REVIEW Diagnostic Evaluation of 18F-FDG PET/CT Imaging in Recurrent or Residual Urinary Bladder Cancer: A Meta-Analysis Minmin XUE, MM, Liping LIU, MB, Guanghui DU, MM, Zhigang FU, MM* Purpose: To assess the diagnostic accuracy of fluorine-18 fluorodeoxyglucose positron emission tomography combined with the computed tomography (18F-FDG PET/CT) in the detection of recurrent or residual urinary bladder cancer with meta-analysis. Methods: We searched PubMed/MEDLINE, Embase, Web of Science, CBM, CNKI, VIP, and Wanfang data- bases through October 2019. Two reviewers independently screened the full articles. The imaging findings were confirmed by either histopathology or clinical follow-up. Sensitivity, specificity likelihood ratio and diagnostic odds ratio were pooled with 95 % confidence intervals (CI). Overall test performance was summarized by a sum- mary receiver operating characteristic (ROC) curve. The Meta-DiSc software (version 1.4) was used to perform the meta-analysis. Results: The meta-analysis included 7 studies. The pooled sensitivity and specificity of PET/CT for the detection of recurrent or residual urinary bladder cancer was 94.0% (95% CI: 91.0%–96.0%) and 92.0% (95% CI: 88.0%– 95.0%), respectively. Positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio were 9.77 (95% CI: 4.91–19.41), 0.99(95% CI: 0.06–0.13) and 95.09 (95% CI: 47.96–188.53), respectively. When residual urinary bladder cancer was excluded, sensitivity changed slightly. Conclusion: This meta-analysis suggested that the diagnostic accuracy of PET/CT was good in detecting recurrent or residual urinary bladder cancer. Keywords: bladder cancer; FDG PET/CT; sensitivity; specificity; meta-analysis INTRODUCTION Bladder cancer is the most common urinary tract cancer with a high mortality rate in worldwide, in 2012 the estimated diagnosed new cases were about 430 000(1). Despite continuing advances in surgical and nonsurgical therapeutic strategies, the patients with urinary bladder cancer have higher risk of recurrence and residue. Cystoscopy is still the gold standard for the diagnosis of bladder cancer, but can still miss 10% of papillary tumors(2). Contrast-enhanced computed tomography and MRI are the commonly used imag- ing techniques for bladder cancer diagnosis, but these methods are not highly diagnostic with an accuracy rate ranged from 35% to 55% in CT and 62% to 85% in MRI(3,4). 18F-FDG PET/CT has been reported as non-invasive imaging methods for many malignancies, but it’s us- ing is limited due to the high urinary excretion activity of the bladder and ureters(5). Recently, several studies have assessed the application value of 18F-FDG PET/ CT in detection recurrence and residue of bladder car- cinoma. However, the population of bladder cancer pa- tients was small and results were inconclusive. The aim of our study was to explore the diagnostic accuracy of 18F-FDG PET/CT in the detection of recurrent or resid- ual bladder cancer by a meta-analysis. Department of Health Management Center, 983 Hospital of Joint Logistics Support Force, Tianjin, 300142, China. *Correspondence: Health Management Center, 983 Hospital of Joint Logistics Support Force, 60 Huangwei Road, Hebei District, Tianjin, China. Tel: (022)84683128, Fax: (022)84683128, Email: fuzhigang983@126.com. Received August 2019 & Accepted December 2019 METHODS Literature search strategy We performed a comprehensive search from the elec- tronic literature databases of PubMed/MEDLINE, Em- base, Web of Science, and Chinese databases (CBM, CNKI, VIP, and Wanfang database). The search was performed from the earliest available date of indexing to October 2019. Our search strategy included terms of “PET, positron emission tomography”, “FDG, fluoro- deoxyglucose” and “bladder cancer”. Two authors in- dependently screened articles. We also scanned refer- ences of articles which were included in the study. Data collection and analysis All included studies based on the following criteria: (i) adult patients with primary bladder cancer; (ii) using 18F-FDG PET/CT for detecting the recurrence and residue of bladder lesions; (iii) definite histological or follow-up outcome; (iv) studies providing the num- ber of true-positive, true-negative, false-positive, and false-negative. The exclusion criteria were as follows: (i) the total num- ber of true positives, false positives, true negatives, and false negatives was not provided; (ii) abstracts, reviews, editorials, comments and letters. Urology Journal/Vol 17 No. 6/ November-December 2020/ pp. 562-567. [DOI: 10.22037/uj.v0i0.5538 ] Data extraction and quality assessment The following information: first author’s name, pub- lication year, country of the study population, patients’ characteristics (number of patients, mean age, gender), study design (retrospective or perspective), doses of 18F-FDG and furosemide, reference test (histopathol- ogy or clinical follow-up was ascertained as the golden standard, all imaging findings were confirmed by either histopathology or clinical follow-up.), imaging time, sensitivity and specificity data were retrieved. Two re- viewers independently reviewed articles and disagree- ments were resolved by consensus after re-evaluation 18F-FDG PET/CT for bladder cancer-Xue et al. Review 563 Study Year Country Patients, Sex Age Image Reference Design Furosemide FDG dose n (M/F) (years) time test S Harkirat (13) 2010 India 22 - - Dual phase: 1 h after PA or FU R 0.5 mg/kg of 370 MBq FDG injection; 60-90 furosemide (10 mCi) min after furosemide Yang Z (14) 2012 China 35 28/7 Mean:56 1 h after FDG PA or FU R - 7.4 MBq/kg 35-96 injection; additional pelvic images: unknown Yildirim- 2013 Turkey 51 42/9 Mean:63.6 Dual phase: 1 h PA or FU R 0.5 mg/kg of 0.15 mCi/kg Poyraz N (15) 32-78 after FDG furosemide injection; 30-45 min after furosemide Li H (16) 2014 China 84 - - Dual phase: 1 h PA or FU R furosemide 270-350 MBq after FDG 40 mg injection; 2 h after furosemide Kitajima K (17) 2016 Japan 83 66/17 Mean:69.7 1 h after FDG PA, FU or RI R - 4.0 MBq/kg 36-88 injection Alongi P (18) 2016 Italy 41 36/5 Mean± SD Dual phase: 1 h PA or FU R - 3.7MBq/Kg 67 ± 10 and 90–120 min after FDG injection Zattoni F (19) 2017 Italy 287 223/64 Mean± SD 1 h after FDG PA or FU R - 3-3.8 MBq/Kg 69 ± 10 injection Table 1. Characteristics of the selected studies R: retrospective; PA: pathology; FU: follow-up including physical examination, laboratory tests, and serial imaging, such as CT or MRI. Figure 1. Flow chart showed detail information for eligible studies selection. Vol 17 No 06 November-December 2020 564 of the references. Research quality was assessed using the standards of the QUADAS-2 tool(6), which was de- veloped as a validated tool for diagnostic studies. The QUADAS-2 consists of four domains: (1) patient selec- tion, (2) index test, (3) reference standard and (4) flow and timing. Those indexes describe the quality of the included studies and heterogeneity. The egger test was not conducted as included studies were less than 10. Statistical analysis We reported data based on the guidelines of meta-anal- ysis evaluating diagnostic tests. Sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR–) and diagnostic odds ratio (DOR) had been presented. It is commonly used to add 0.5 to all counts in the table automatically when zero values exist(7). Pooled sensitivity and specificity also displayed with 95% confidence intervals. I2 index was used to evalu- ate heterogeneity between included studies. A summary receiving operator characteristics (ROC) curve and area under the curve (AUC) were used to testify the overall accuracy of 18F-FDG PET/CT based on selected stud- ies. All meta-analyses were performed using the Me- ta-DiSc software (version 1.4)(8). RESULTS Literature Review A total of 316 publications about FDG PET/CT for re- current or residual urinary bladder cancer was eligible for inclusion. After reviewing the titles, abstracts and full texts, 305 studies were removed (Figure 1). Of the remaining 11 studies, 1 study was excluded by review- ing the full text because of unclear classification(9), 2 studies were excluded since the test was conducted only in the patients who were confirmed recurrent or residual urinary bladder cancer (10,11). Besides 1 study(12) was ex- cluded from our meta –analysis because 2 studies were from the same team, one in English and one in Chinese. Although the sample quantities of the two articles were different, the final valid data were the same, and we fi- nally chose the English article. Therefore, 7 studies(13-19) finally met the inclusion criteria. The information of the included studies was listed in Table 1 and Table 2. Qualitative analysis (systematic review) Among the 7 included publications, 6 studies were pub- lished in English and 1 study in Chinese. Those includ- ed studies were conducted in five different counties. The sample size ranged from 22 to 287. All the studies were retrospective, included a valid reference test, and the imaging time was 1 hour after the FDG injection. Furosemide was used in 3 of the selected studies, and 5 studies used additional pelvic delayed imaging to better show bladder lesions. The graph of QUADAS-2 dis- plays the evaluation of the risk of the bias and concerns regarding applicability of those selected study (Figure 2). In current study, no obviously bias was observed. Quantitative analysis (meta-analysis) 603 patients included in the 7 studies had bladder le- sions. Pooled sensitivity and specificity were calculated by a random effects model. The sensitivity was 0.94 (95 % CI, 0.91 to 0.96, Q=7.73, P = 0.2588), and speci- ficity was 0.92 (95 % CI, 0.88 to 0.95, Q=25.13, P = 0.0003) (Figures 3 and 4). The overall LR+, LR– and DOR were 9.77 (95% CI: 4.91–19.41), 0.09 (95% CI: 0.06–0.13) and 95.09 (95% CI: 47.96–188.53), with the Q value of 12.20, 3.94 and 5.53 respectively (all P > 0.05). The SROC curve represents a global test perfor- mance which is based on the combination of sensitivity and specificity. The Q* index is defined as the maxi- mum joint sensitivity and specificity, where the proba- bilities are equal for sensitivity and specificity. Figure Table 2. Diagnostic accuracy data of 18F-FDG PET/CT imaging in recurrent or residual urinary bladder cancer author year Recurrence or Residue Recurrence TP FP TN FN TP FP TN FN S Harkirat (13) 2010 13 0 7 2 13 0 7 2 Yang Z (14) 2012 11 3 20 1 11 3 20 1 Yildirim-Poyraz N (15) 2013 30 2 19 0 Li H (16) 2014 22 3 57 2 22 3 57 2 Kitajima K (17) 2016 8 0 75 0 8 0 75 0 Alongi P (18) 2016 20 1 17 3 20 1 17 3 Zattoni F (19) 2017 189 11 38 11 189 11 38 11 Figure 2. Methodological evaluation according to QUADAS-2 of the included studies. 18F-FDG PET/CT for bladder cancer-Xue et al. Review 565 5 showed the SROC curves of 18F-FDG PET/CT for recurrent or residual urinary bladder cancer. The Q* in- dex was 0.9197. The AUC was 0.9699, indicating that the overall accuracy was relatively high. Subgroup analysis When residual urinary bladder cancer was excluded, sensitivity changed slightly while there was no change in specificity. The pooled sensi- tivity of PET/CT for the detection of recurrent urinary bladder cancer was 93.0% (95% CI: 90.0–96.0%). Pos- itive likelihood ratio was 10.66. DISCUSSION Medical imaging technologies played a critical role in clinical oncology. Clinicians could locate where a tu- mor is with the help of molecular imaging that can vis- ualize the expression and activity of specific molecules which are very important to the future of patients(20,21). Accurate assessment of the recurrence and/or residue of bladder lesions is critical for follow-up treatment of bladder cancer patients. Usually, CT and MRI are widely used in the disease surveillance after bladder preservation therapy(22). Residual or recurrent lesions are difficult to be identified morphologically due to the shape change of the bladder wall after treatment(23). PET/CT plays an important role in the diagnosis, stag- ing and therapy monitoring of malignant diseases(24), and can generally detect the activity of biological tum- ors (11). In urinary tumors, FDG-PET/CT has been used to accurately assess lymph nodes or distant metastases, but is rarely used to image recurrent or residual lesions (25-27), primarily due to the high concentration of FDG in the urine(28). In order to improve 18F-FDG PET/CT imaging, several strategies such as adequate hydration, bladder irrigation and forced diuresis with furosemide have been used to delay PET/CT imaging of bladder tumors(29,30). We identified 7 studies comprising 603 patients and the pooled sensitivity and specificity of 18F-FDG PET/CT Vol 17 No 05 September-October 2020 437 Figure 3. Sensitivity for 18 F-FDG PET/CT in detection of recurrent or residual urinary bladder cancer. Figure 4. Specificity for 18 F-FDG PET/CT in detection of recurrent or residual urinary bladder cancer. 18F-FDG PET/CT for bladder cancer-Xue et al. Vol 17 No 06 November-December 2020 112 for the detection of recurrent or residual urinary blad- der cancer was 94.0% and 92.0%, respectively. Among those studies, 5 of 7 studies used additional pelvic de- layed imaging in order to better show bladder lesions (13-16,18). The results showed a relatively high sensitivity and specificity. The Q value (0.9197) which represents the highest common value of sensitivity and specificity and the AUC (0.9699) which is the area under ROC curve demonstrate that 18F-FDG PET/CT is accurate diagnostic methods for the detection of recurrent or re- sidual urinary bladder cancer. Thus, 18F-FDG PET/CT has an accurate and effective diagnostic performance for recurrent or residual urinary bladder cancer. Our meta-analysis has some limitations. All forms of meta-analyses cannot avoid publication bias. For exam- ple, non-significant or negative studies are often reject- ed and conference abstracts, letters to journal studies were excluded in our meta-analysis. We rechecked all documents in the search stage, including conference pa- pers, and find that no conference abstracts, letters meet the inclusion criteria. Considering the methodological evaluation according to QUADAS-2, publication bias was not obviously in current analysis. Besides, lan- guage existed because the studies which we searched were published in English or Chinese only, so studies published in other languages would be omitted. Second, several studies had small sample size. Furthermore, het- erogeneity in elements such as study design, imaging techniques and quality of the selected studies existed. 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