Methods
Protocol and registration
The systematic review and meta-analysis was conducted under the
principles of the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses
(PRISMA) 2009 checklist (15) and registered at
Prospective Register of Systematic
Reviews (PROSPERO) (CRD42020223177). Tianjin First Central Hospital
Research Ethics Committee had confirmed that no ethical approval was
required.
Eligibility criteria
We screened literature following PICOS questions. The population
included patients with HNC; the intervention included treatment either
PD-1/PD-L1 immunotherapy alone or combining conventional therapies
(e.g., chemotherapy, radiotherapy, and cetuximab); the comparison
included standard‐of‐care therapy; the outcome included OS, PFS, AE,
ORR, and DCR; the study design included RCTs and prospective single-arm
clinical trials. The language type was English, and the types of
articles excluded were conference abstracts, reviews, letters, personal
opinions, book chapters, trial protocols, systematic reviews and
meta-analyses because of the lack of complete and reliable data.
Publications that reported duplicated data from the same clinical trials
were also excluded, and the most complete of them were included.
Information sources, search, and study selection
We searched in the electronic databases Cochrane Library, Embase,
PubMed, and Web of Science until November 20, 2020. The search
strategies were uploaded in Supplementary File 1 . Duplicate
references were removed with reference manager software (EndNote®), and
the rest of the references were personally screened. We performed the
first screen based on titles and abstracts and excluded the references
that do not meet the eligibility criteria after getting access to
full-text articles on the second screen.
Data extraction
Data from full‐text articles were extracted by us independently. Study
characteristics (the trial name, publication year, phase of studies),
baseline characteristics of patient populations (amount of participates,
amount and proportion of males, age, HPV, smoke status, Eastern
Cooperative Oncology Group (ECOG) performance status score), study
design (type and dosage of PD‐1/PD‐L1 immune inhibitors), outcomes (OS,
PFS, ORR, DCR, the median time to response, the median duration of
follow-up and response,) and amount of any‐grade and grade ≥3 AEs in the
articles were collected from individual studies.
Data synthesis and statistical analysis
OS and PFS were the primary outcomes, while the secondary outcomes
included ORR, DCR, any grade, and grade≥3 AE. Survival data from the
figures in the references were extracted by Engauge Digitizer 4.1
software(16), and ln[Hazard Ratio](ln[HR]) and Seln[HR] of
survival curves were calculated by the Microsoft Excel program file(17).
Cochrane Collaboration’s Review Manager®5.4 software (RevMan5.4) was
used to conducted meta-analyses. Inconsistency indices (I²) were used to
test the studies’ substantial amount of heterogeneity; fixed-effect
models were performed when I²≤ 50 %. Otherwise, heterogeneity was
considered among the studies, either through sensitivity analysis or
subgroup analysis to explore heterogeneous sources, and random effect
models were performed after eliminating evident clinical and
methodological heterogeneity. Summary measure was the odds ratio (OR).
P < 0.05 indicated a statistically significant difference.
Risk of bias
The risk of bias of individual studies was assessed by the Cochrane
collaboration’s Risk of Bias Tool based on the following seven domains:
selection bias, selection bias, performance bias, detection bias,
attrition bias, reporting bias, and other biases. Each risk of bias was
defined as low, unclear, or high by Xin Huang and Jie Zhang
independently.
The quality of evidence and the strengths of recommendations were
evaluated following the Grading of Recommendation, Assessment,
Development, and Evaluation (GRADE) guidelines (18, 19) through
informatics tools from GRADEpro (20) based on study design, risk of
bias, inconsistency, indirectness, imprecision, and other
considerations. Egger’s test evaluated latent publication bias in Stata
16 software.