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A hallmark of gastrointestinal cancer, especially pancreatic cancer, is the dense stromal tumor microenvironment in which cancer-associated fibroblasts (CAFs) represent the major stromal cell type. Preclinical studies have demonstrated that depletion of fibroblast activation protein (FAP)–positive CAFs results in increased survival.
We present the protocol for a systematic review and meta-analysis that aim to assess the currently available evidence on the effect of FAP expression on survival and clinical characteristics in gastrointestinal cancers.
The literature search and data analysis will be conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 statement. The databases PubMed/MEDLINE, Web of Science Core Collection, Cochrane Library, and ClinicalTrials.gov will be searched via their respective online search engines. A meta-analysis comparing patients with and without FAP overexpression with the following outcomes will be performed: postoperative survival (overall and median survival; 1-, 2-, 3-, and 5-year survival rates), histological differentiation (grading), local tumor invasion, lymph node metastases, and distant metastases. Odds ratios will be calculated for binary data, and weighted mean differences and relative SD differences will be determined for continuous data. The 95% CI, heterogeneity measures, and statistical significance will be reported for each outcome. The chi-square and Kruskal-Wallis tests will be used to evaluate statistical significance. A
Database searches will commence in April 2023. The meta-analysis will be completed by December 2023.
In recent years, several publications on FAP overexpression in gastrointestinal tumors have been published. The only published meta-analysis on this topic dates to 2015. It included 15 studies on various solid tumors and only 8 studies focusing exclusively on gastrointestinal tumors. The expected results of the present analysis will provide new evidence on the prognostic value of FAP in gastrointestinal tumors and thereby support health care professionals and patients in their decision-making.
PROSPERO CRD42022372194; https://tinyurl.com/352ae8b8
PRR1-10.2196/45176
Cancers of the gastrointestinal (GI) tract include colorectal, esophageal, liver, pancreas, and stomach cancer. These 5 major types of GI cancer represented 26% of the global cancer incidence and 35% of all cancer-related deaths in 2018 [
FAP is a type II transmembrane serine protease, which shares a high-sequence identity with dipeptidyl peptidase 4 [
To assess the currently available evidence on the effect of FAP expression on survival and clinical characteristics in GI cancers, we plan to conduct a systematic review and meta-analysis. With this research protocol, we further aim to achieve reproducibility and transparency of our meta-analysis on the published literature as previously demonstrated [
The literature search and data analysis will be conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 statement [
The databases PubMed/MEDLINE, Web of Science Core Collection, Cochrane Library, and ClinicalTrials.gov will be searched via their respective online search engines. Citavi 6 (Swiss Academic Software GmbH) will be used as an automatic deduplication system for the studies retrieved from the various databases (
Titles and abstracts will be evaluated independently in a standardized manner by 2 authors to assess eligibility for inclusion or exclusion. All the potential studies identified from the search will be coded as either “retrieve” (eligible, potentially eligible, or unclear) or “do not retrieve.” For studies coded “retrieve,” 2 reviewers will independently screen the full text and recommend inclusion or exclusion. Disagreements between the reviewers will be resolved by consensus; if no agreement can be reached, a third reviewer will decide whether to include the respective study. The reference lists of the included studies will be manually searched to find additional relevant articles.
PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flowchart.
Search strategy.
Database | Search strategy |
PubMed/MEDLINE | “surface expressed protease”[tw] OR |
Web of Science Core Collection (all fields) | (“surface expressed protease” OR |
Cochrane Library (title, abstract, keyword) | (“surface expressed protease” OR |
ClinicalTrials.gov |
Only articles in the English language will be considered. Studies comparing patients with and without FAP overexpression in GI tumors and reporting on at least one of the following a priori defined outcomes will be included: postoperative survival (overall and median survival; 1-, 2-, 3-, and 5-year survival rates), histological differentiation (grading), local tumor invasion (as defined in the included studies), lymph node metastases, and distant metastases. Review articles, case reports, case series with less than 5 patients, commentaries, and letters will not be included (
Inclusion and exclusion criteria.
|
Inclusion criteria | Exclusion criteria |
Article or study type |
Comparative observational studies Randomized controlled trials |
Reviews Case reports Case series with less than 5 patients Commentaries Letters |
Study population |
Patients with gastrointestinal tumors in which fibroblast activation protein expression was measured |
Other patients |
Reported outcomes | Any of the following: Median overall survival 1-, 2-, 3-, or 5-year survival Histological differentiation (grading) Local tumor invasion Lymph node metastases Distant metastases |
None of the outcomes mentioned as inclusion criteria |
Language |
English |
Other languages |
Data from the included studies will be extracted separately by 2 authors and stored in a dedicated database. The following descriptive data will be documented for each selected study: first author, year of publication, inclusion period of the study, country and city where the study was conducted, sample size, and mean or median follow-up time. The distribution of the following patient characteristics will be documented: tumor type, histopathological tumor stage (using the UICC [Union for International Cancer Control] TNMG [tumor, node, metastasis, grade] classification system), presence and type of neoadjuvant therapy, presence and type of adjuvant therapy, FAP detection method, FAP antibody, FAP location, number of FAP-positive cases, and cutoff for overexpression.
The following predefined outcomes will be extracted: postoperative survival (overall and median survival, 1-, 2-, 3-, and 5-year survival rates), histological differentiation (grading), local tumor invasion (as defined in the included studies), lymph node metastases, and distant metastases. Subgroup analysis will be performed for location of FAP expression (tumor stroma or tumor cells or both) and tumor type (colon cancer, esophageal cancer, gastric cancer, hepatocellular carcinoma, cholangiocellular carcinoma, pancreatic cancer, and rectal cancer).
For each observational study, the risk of bias will be assessed using the ROBINS-I (Risk of Bias in Non-randomized Studies of Interventions) tool suggested by the Cochrane Collaboration [
A meta-analysis comparing patients with and without FAP overexpression with the following outcomes will be performed: postoperative survival (overall and median survival, 1-, 2-, 3-, and 5-year survival rates), histological differentiation (grading), local tumor invasion (as defined in the included studies), lymph node metastases, and distant metastases. Random-effects models will be used. The ReviewManager (RevMan) software (version 5.4; Cochrane Collaboration) will be used. The magnitude of the effect estimate will be visualized by forest plots. Odds ratios will be calculated for binary data, and weighted mean differences and relative SD differences will be determined for continuous data. The 95% CI, heterogeneity, and statistical significance will be reported for each outcome. The chi-square and Kruskal-Wallis tests will be used to evaluate statistical significance. A
Sensitivity analyses will be conducted according to the ascertained risk of bias as described above. For these, all studies with a high or serious risk of bias will be excluded, and the analyses of the outcomes, as described above, will be conducted.
Database searches will commence in April 2023. Extraction of data from individual studies will be performed by May 2023. Data appraisal, preparation, summarization, and analysis will start in June 2023. The meta-analysis will be completed by December 2023.
This systematic review and meta-analysis will synthesize all available evidence on the clinical implications of FAP overexpression in GI tumors.
In recent years, several studies on this topic have been published. The last published meta-analysis on this topic dates to 2015 and included 15 studies about various solid tumors and only 8 studies focusing exclusively on GI tumors [
The main limitation of the present meta-analysis is that we do not expect randomized controlled trials on this topic to be available. Nevertheless, to ensure transparency and reduce the risk of bias, this review will be conducted according to the defined protocol presented here and will be reported following the recommendations stipulated in the PRISMA 2020 statement [
The expected results will provide new information on the prognostic value of FAP in GI tumors and thereby support health care professionals and patients in their decision-making, as well as aid in patient selection for multimodal cancer therapy.
α–smooth muscle actin
cancer-associated fibroblast
fibroblast activation protein
gastrointestinal
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
International Prospective Register of Systematic Reviews
Risk of Bias 2
Risk of Bias in Non-randomized Studies of Interventions
tumor, node, metastasis, grade
Union for International Cancer Control
The data sets generated during this study will be available from the corresponding author upon request.
None declared.