ) and 6.44 (95% CI: 1.39–29.79, ), respectively, and the RR for all-grade amylase elevation under combination treatment was 6.08 (95% CI: 1.51–24.44, ). Our meta-analysis has demonstrated that both CTLA-4 inhibitors alone and combination treatment of nivolumab and ipilimumab could increase the risk of amylase or lipase elevation, but not significantly increase the risk of pancreatitis when compared with controls.

1. Introduction

Up to now, cancers have been treated with surgery, chemotherapy, radiotherapy, and targeted molecular therapy including EGFR-TKI (epidermal growth factor receptor-tyrosine kinase inhibitor) [1]. Recently, immunotherapies involving immune checkpoint inhibitors (ICIs) include cytotoxic T lymphocyte-associated protein 4 (CTLA4) and programmed cell death protein 1 and ligand 1 (PD-1 and PD-L1) monoclonal antibodies. ICIs have emerged as a new effective treatment of advanced solid tumors such as advanced melanoma (MM), nonsmall cell lung cancer (NSCLC), and urothelial carcinoma [24]. In 2011, ipilimumab, the first ICI, has received US Food and Drug Administration (FDA) approval for the use in advanced melanoma [3, 4]. Since 2011, there have been additional five ICIs approved for the treatment of various solid tumors [2]. Unfortunately, when used both alone and combined, ICIs have generated new kinds of toxicity profiles, specifically referred to as immune-related adverse events (irAEs), which included but were not limited to thyroid dysfunction, colitis, pneumonitis, dermatitis, and hepatitis [5]. A less commonly seen irAE was immune-related pancreatitis [616]. The diagnosis of acute pancreatitis (AP) could be supported by increases of serum amylase and lipase. Values of serum amylase or lipase in excess of three times the upper limit of normal were characteristic of AP [17]. This study is conducted to evaluate the risk of immune-associated pancreatitis in cancer patients treated with ICIs. To our knowledge, this study is the first meta-analysis to report on the risk of immune-related pancreatitis under ICI treatment. We believe this meta-analysis study will improve awareness of the incidence and characteristics of immune-related pancreatitis, which may lead to more appropriate utilization of immune checkpoint inhibitors in clinical practice.

2. Methods

Our systematic review and meta-analysis was conducted according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions [18] and the PRISMA Statement [19].

2.1. Strategy of Literature Searching

Random controlled trials (RCTs) exploring CTLA-4, PD-1, and PD-L1 antibodies in solid tumors were searched on the following databases: Embase, PubMed, and ClinicalTrials.gov. RCTs conducted between January 1990 and July 2017 were included. The medical subject heading (MeSH) terms included for searching the relevant studies contained one term that refers to cancer (neoplasm, carcinoma, cancer, or tumor), one term indicating the ICIs (anti-CTLA-4, anti-PD-1, ipilimumab, tremelimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, or avelumab), and one term related to randomized controlled trials, connected by “and” (Supplementary Table 1).

2.2. Inclusion and Exclusion Criteria

Studies with the following information were included in our meta-analysis: (1) phase II/III RCTs with primary endpoints such as overall survival (OS), progression-free survival (PFS), or objective response rate (ORR); (2) histologically confirmed solid cancer such as lung cancer and melanoma (MM); (3) containing the information of ICIs and pancreatitis or amylase or lipase; and (4) sharing some similarity in experimental method across different studies.

However, studies were excluded if they were (1) reviews, duplicate reports, letters, unfinished studies, or conference reports; (2) papers in languages other than English; (3) studies where pancreatitis could not be confirmed due to insufficient data; (4) studies conducted with cell lines, animal models, or on nonsolid cancers; (5) studies whose experimental method was substantially different from other selected RCTs; and (6) RCTs in phase I.

2.3. Data Extraction

Two reviewers (Qiang Su and Yan-li Hou) independently searched all the relevant studies and read the titles, abstracts, and full texts of the identified studies. Cases of disagreement were resolved through discussion with the third reviewer (Chen-guang Zhang). The following information was extracted from the selected studies: year of publication, authors’ family names, methods of trails, number of ICI treatment type, number of control treatment, number of pancreatitis, amylase, and lipase of all grades (grades 1–5) and high grade (grades 3–5).

2.4. Data Analysis

In our meta-analysis, risk of bias analysis was performed using Review Manager 5.3 software (Cochrane Collaboration 2014, Nordic Cochrane Center, Copenhagen, Denmark). Two independent reviewers (Qiang Su and Yan-li Hou) assessed the quality of the included studies according to the Cochrane risk of bias tool. Specifically, the following seven domains were assessed: selection bias (including both random sequence generation and allocation concealment), performance bias, detection bias, attrition bias, reporting bias, and other biases. The Stata version 12.0 statistical software (Stata Corporation, College Station, Texas, USA) was used for meta-analysis. Risk ratio (RR) was used to estimate pancreatitis of grades 1–5 and grades 3–5. indicates higher risk or higher incidence of pancreatitis, amylase, or lipase in patients treated with ICIs. In addition, the statistics was used to assess the heterogeneity among the RCTs. values of <30%, 30%–59%, 60%–75%, and >75% were classified as low, moderate, substantial, and considerable heterogeneity, respectively [20]. We used the random effects model (REM) [21] to calculate pooled RR and 95% confidence interval (CI). Sources of heterogeneity were explored using subgroup analyses (different ICIs). The Begg’s and Egger’s tests were used to analyze the publication bias across RCTs. All values were 2 tailed, and a probability level < 0.05 was considered statistically significant.

2.5. Quality Assessment

Our analysis was performed by pair-wise comparisons of the ICI arms and the control arms. Among the studies (see Table 1), there were five three-arm trials [11, 13, 16, 17, 22]. During the statistical process, one arm in each three-arm RCT maybe was entered twice in our database. The number of patients in this arm, which was used twice, was divided by two to avoid an increased influence of the arm on the overall result. In addition, we paid attention to the heterogeneity among the RCTs by using subgroup analysis. REM was employed for our meta-analysis to test and verify the statistical results.
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