Information sources

We will search Wanfang Database, SinoMed, China National Knowledge Infrastructure (CNKI), Embase, Web of Science, Pubmed, and Cochrane Library for relevant articles that may be eligible for inclusion published before July, 2021. We will also identify other articles from the review’s references that meet the criteria. We will also search the unpublished clinical trials of neoadjuvant immunotherapy in esophageal cancer in preprint website (such as bioRXiv and medRxiv) up to July, 2021.

Search strategy

The two reviewers (Guocan Yu and Wenfeng Yu) will use the keywords or subject terms corresponding to medical subject heading (MeSH) terms to design search strategies for each database and perform searches in each database to identify eligible articles. No language restrictions will be applied in the search process. The search strategies for PubMed are showed as follows:

#1 "Immunotherapy"[Mesh] OR Immunotherapies OR

#2 "Programmed Cell Death 1 Receptor"[Mesh] OR “PD-1 Protein” OR “PD 1 Protein” OR “PD-1 Receptor” OR “PD 1 Receptor” OR “Receptor, PD-1” OR “Antigens, CD279” OR “CD279 Antigens” OR “CD279 Antigen” OR “Antigen, CD279” OR “PD1 Receptor” OR “Receptor, PD1” OR “Programmed Cell Death Protein 1” OR “Programmed Cell Death 1 Protein”

#3 "Immune Checkpoint Inhibitors"[Mesh] OR “Checkpoint Inhibitors, Immune” OR “Immune Checkpoint Inhibitor” OR “Checkpoint Inhibitor, Immune” OR “Immune Checkpoint Blockers” OR “Checkpoint Blockers, Immune” OR “Immune Checkpoint Blockade” OR “Checkpoint Blockade, Immune” OR “Immune Checkpoint Inhibition” OR “Checkpoint Inhibition, Immune” OR “PD-L1 Inhibitors” OR “PD L1 Inhibitors” OR “PD-L1 Inhibitor” OR “PD L1 Inhibitor” OR “Programmed Death-Ligand 1 Inhibitors” OR “Programmed Death Ligand 1 Inhibitors” OR “CTLA-4 Inhibitors” OR “CTLA 4 Inhibitors” OR “CTLA-4 Inhibitor” OR “CTLA 4 Inhibitor” OR “Cytotoxic T-Lymphocyte-Associated Protein 4 Inhibitors” OR “Cytotoxic T Lymphocyte Associated Protein 4 Inhibitors” OR “Cytotoxic T-Lymphocyte-Associated Protein 4 Inhibitor” OR “Cytotoxic T Lymphocyte Associated Protein 4 Inhibitor” OR “PD-1 Inhibitors” OR “PD 1 Inhibitors” OR “PD-1 Inhibitor” OR “Inhibitor, PD-1” OR “PD 1 Inhibitor” OR “Programmed Cell Death Protein 1 Inhibitor” OR “Programmed Cell Death Protein 1 Inhibitors” OR “PD-1-PD-L1 Blockade” OR “Blockade, PD-1-PD-L1” OR “PD 1 PD L1 Blockade”

#4 #1 OR #2 OR #3

#5 "Esophageal Neoplasms"[Mesh] OR “Esophageal Neoplasm” OR “Neoplasm, Esophageal” OR “Esophagus Neoplasm” OR “Esophagus Neoplasms” OR “Neoplasm, Esophagus” OR “Neoplasms, Esophagus” OR “Neoplasms, Esophageal” OR “Cancer of Esophagus” OR “Cancer of the Esophagus” OR “Esophagus Cancer” OR “Cancer, Esophagus” OR “Cancers, Esophagus” OR “Esophagus Cancers” OR “Esophageal Cancer” OR “Cancer, Esophageal” OR “Cancers, Esophageal” OR “Esophageal Cancers”

#6 "Neoadjuvant Therapy"[Mesh] OR “Neoadjuvant Therapies” OR “Therapy, Neoadjuvant” OR “Neoadjuvant Treatment” OR “Neoadjuvant Treatments” OR “Treatment, Neoadjuvant” OR “Neoadjuvant Radiotherapy” OR “Neoadjuvant Radiotherapies” OR “Radiotherapy, Neoadjuvant” OR “Neoadjuvant Radiation Treatment” OR “Neoadjuvant Radiation Treatments” OR “Radiation Treatment, Neoadjuvant” OR “Treatment, Neoadjuvant Radiation” OR “Neoadjuvant Radiation Therapy” OR “Neoadjuvant Radiation Therapies” OR “Radiation Therapy, Neoadjuvant” OR “Therapy, Neoadjuvant Radiation” OR “Neoadjuvant Radiation” OR “Neoadjuvant Radiations” OR “Radiation, Neoadjuvant” OR “Neoadjuvant Systemic Therapy” OR “Neoadjuvant Systemic Therapies” OR “Systemic Therapy, Neoadjuvant” OR “Therapy, Neoadjuvant Systemic” OR “Neoadjuvant Systemic Treatment” OR “Neoadjuvant Systemic Treatments” OR “Systemic Treatment, Neoadjuvant” OR “Treatment, Neoadjuvant Systemic” OR “Neoadjuvant Chemotherapy” OR “Chemotherapy, Neoadjuvant” OR “Neoadjuvant Chemotherapies” OR “Neoadjuvant Chemotherapy Treatment” OR “Chemotherapy Treatment, Neoadjuvant” OR “Neoadjuvant Chemotherapy Treatments” OR “Treatment, Neoadjuvant Chemotherapy” OR “Neoadjuvant Chemoradiotherapy” OR “Chemoradiotherapy, Neoadjuvant” OR “Neoadjuvant Chemoradiotherapies” OR “Neoadjuvant Chemoradiation Therapy” OR “Chemoradiation Therapy, Neoadjuvant” OR “Neoadjuvant Chemoradiation Therapies” OR “Therapy, Neoadjuvant Chemoradiation” OR “Neoadjuvant Chemoradiation Treatment” OR “Chemoradiation Treatment, Neoadjuvant” OR “Neoadjuvant Chemoradiation Treatments” OR “Treatment, Neoadjuvant Chemoradiation” OR “Neoadjuvant Chemoradiation” OR “Chemoradiation, Neoadjuvant” OR “Neoadjuvant Chemoradiations” OR “pre-surgical” OR “presurgical” OR “pre-operative” OR “preoperative” OR neoadjuvant

#7 #4 AND #5 AND #6

The SinoMed, Wanfang Database, CNKI, Embase, and Cochrane Library search strategies will be similar to Pubmed.

Eligibility criteria

Study selection

Endnote X9.2 software will be used to manage the articles obtained by searching the relevant databases. In the first step, two reviewers (Guocan Yu and Wenfeng Yu) will independently filter duplicate articles through Endnote and exclude them, then exclude articles that do not meet the inclusion criteria by investigating the title and abstract, and finally screen the full text of remaining articles to finalize the eligible articles. If there are disagreements between the two reviewers, a discussion with the third reviewer (Liwei Yao) will be conducted as a way to resolve the disagreements.

Data extraction

The same two reviewers (Guocan Yu and Wenfeng Yu) as in the study selection phase will independently extract the necessary data from the articles included. Cross-check will be done to find controversial data and resolve by discussing with a third author (Liwei Yao).

The following data from the included articles will be extracted: first author name, year of publication, countries, article type, clinical trial, registration number, study phase, masking, main inclusion criteria, type of pathology, the ICI drug, ICIs dose, programmed cell death-ligand-1 [PD-L1]/ programmed cell death 1 [PD-1] expression levels in tumoral and immune cells, expected inclusion, size of sample, male, median age, MPR, pCR, incidence of TRAE, surgical resection rate, incidence of surgical complication, and surgical delay rate.

Risk of bias

Two authors (Guocan Yu and Wenfeng Yu) will independently assess the risk of bias of each article included. The Cochrane Handbook for Systematic Reviews of Interventions will be used for the evaluation of the risk of bias [20]. We will assess the risk of bias according to the following ranges: selection bias, performance bias, detection bias, attrition bias, reporting bias, and other biases. Each domain will be assessed as high, low or uncertain risk of bias. The risk of bias graph will be reported to demonstrate the results and details of assessment.

Statistical analysis

We will use Review Manager software, version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) for statistical analysis of the meta-analysis. We will calculate pooled risk ratios (HRs) for MPR, pCR, incidence of TRAE, surgical resection rate, incidence of surgical complication, and surgical delay rate with comparative binary data in RevMan 5.3. HR with 95% confidence interval (CI) will be the effect measures. The statistical heterogeneity between studies will be evaluated by the Q-statistic [21]. The P-value of the Q-statistic < 0.1 or an I² > 50% will be considered as statistically significant heterogeneity between studies [22]. Data will be analyzed using a fixed-effects model if the heterogeneity is insignificant and a random-effects model if the heterogeneity is significant [23]. A P < 0.05 was considered statistically different.

Publication bias

We will use funnel plots and Egger test to assess publication bias when more than 10 eligible articles are included [24]. If publication bias is suspected in a study, we will consult the corresponding author for more information. If publication bias does exist, we will use the fill and trim method to further analyze publication bias in the studies.

Evidence evaluation

We will evaluate all the strength of the body of evidence according to The Grading of Recommendations Assessment, Development and Evaluation (GRADE) guideline [25]. The quality of evidence will be classified into 4 levels: high, moderate, low, and very low.