Online Appendices: GA-MRI for Secondary Liver Lesions

Online Supplemental Material

Manuscript: Comparative diagnostic accuracy of gadoxetic acid (Gd-EOB-DTPA) enhanced MR imaging and contrast enhanced CT for the detection of liver metastases: A systematic review and meta-analysis

Authors: Thomas D Vreugdenburg,1 PhD, Ning Ma,1 BHSc, BMaCompSc, Joanna K Duncan,1 PhD, Dagmara Riitano,1 BHSc (Hons), Alun L Cameron,1 PhD, Guy Maddern,1,2 MBBS, PhD

1Australian Safety and Efficacy Register of New Interventional Procedures – Surgical, Royal Australasian College of Surgeons, Adelaide, South Australia, Australia

2Discipline of Surgery, University of Adelaide and The Queen Elizabeth Hospital, Adelaide, South Australia, Australia

Corresponding author info:

Dr Thomas Vreugdenburg, ASERNIP-S

199 Ward Street, North Adelaide, SA 5006, Australia.

Email:

Contents

Online Supplemental Material 1

Appendix A – Search strategy 2

Appendix B – QUADAS-II criteria 4

Appendix C – Quality appraisal of change in management studies 5

Appendix D – Extracted diagnostic accuracy outcomes 6

Appendix E – Excluded studies 8

Online Appendices Reference List 77

Appendix A – Search strategy

Table 1 Search strategy

Search criteria / Search terms /
Population / liver[MeSH Terms] OR liver OR liver neoplasms[MeSH] OR Carcinoma, hepatocellular[MeSH] OR “focal lesions”
Intervention / Primovist OR Eovist OR Gd-EOB-DTPA OR “Gadolinium ethoxybenzyl dimeglumine” OR “Disodium gadoxetate” OR “Gadoxetic acid” OR “gadoxetic acid disodium” OR “gadoxetate disodium” OR “gadolinium ethoxybenzyl DTPA” OR gadolinium ethoxybenzyl DTPA [Supplementary Concept] OR
“Gadoxetic acid-enhanced MRI” OR “liver-specific agent” OR “contrast enhanced” OR “contrast-enhanced”
AND
MRI OR Magnetic Resonance Imag* OR Magnetic Resonance Imaging[MeSH Terms] OR DCE-MRI OR CE-MRI OR “magnetic resonance” OR “contrast-enhanced MRI” OR “contrast enhanced MRI”
Comparator(s) / N/A
Outcomes / N/A
Search limits / Primovist was first referenced in the literature in 1991, therefore the search dates will be restricted to studies published since 1991.

Table 2 Bibliographic databases searched

Database with link to resource / Period covered
Cochrane Library / 1991 - 2015
PubMed / 1991 - 2015
EMBASE / 1991 - 2015
Current Contents Connect / 1991 - 2015
TRIP database / 1991 - 2015
The University of York Centre for Reviews and Dissemination / 1991 - 2015

Table 3 Electronic internet databases searched

Database with link to resource / Period covered
National Health Service (NHS) Evidence / 1991 - 2015
National Guideline Clearinghouse / 1991 - 2015
NZ Guideline Group / 1991 - 2015
Guidelines International Network / 1991 - 2015
BMJ best practice / 1991 - 2015
Current Controlled Trials metaRegister / 1991 - 2015
Australian New Zealand Clinical Trials Registry / 1991 - 2015
ClinicalTrials.gov / 1991 - 2015
MBS / N/A
AIHW Hospital data / 1991 - 2015
Royal Australasian College of Radiologists / 1991 - 2015
American College of Radiology / 1991 - 2015
Radiological Society of North America / 1991 - 2015

Table 4 Health technology assessment Internet sites

Agency for Healthcare Research and Quality
Institute for Clinical and Economic Review (ICER)
The Canadian Agency for Drugs And Technologies in Health (CADTH)
NICE (NHS)

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Online Appendices: GA-MRI for Secondary Liver Lesions

Appendix B – QUADAS-II criteria

1. Was a consecutive or random sample of patients enrolled?

2. Was a case-control design avoided?

3. Did the study avoid inappropriate exclusions?

4. Is there concern that the included patients do not match the review question?

5. Were the index test results interpreted without knowledge of the results of the reference standard?

6. Were the index test results interpreted without knowledge of the results of a comparator test?

7. If a threshold was used, was it pre-specified?

8. Were the comparator test results interpreted without knowledge of the results of the reference standard?

9. Were the comparator test results interpreted without knowledge of the results of the index test?

10. If a threshold was used, was it pre-specified?

11. Is the reference standard likely to correctly classify the target condition?

12. Were the reference standard results interpreted without knowledge of the results of the index test?

13. Were the reference standard results interpreted without knowledge of the comparator test?

14. Was there an appropriate interval between index test(s) and reference standard? (<30 days)

15. Did all patients receive a reference standard?

16. Did patients receive the same reference standard?

Were all patients included in the analysis?

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Appendix C – Quality appraisal of change in management studies

Table 3 Quality appraisal of direct evidence and change in management studies

Study (Author, Year) / A. Were the eligibility criteria specified? / B1. Was randomisation performed adequately? / B2. Was treatment allocation concealed? / C. Were the groups similar at baseline? / D. Were the index and control interventions explicitly described? / E. Were co-interventions avoided or comparable? / F. Was the patient blinded to the intervention? / G. Was the provider blinded to the intervention? / H. Was the outcome assessor blinded to the intervention? / I. Were the outcome measures relevant? / J. Were adverse events described? / K. Was the withdrawal/dropout rate described and acceptable? / L1. Was a short-term follow-up measurement performed? / L2. Was a long-term follow-up measurement performed? / M. Was the timing of the outcome assessment comparable in both groups? / N. Was the sample size for each group described? / O. Did the analysis include an intention-to-treat analysis? / P. Were point estimates and measures of variability presented for the primary outcome measures? / Internal validity (score from 10) / External validity (score from 6) /
Cho et al. (2015) (1) / ü / NA / NA / ü / ü / ü / NA / NA / X / ü / X / ü / ü / ü / ü / ü / NA / ü / 4 / 5
Kim et al. (2015) (2) / ü / NA / NA / ü / ü / ü / NA / NA / ü / ü / X / ü / ü / X / ü / ü / NA / ü / 5 / 4
Patel et al. (2014) (3) / ü / NA / NA / ü / ü / ü / NA / NA / X / ü / X / ü / ü / X / ü / ü / NA / ü / 4 / 4
Zech et al. (2014) (4) / ü / ü / ü / ü / ü / ü / NA / NA / X / ü / X / ü / ü / ü / ü / ü / NA / ü / 6 / 5

NA = Not applicable or not possible because of the nature of the intervention

Internal validity criteria: B, E, F, G, H, I, K, M, O; External validity criteria: A, C, D, J, L; Statistical criteria: N, P

Internal validity: good ≥8, moderate 7-5, poor <5. External validity: good ≥ 5, moderate 3-4, poor<3

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Appendix D – Extracted diagnostic accuracy outcomes

Table 6 Per-lesion diagnostic accuracy of GA-MRI and CE-CT

Study (reference) / Index Test / Sensitivity (n) / Specificity (n) / PPV (n) / NPV (n)
Chan et al. 2012 (5) / GA-MRI / 0.962 (51/53) / N/A / 0.910 (51/56) / N/A
CE-CT / 0.717 (38/53) / N/A / 0.880 (38/43) / N/A
Kim et al. 2015 (2) / GA-MRI* / 0.952 (99/104) / N/A / 0.892 (99/111) / N/A
CE-CT* / 0.846 (88/104) / N/A / 0.727 (88/121) / N/A
Kim et al. 2012 (6) / GA-MRI* / 0.973 (107/110) / 0.980 (49/50) / 0.991 (107/108) / 0.942 (49/52)
CE-CT* / 0.791 (87/110) / 0.980 (49/50) / 0.989 (87/88) / 0.681 (49/72)
Lee et al. 2013 (10) / GA-MRI* / 0.869 (119/137) / 0.802 (81/101) / 0.856 (119/139) / 0.818 (81/99)
CE-CT* / 0.518 (119/137) / 0.772 (78/101) / 0.755 (71/94) / 0.542 (78/144)
Motosugi et al. 2011 (9) / GA-MRI† / 0.935 (58/62) / N/A / 0.983 (58/59) / N/A
CE-CT† / 0.742 (46/62) / N/A / 0.979 (46/47) / N/A
Muhi et al. 2011 (7) / GA-MRI / 0.949 (56/59) / N/A / 0.982 (56/57) / N/A
CE-CT / 0.634 (71/112) / N/A / 0.959 (71/74) / N/A
Patel et al. 2014 (3) / GA-MRI / 1.000 (56/56) / N/A / 0.875 (56/64) / N/A
CE-CT / 0.804 (45/56) / N/A / 0.957 (45/47) / N/A
Scharitzer et al. 2013 (8) / GA-MRI† / 0.917 (88/96) / N/A / 0.898 (88/98) / N/A
CE-CT† / 0.833 (80/96) / N/A / 0.909 (80/88) / N/A
Schulz et al. 2015 (11) / GA-MRI / 0.900 (126/140) / 0.866 (175/202) / 0.824 (126/153) / 0.926 (175/189)
CE-CT / 0.679 (95/140) / 0.941 (190/202) / 0.888 (95/107) / 0.809 (190/235)

CE-CT = contrast-enhanced computed tomography. GA-MRI = gadoxetate-enhanced magnetic resonance imaging. TP = true positive. FP = false positive. TN = true negative. FN = false negative. PPV = positive predictive value. NPV = negative predictive value. AUC = area under the curve. NR = not reported. N/A = not applicable.

* results averaged across two readers

† results averaged across three readers

Table 7 Per-lesion diagnostic accuracy of GA-MRI and CE-CT for lesions smaller than 10mm

Study (reference) / Index Test / Sensitivity (n) / Specificity (n) / PPV (n) / NPV (n)
Kim et al. 2015 (2) / GA-MRI* / 0.857 (24/28) / N/A / 0.727 (24/33) / N/A
CE-CT* / 0.500 (14/28) / N/A / 0.326 (14/43) / N/A
Lee et al. 2013 (10) / GA-MRI* / 0.810 (64/79) / 0.773 (58/75) / 0.790 (64/81) / 0.795 (58/73)
CE-CT* / 0.266 (21/79) / 0.827 (62/75) / 0.618 (21/34) / 0.517 (62/120)
Motosugi et al. 2011 (9) / GA-MRI† / 0.905 (38/42) / N/A / 0.974 (38/39) / N/A
CE-CT† / 0.619 (26/42) / N/A / 0.963 (26/27) / N/A
Muhi et al. 2011 (7) / GA-MRI / 0.923 (24/26) / N/A / 1.000 (24/24) / N/A
CE-CT / 0.260 (13/50) / N/A / 0.929 (13/14) / N/A
Scharitzer et al. 2013 (8) / GA-MRI† / 0.806 (25/31) / N/A / N/A / N/A
CE-CT† / 0.645 (20/31) / N/A / N/A / N/A
Schulz et al. 2015 (11) / GA-MRI / 0.744 (32/43) / 0.882 (135/153) / 0.640 (32/50) / 0.930 (135/146)
CE-CT / 0.163 (7/43) / 0.961 (147/153) / 0.538 (7/13) / 0.803 (147/183)

* results are averaged across two readers

† results are averaged across three readers

Table 8 Per-patient diagnostic accuracy of GA-MRI and CE-CT

Study (reference) / Index Test / Sensitivity (n) / Specificity (n) / PPV (n) / NPV (n)
Kim et al. 2012 (6) / GA-MRI* / 0.939 (46/49) / 1.000 (18/18) / 1.000 (46/46) / 0.857 (18/21)
CE-CT* / 0.653 (32/49) / 1.000 (18/18) / 1.000 (32/32) / 0.514 (18/35)
Lee et al. 2013 (10) / GA-MRI* / 0.941 (48/51) / 0.823 (51/62) / 0.814 (48/59) / 0.994 (51/54)
CE-CT* / 0.784 (40/51) / 0.726 (45/62) / 0.702 (40/57) / 0.804 (45/56)
Motosugi et al. 2011 (9) / GA-MRI† / 0.800 (12/15) / 0.974 (38/39) / 0.923 (12/13) / 0.927 (38/41)
CE-CT† / 0.600 (9/15) / 0.974 (38/39) / 0.900 (9/10) / 0.864 (38/44)
Schulz et al. 2015 (11) / GA-MRI / 1.000 (42/42) / 0.250 (1/4) / 0.933 (42/45) / 1.000 (1/1)
CE-CT / 0.929 (39/42) / 0.500 (2/4) / 0.951 (39/41) / 0.400 (2/5)

* results are averaged across two readers

† results are averaged across three readers

Appendix E – Excluded studies

Inappropriate population

Adam, G, Neuerburg, J, Spuntrup, E, Muhler, A, Scherer, K & Gunther, RW 1994, 'Dynamic contrast-enhanced mr imaging of the upper abdomen: Enhancement properties of gadobutrol, gadolinium-dtpa-polylysine, and gadolinium-dtpa-cascade-polymer', Magn Reson Med, vol.32(5), pp. 622-8.

2. Akai, H, Kiryu, S, Matsuda, I, Satou, J, Takao, H, Tajima, T, Watanabe, Y, Imamura, H, Kokudo, N, Akahane, M & Ohtomo, K 2011, 'Detection of hepatocellular carcinoma by gd-eob-dtpa-enhanced liver mri: Comparison with triple phase 64 detector row helical ct', Eur J Radiol, vol.80(2), pp. 310-5.

3. Alaboudy, A, Inoue, T, Hatanaka, K, Chung, H, Hyodo, T, Kumano, S, Murakami, T, Moustafa, EF & Kudo, M 2011, 'Usefulness of combination of imaging modalities in the diagnosis of hepatocellular carcinoma using sonazoid(r)-enhanced ultrasound, gadolinium diethylene-triamine-pentaacetic acid-enhanced magnetic resonance imaging, and contrast-enhanced computed tomography', Oncology, vol.81 Suppl 1pp. 66-72.

Alegre Castellanos, A, Molina Granados, JF, Escribano Fernandez, J, Gallardo Munoz, I & Trivino Tarradas Fde, A 2012, 'Early phase detection of bile leak after hepatobiliary surgery: Value of gd-eob-dtpa-enhanced mr cholangiography', Abdom Imaging, vol.37(5), pp. 795-802.

5. Baek, CK, Choi, JY, Kim, KA, Park, MS, Lim, JS, Chung, YE, Kim, MJ & Kim, KW 2012, 'Hepatocellular carcinoma in patients with chronic liver disease: A comparison of gadoxetic acid-enhanced mri and multiphasic MD-CT', Clin Radiol, vol.67(2), pp. 148-56.

Balci, NC, Inan, N, Anik, Y, Erturk, MS, Ural, D & Demirci, A 2006, 'Low-dose gadobenate dimeglumine versus standard-dose gadopentate dimeglumine for delayed contrast-enhanced cardiac magnetic resonance imaging', Academic Radiology, vol.13(7), pp. 833-39.

7. Bluemke, DA, Sahani, D, Amendola, M, Balzer, T, Breuer, J, Brown, JJ, Casalino, DD, Davis, PL, Francis, IR, Krinsky, G, Lee, FT, Lu, D, Paulson, EK, Schwartz, LH & Siegelman, ES 2005, 'Efficacy and safety of mr imaging with liver-specific contrast agent: Us multicenter phase iii study', Radiology, vol.237(1), pp. 89-98.