Eligibility criteria
Studies will be selected for review according to the eligibility criteria below.
Study design and participants
This review will include randomised control trials, observational cohort, cross-sectional and case-control studies reporting original response rate data in adult human participants. Participants will be patients with biopsy-proven oesophageal, or gastro-oesophageal junction adenocarcinoma (confirmed by histopathologist), who have been treated with neo-adjuvant chemotherapy or neo-adjuvant chemo-radiotherapy prior to surgical resection and had an early PET/CT examination (after one-cycle of neo-adjuvant therapy). (Fig. 1) Recurrent oesophageal adenocarcinoma will not be included. Studies of patients with histology other than adenocarcinoma and those who did not have an early PET/CT examination will be excluded. Studies with mixed patient cohorts will also be excluded.
PET/CT examinations
The radioactive isotope FDG must have been used for the PET/CT examination. Studies using other radioactive isotopes will be excluded but if the article contains FDG data, attempt will be made to extract these data. The SUVmax must have been measured by an appropriately trained and experienced professional. SUVmax is defined as the voxel with the highest SUV value within the tumour [18].
Treatment response
The threshold for response classification, defined in terms of the percentage reduction in SUVmax, must be pre-specified at 35%. The reference standard will be the pathological TRG, defined by validated pathological classification systems Becker [15] or Mandard [16]. Occasionally, patients will progress during neo-adjuvant therapy and no longer be suitable for surgery. Attempt will be made to capture these data also.
Searches
Electronic Searches
A comprehensive search strategy using text words and controlled vocabulary has been designed using MEDLINE (OVID). (Table 1)
Table 1. Search terms and strategy
#
|
Searches
|
1
|
Esophageal Neoplasms/
|
2
|
((oesophag* or esophag*) adj (neoplas* or adenocarcinoma or tumo?r*)).tw.
|
3
|
1 or 2
|
4
|
exp Adenocarcinoma/
|
5
|
(oesophag* or esophag*).tw.
|
6
|
4 and 5
|
7
|
3 or 6
|
8
|
Positron Emission Tomography Computed Tomography/
|
9
|
(PET-CT or PET CT).tw.
|
10
|
((early or interim or ad interim or endpoint or timepoint) adj2 (PET or FDG-PET)).tw.
|
11
|
Positron-Emission Tomography/
|
12
|
(PET or FDG-PET or 18-FDG).tw.
|
13
|
Fluorodeoxyglucose F18/
|
14
|
or/8-13
|
15
|
7 and 14
|
16
|
exp Treatment Outcome/
|
17
|
exp "Predictive Value of Tests"/
|
18
|
exp "sensitivity and specificity"/
|
19
|
exp Disease-Free Survival/
|
20
|
exp Prognosis/
|
21
|
(sensitivity or specificity).tw.
|
22
|
((treatment or therapeutic) adj1 (response or outcome*)).tw.
|
23
|
(predict* or prognos*).tw.
|
24
|
((tumo?r or metabolic) adj2 response).tw.
|
25
|
tumo?r glucose.tw.
|
26
|
(glucose adj (standard uptake or SUV)).tw.
|
27
|
Glucose/
|
28
|
or/16-27
|
29
|
15 and 28
|
30
|
limit 29 to (english language and yr="2005 -Current")
|
31
|
randomized controlled trial.pt.
|
32
|
controlled clinical trial.pt.
|
33
|
randomized.ab.
|
34
|
placebo.ab.
|
35
|
drug therapy.fs.
|
36
|
randomly.ab.
|
37
|
trial.ab.
|
38
|
groups.ab.
|
39
|
or/31-38
|
40
|
exp animals/ not humans.sh.
|
41
|
39 not 40
|
42
|
epidemiologic studies/
|
43
|
exp case control studies/
|
44
|
exp cohort studies/
|
45
|
Case control.tw.
|
46
|
exp Longitudinal Studies/
|
47
|
exp Retrospective Studies/
|
48
|
exp Prospective Studies/
|
49
|
(cohort adj (study or analys* or studies)).tw.
|
50
|
exp Follow-Up Studies/
|
51
|
(Follow up adj (study or studies)).tw.
|
52
|
exp Cross-Sectional Studies/
|
53
|
(observational adj (study or studies)).tw.
|
54
|
(Longitudinal or Retrospective or Cross sectional).tw.
|
55
|
or/42-54
|
56
|
41 or 55
|
57
|
30 and 56
|
This strategy will be translated and run in the following electronic databases: MEDLINE [OVID], Embase [OVID], Cochrane Library [Wiley], Cumulative Index of Nursing and Allied Health Literature (CINAHL) [Ebsco], Scopus [Elsevier], Web of Science [Thomson Reuter], International Clinical Trials Registry Platform (ICTRP) Search Portal [World Health Organisation] and ClinicalTrials.gov.
The search will be limited to articles published in English from 2005 onwards, because 3D PET became integrated into most PET/CT scanners providing more standardisation in SUVmax from this timepoint onwards [13]. Study filters for randomised control trials and observational study types will be applied. Reference lists of all eligible studies will be checked and undergo citation tracking for additional eligible studies.
Selection process
Following the systematic search described above, all titles and abstracts will be screened by two independent authors against the defined eligibility criteria. Duplicate items will be identified and one of the copies deleted prior to screening. Full text articles will be obtained for all studies that meet the criteria. In cases of disagreement following screening of titles and abstracts, a third author will be asked to review and decide upon the suitability of the study. Reasons for exclusion will be recorded. A flowchart will be used to summarise the numbers of included and excluded studies at each stage of the selection process.
Data management and extraction process
The results of the screening process will be shared between the reviewers using an output file that can be imported into Mendeley Desktop 1.19.4. Authors will be instructed to create a new library to keep the screened studies separate. The full-text articles will be included in the output file.
Relevant data will be extracted from the final set of eligible articles. Data will be inputted into a Microsoft Excel 365 spreadsheet designed specifically for this review (additional file 2 - SystRev_DataItems_Extraction). Two independent authors will extract the relevant data from the articles. In cases of disagreement, a third author will be asked to review the article and decide upon the data to be recorded. Articles reporting findings from duplicate sets of patients will be combined and extracted as a single study.
Data items
- Patient characteristics; number of patients included, age, gender, tumour location, neo-adjuvant regimen, pathological response rate at surgery, length of survival.
- Study characteristics; primary author, publication year, study dates, country of study, study design, number of centres, length of time between early PET and surgery, length of time between early PET and surgery, conclusions of study, risk of bias.
- PET/CT characteristics; timing of early PET/CT (days after treatment inception), type of scanner and acquisition (including PET reconstruction method), length of fasting before injection, time between FDG injection and PET, PET quantification method, interpreter(s), threshold criteria for defining response, proportion of patients with early response after one cycle of neo-adjuvant therapy.
- Diagnostic accuracy data; true positives, false positives, false negatives, true negatives, sensitivity, specificity, positive predictive value, negative predictive value.
Outcomes
The primary outcome of the systematic review will be the early response rate on PET/CT after one cycle of neo-adjuvant therapy. The secondary outcome will be diagnostic accuracy of early metabolic response, defined as the sensitivity and specificity of PET/CT to predict pathological response using the 35% SUVmax reduction threshold. The reference standard for pathological response will be the tumour regression grade (TRG). Pathological responders will be classified at pathology as having a Mandard TRG 1-2 or Becker TRG 1, and non-responders as Mandard TRG 3-5 or Becker TRG 2-3.
Quality assessment and risk of bias
The methodological quality of eligible studies will be assessed using two pre-specified quality assessment tools; the Newcastle Ottowa scale (modified for this review) [23] and the Quality Assessment of Studies of Diagnostic Accuracy Included in Systematic Reviews (QUADAS-2) criteria [24]. The Newcastle Ottowa scale will be used for the primary objective and QUADAS-2 for the secondary objective. The overall components of the quality assessment for each study will be reported using the star-rating system of the Newcastle Ottowa scale. Studies with no stars for any of the individual components of the NOS (selection, comparability and outcome assessment) will not be included in the quantitative synthesis. (additional file 3 - Modified NOS) For QUADAS-2, perceived quality will be graded low, high or unclear risk. The question “were uninterpretable and/or intermediate test results reported?” has been added to the QUADAS-2 checklist. (additional file 4 – QUADAS-2) The strength of the overall weight of evidence for both primary and secondary outcomes will be judged using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group methodology [25].
Data synthesis
If the studies are sufficiently homogenous in their design, outcome assessment and follow-up, we will conduct a meta-analysis using a random effects model (DerSimonian and Laird [26]) using the current version of R (R Foundation for statistical computing, Vienna, Austria) [27]. We will combine the percentage of patients with early metabolic response in each individual study to estimate a pooled early response rate with a 95% confidence interval (CI).
The sensitivity and specificity of early PET/CT using the 35% threshold level to define metabolic response in individual studies will be calculated and subjected to meta-analysis, if feasible. The results of the individual studies will be displayed with a receiver operator curve (ROC) curve, and a weighted symmetric summary ROC (sROC) curve with a 95% CI will be computed [28].
We will assess heterogeneity between specific study estimates using the inconsistency index (I2 statistic [29]). If heterogeneity is considerable (I2 > 75%) and the p value <0.1, quantitative data synthesis will not be performed [22]. Publication bias will be assessed by visually inspection or funnel plots [30].
We will also investigate sources of heterogeneity between studies using meta-regression subgroup analyses by stratifying original co-variates according to methodological quality (Newcastle Ottowa and QUADAS-2 score), sample size, PET injection time, neo-adjuvant therapy regimen, type of neo-adjuvant therapy and TRG classification used. The time interval between injection of FDG and scanning can affect the SUVmax of the tumour [31]. Differences in pathological response rates have been reported depending on the type of neo-adjuvant therapy used [8, 10]. Also, the effect of the TRG classification system will be explored.