FACULTY
OF
M EDIC INE – U NIVERSITY
OF
P ORTO
Department of Biostatistics and Medical Informatics
Introdução à Medicina 2005/2006
A SYSTEMATIC REVIEW OF THE VALIDITY OF
ENDOSCOPIC ULTRASOUND IN GASTRIC
CARCINOMA STAGING
Dourado, M
Bastos, J
[email protected]
[email protected]
Leite, M
Pereira, MM
Marinho, M
Bernardes, MJ
[email protected] [email protected]
Pereira, S
Machado, C
[email protected] [email protected] [email protected] [email protected]
Armas, MI
Rego, MT
[email protected]
[email protected]
Faria, MJ
Ribeiro, MJ
[email protected] [email protected]
Adviser: Ribeiro, MD, Adviser’s e-mail: [email protected], Class: Class 15
Abstract
Background: Endoscopic ultrasound (EUS) may be used for preoperative staging of gastric carcinoma.
However, as performance values of EUS given in the literature differ, it is not considered a standard
procedure. Aim: To perform a systematic review of the validity of EUS in gastric carcinoma staging,
according to the TNM system. Methods: Article search was performed using Medline and Scopus
databases. The abstracts and then the full papers of the included articles were retrieved and reviewed
independently by two reviewers, according to predefined inclusion and exclusion criteria. Disagreement
between reviewers was solved by consensus. Tables were constructed for study quality assessment, using
the STARD checklist, and 2×2 contingency tables were completed for estimation of sensitivities and
specificities. Three thresholds were considered in T staging − T1vsT2T3T4, T1T2vsT3T4, T1T2T3vsT4 −
and one in N staging − N0vsN+. Forest plots were used to assess studies consistency. Results: Fourteen
articles were analyzed. For T staging, T1vsT2T3T4 threshold provided the most consistent and best the
pooled sensitivity of 0.96 (95% CI: 0.95-0.97) for a specificity of 0.90 (95% CI: 0.87-0.93), whereas
T1T2T3vsT4 provided the best pooled specificity of 0.97 (95% CI: 0.95-0.98) for a sensitivity of 0.40
(95% CI: 0.35-0.46). For N staging, pooled sensitivity and specificity were, respectively, 0.77 (95% CI:
0.73-0.80) and 0.76 (95% CI: 0.72-0.80). Conclusions: EUS has high sensitivity and specificity in
detection of early gastric carcinoma (T1) and low sensitivity but high specificity in excluding advanced
invasion (T4 and N+). Thus, EUS may have a role in gastric carcinoma staging, namely for early stage
detection or in precluding surgery when invasion of major organs is present.
Keywords: Gastric carcinoma; TNM staging; Endoscopic ultrasound.
Introduction
Though the incidence of gastric cancer is declining worldwide, it still remains the
second most common cause of cancer-related death in the world. Typically, gastric
cancer is asymptomatic when is at an early stage, the majority of patients presenting in
advanced stage, with a still very high mortality rate. [1]
Staging of gastric cancer is important in designing the strategy of treatment. Early
gastric cancer can be treated by minimally invasive therapy, whereas advanced gastric
cancer should be treated by surgery and/or chemotherapy. [2] The generally accepted
describing method for the extent of cancer is the anatomically based TNM (Tumor,
Node, Metastases) staging system, which classifies the cancer as to its local, regional
and distant extent. [3]
Endoscopic ultrasound (EUS) may be used for preoperative staging of gastric
carcinoma, namely as it allows the definition of T and N parameters. However, as
performance values given in the literature differ, it is not considered a standard
procedure. [4]
In 2001, Kelly et al. performed a systematic review of EUS performance in gastrooesophageal carcinoma staging. [2] The aim of this study is to perform an updated
systematic review of the validity of EUS in gastric carcinoma staging, according to the
TNM system.
Methods
Study design and data sources
A systematic review was conducted using Medline and Scopus databases. To retrieve
indexed papers on the validity of EUS in gastric carcinoma staging the following query
was used based on MeSH terms and on a previously validated query: [5]
(((((((((((sensitivity and specificity OR sensitivity and specificity/standards) OR
specificity) OR screening) OR false positive) OR false negative) OR accuracy) OR
((((predictive value OR predictive value of tests) OR predictive value of tests/standards)
OR predictive values) OR predictive values of tests)) OR ((reference value OR
reference values) OR reference values/standards)) OR (((((((((((roc OR roc analyses)
OR roc analysis) OR roc and OR roc area) OR roc auc) OR roc characteristics) OR roc
curve) OR roc curve method) OR roc curves) OR roc estimated) OR roc evaluation))
OR likelihood ratio) AND human) Field: All Fields, Limits: 10 Years, Humans,
MEDLINE
2
AND "Endosonography"[MeSH]
AND ("Stomach Neoplasm"[MeSH] AND "Neoplasm Staging"[MeSH]) NOT
"Lymphoma"[MeSH]
Study selection
The abstracts retrieved in the Medline and Scopus search and then the included full
papers were reviewed independently by two reviewers, regarding predefined inclusion
and exclusion criteria:
Inclusion criteria
English, French and Spanish written papers considering the validity of EUS versus
surgical specimens in patients with gastric carcinoma;
Exclusion criteria
Papers without explicit reference to TNM classification or that did not supply sufficient
information to construct 2x2 contingency tables of results were excluded as well as
papers that were not found on MedLine or Scopus databases or at IPO or FMUP
libraries.
Only abstracts and full papers satisfying the criteria were considered for further
analysis. Any disagreement between reviewers was solved by consensus.
References lists of each paper included were hand searched. When necessary, namely
for the completeness of data to be extracted, the authors of the selected papers were
contacted for further information.
Data extraction
Tables were constructed for data extraction regarding study quality assessment, using
the Standards for Reporting of Diagnostic Accuracy (STARD) [6], to extract data
related to the number of participants, year of procedure, ultrasound instrument brand
and frequency, number of operators (Table 1) and T and N stages (Table 2). Twenty
five was considered the best STARD score possible.
Statistical Analysis
To assess the validity of EUS, two main parameters were analysed: sensitivity and
specificity. Sensitivity refers to the proportion of ill individuals whose test is positive.
Specificity regards the proportion of non ill individuals whose test is negative. For each
paper and for final pooled analysis, three different thresholds were considered for T
staging and one threshold for N staging. The first T threshold considered T1 stage a
negative diagnosis and the other T2, T3 and T4 stages positive diagnosis. On the
second T threshold, both T1 and T2 stages were considered as negative diagnosis,
3
whereas T3 and T4 stages were considered as positive diagnosis. Finally on the third T
threshold, only the T4 stage was regarded as a positive diagnosis. For the N staging, N0
stage was considered a negative diagnosis and N+ stages positive diagnosis.
Forest plots[7] were drawn to assess the heterogeneity between the studies, using the
Meta-Disc® 1.2 software (Figures 1 and 2). The threshold that minimised both
understaging and overstaging was considered the most appropriate. Ninety five percent
confidence intervals (95% CI) were calculated when appropriate.
Results
Fourteen articles were included and analyzed. Table 1 shows the year of procedure,
number of cases, ultrasound instrument features, number of operator and STARD score,
for each article included in the study. The median number of participants in each study
was 114 with a minimum of 22 and a maximum of 1120. The publication year ranged
between 1993 and 2004. The type of instruments varied considerably. The STARD
score ranged between 13 and 21. Table 2 and Figures 1 and 2 show the consistency,
sensitivities and specificities of EUS in T and N staging of gastric carcinoma for each
article considered in the study and final pooled analysis. Considering T1 vs T2 T3 T4,
sensitivities were high, varying between 0.88 and 1.00 with a pooled sensitivity of 0.96,
whereas specificities varied between 0.50 and 1.00 with a pooled specificity of 0.90.
The values were more heterogeneous for specificity. However, heterogeneity was
observed for both sensitivity and specificity (p<0.05). Considering T1 T2 vs T3 T4,
sensitivities varied between 0.74 and 1.00 with a pooled sensitivity of 0.90, whereas
specificities varied between 0.76 and 1.00 with a pooled specificity of 0.92.
Heterogeneity was observed for both sensitivity and specificity (p<0.05). Considering
T1 T2 T3 vs T4, sensitivities varied between 0.09 and 1.00 with a pooled sensitivity of
0.40, whereas specificities varied between .40 and 1.00. The values were more
heterogeneous for sensitivity. However, heterogeneity was observed for both sensitivity
and specificity (p<0.05). Considering N staging sensitivities varied between 0.54 and
0.96 with a pooled sensitivity of 0.77, whereas specificities varied between 0.55 and
0.93 with a pooled specificity of 0.76. Heterogeneity was observed for both sensitivity
and specificity. In summary, for T staging, T1vsT2T3T4 threshold provided the most
consistent and best pooled sensitivity of 0.96 (95% CI: 0.95-0.97) for a specificity of
0.90 (95% CI: 0.87-0.93), whereas T1T2T3vsT4 provided the best pooled specificity of
0.97 (95% CI: 0.95-0.98) for a sensitivity of 0.40 (95% CI: 0.35-0.46). For N staging,
4
pooled sensitivity and specificity were, respectively, 0.77 (95% CI: 0.73-0.80) and 0.76
(95% CI: 0.72-0.80).
Table 1. Year of procedure, number of participants, ultrasound instrument features, number of operator
and STARD score, for each article included in the study.
5
Table 2. Authors, year of publication, sensitivities and specificities, with 95% confidence intervals, regarding T and N staging of gastric carcinoma using EUS for each
article considered in the study. For T staging, three thresholds were considered: T1vsT2T3T4, T1T2vsT3T4 and T1T2T3vsT4.
T staging
T1 vs T2 T3 T4
N staging
T1 T2 vs T3 T4
T1 T2 T3 vs T4
N0 vs N+
Article
Sensitivity%
(95% CI)
Specificity%
(95% CI)
Sensitivity%
(95% CI)
Specificity%
(95% CI)
Sensitivity%
(95% CI)
Specificity%
(95% CI)
Sensitivity%
(95% CI)
Specificity%
(95% CI)
Dittler, HJ, 1993 [8]
98 (95-99)
96 (78-100)
92 (87-96)
86 (76-93)
70 (50-86)
98 (95-99)
96 (92-99)
55 (46-65)
Grimm, H, 1993 [9]
94 (90 – 97)
90 (74-98)
78 (66-87)
96 (90-99)
9 (5-13)
40 (5-85)
87 (77-94)
79 (67-88)
Hunerbein, M, 1998 [10]
88 (64-99)
100 (48-100)
80 (44-97)
100 (74-100)
-
-
-
-
Wang, JY, 1998 [11]
96 (89-99)
68 (48-84)
90 (80-96)
86 (75-94)
53 (29-76)
93 (86-97)
74
73
Fujino,Y 1999 [12]
88 (81-94)
99 (96-100)
93 (86-97)
99 (96-100)
98 (88-100)
100 (99-100)
-
-
Kuntz, C, 1999 [13]
100 (95-100)
100 (66-100)
74 (60-85)
100 (89-100)
100 (54-100)
95 (87-99)
89 (77-96)
82 (63-94)
Nakamura, K, 1999 [14]
-
-
-
-
-
-
38 (14-68)
83 (59-96)
Schlick, T, 1999 [15]
89 (81-95)
100 (77-100)
90 (79-97)
76 (61-87)
33 (1-91)
99 (94-100)
-
-
Tseng, LJ, 2000 [16]
97 (89-100)
100 (74-100)
100 (91-100)
89 (73-97)
86 (42-100)
94 (85-98)
74 (58-87)
86 (70-95)
Willis, S, 2000 [17]
98 (93-100)
57 (29-82)
80 (69-89)
91 (79-98)
76 (55-91)
96 (89-99)
91 (80-97)
84 (72-92)
Hunerbein, M, 2003 [18]
98 (88-100)
82 (65-93)
92 (74-99)
96 (87-100)
-
-
-
-
Xi, WD, 2003 [19]
100 (88-100)
50 (1-99)
96 (78-100)
78 (40-97)
100 (48-100)
89 (71-98)
54 (25-81)
74 (49-91)
Hunerbein, M, 2004 [20]
97 (83-100)
78 (52- 94)
100 (79-100)
97 (84-100)
-
-
-
-
Javaid, G, 2004 [21]
100 (98-100)
81 (62-94)
94 (89-97)
82 (72-90)
73 (58-93)
97 (93-98)
56 (48-63)
93 (84-98)
6
Figure 1. Forest plots of the analysis of sensitivity and specificity of EUS in T staging of gastric
carcinoma, for each article included in the study, considering different thresholds: T1vsT+, T1T2vsT3T4
and T4 vsOthers
7
Figure 2. Forest plots of the analysis of sensitivity and specificity of EUS in N staging of gastric
carcinoma, for each article included in the study,
Discussion
EUS for preoperative T and N staging of gastric carcinoma may not yet be used with
confidence as performance values given in the literature still differ. [4]. Several reasons
have been presented for these discrepancies, namely difficulties in passing ultrasound
probes through stenosed lesions, as stated in the systematic review by Kelly et al. [2]
Other reasons may be related with the ultrasound instrument, diagnostic technique or
threshold values used in the analysis of sensitivity and specificity.
In this study, we present an updated systematic review of the validity of EUS in gastric
carcinoma staging, according to the TNM system, introducing new aspects in the
analysis of this issue. The STARD study quality assessment was used, Forest plots were
developed and sensitivity and specificity analysis were performed using all the possible
threshold levels for T staging.
As other authors, we found lack of some information, less than good quality of many
studies and heterogeneity for the values of sensitivity and specificity revealing poor
consensus about the validity of EUS. However, analysis of T staging using different
thresholds provided new interesting insights. For T staging, T1vsT2T3T4 threshold
8
provided the most consistent and the best pooled sensitivity of 0.96 (95% CI: 0.95-0.97)
for a specificity of 0.90 (95% CI: 0.87-0.93), whereas T1T2T3vsT4 provided the best
pooled specificity of 0.97 (95% CI: 0.95-0.98) for a sensitivity of 0.40 (95% CI: 0.350.46). For N staging, pooled sensitivity and specificity were, respectively, 0.77 (95%
CI: 0.73-0.80) and 0.76 (95% CI: 0.72-0.80). This supports the use of EUS for very
early stage detection or in precluding surgery when invasion of major organs is present.
This is in agreement with other authors [11,13,19] but our finding of more consistent
and valid threshold values between T1vsT2T3T4 and T1T2vsT3T4, for early or late
stage detection, respectively, rather than between T1T2vsT3T4, as proposed by others
[2] opens new perspectives.
Some limitations of our study should be particularly mentioned. Bibliographic search
was restricted to the Medline and Scopus and only papers whose abstract were available
in these databases were considered for inclusion. However, considering that these are
major databases we doubt that a significant number of articles could be obtained
extending the search to other databases. Also, a language restriction was made,
considering only English, French and Spanish written articles. Yet again, this didn’t
seem to be a limitation of the study as only a few papers were excluded, based on this
criterion, and so it is most likely to consider that it would not affect the results obtained.
Though it may not be considered a limitation of this study, the lack of information about
the operator, frequency, instrument used and the year of procedure in many of the
papers included constituted a limitation in the analysis carried out in our study as it not
allow a conclusive subgroups analysis.
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