title: Contrast-enhanced ultrasound using SonoVue® (sulphur hexafluoride microbubbles) compared with contrast-enhanced computed tomography and contrast-enhanced magnetic resonance imaging for the characterisation of focal liver lesions and detection of liver metastases: a systematic review and cost-effectiveness analysis.
abstract: BACKGROUND
  Medical imaging techniques are important in the management of many patients with liver disease. Unenhanced ultrasound examinations sometimes identify focal abnormalities in the liver that may require further investigation, primarily to distinguish liver cancers from benign abnormalities. One important factor in selecting an imaging test is the ability to provide a rapid diagnosis. Options for additional imaging investigations include computed tomography (CT) and/or magnetic resonance imaging (MRI) and biopsy when the diagnosis remains uncertain. CT and MRI usually require referral with associated waiting time and are sometimes contraindicated. The use of contrast agents may improve the ability of ultrasound to distinguish between liver cancer and benign abnormalities and, because it can be performed at the same appointment as unenhanced ultrasound, more rapid diagnoses may be possible.
  
  
  OBJECTIVE
  To compare the clinical effectiveness and cost-effectiveness of contrast-enhanced ultrasound (CEUS) using SonoVue(®) with that of contrast-enhanced computed tomography (CECT) and contrast-enhanced magnetic resonance imaging (CEMRI) for the assessment of adults with focal liver lesions (FLLs) in whom previous liver imaging is inconclusive.
  
  
  METHODS
  Eight bibliographic databases including MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects were searched from 2000 to September/October 2011. Research registers and conference proceedings were also searched.
  
  
  METHODS
  Systematic review methods followed published guidance. Risk of bias was assessed using a modified version of the QUADAS-2 tool. Results were stratified by clinical indication for imaging (characterisation of FLLs detected on ultrasound surveillance of cirrhosis patients, detection of liver metastases, characterisation of incidentally detected FLLs, assessment of treatment response). For incidental FLLs, pooled estimates of sensitivity and specificity, with 95% CIs, were calculated using a random-effects model. For other clinical indications a narrative summary was used. The cost-effectiveness of CEUS was modelled separately for the three main clinical applications considered [characterisation of FLLs detected on ultrasound surveillance of cirrhosis patients, detection of liver metastases in patients with colorectal cancer (CRC), characterisation of incidentally detected FLLs].
  
  
  RESULTS
  Of the 854 references identified, 19 (describing 18 studies) were included in the review. Hand searching of conference proceedings identified a further three studies. Twenty of the 21 studies included in the systematic review were diagnostic test accuracy studies. Studies in cirrhosis patients reported varying estimates of test performance. There was no consistent evidence of a significant difference in performance between imaging modalities. It was unclear whether or not CEUS alone is adequate to rule out hepatocellular carcinoma (HCC) for FLLs of < 30 mm; one study indicated that CEUS may be better at ruling out HCC for FLLs of 11-30 mm [very small FLLs (< 10 mm) excluded]. There was no consistent evidence of a difference in test performance between imaging modalities for the detection of metastases; CEUS alone may be adequate to rule out liver metastases in colorectal cancer. In patients with incidentally detected FLLs, the pooled estimates of sensitivity for any malignancy using CEUS and CECT were 95.1% and 94.6%, respectively, and the corresponding specificity estimates were 93.8% and 93.1% respectively. One study comparing CEUS with CEMRI reported similar sensitivity and lower specificity for both modalities. In the surveillance of cirrhosis, CEUS was as effective as but £379 less costly than CECT. CEMRI was £1063 more costly than CEUS and gained 0.022 QALYs. In the detection of liver metastases from CRC, CEUS cost £1 more than CECT, and at a lifetime time horizon they yielded equal QALYs. CEMRI was dominated by CECT. In the characterisation of incidentally detected FLLs, CEUS was slightly more effective than CECT and CEMRI (by 0.0002 QALYs and 0.0026 QALYs respectively) and less costly (by £52 and £131 respectively).
  
  
  CONCLUSIONS
  There were a number of methodological issues specific to the studies included in this review. The main indication for liver imaging in the populations considered is likely to be to rule out primary liver cancer or metastases. Therefore, patient-level analyses of test performance are of particular interest. Some of the studies included in this review reported per-patient analyses; however, no study clearly stated how results were defined (e.g. was the presence of any positive lesion regarded as a positive test for the whole patient). In addition, a number of studies reported data for one lesion per patient (treated as per-patient data in this assessment). These studies generally selected the largest lesion or the lesion 'most suspicious for malignancy' for inclusion in analyses, with the consequence that estimates of test performance may have been exaggerated. The applicability of studies included in this review may be limited, as the majority of imaging studies were interpreted by multiple, experienced operators and the prevalence of malignancy in included studies appeared higher than might be expected in clinical practice. The cost-effectiveness analyses did not take into account the potential benefits of reduced anxiety that may arise from potentially shorter waiting times associated with SonoVue CEUS.
  
  
  CONCLUSIONS
  SonoVue CEUS could provide similar diagnostic performance to other imaging modalities (CECT and CEMRI) for the assessment of FLLs. Economic analyses indicated that CEUS was a cost-effective replacement for CEMRI. The use of CEUS instead of CECT was considered cost-effective in the surveillance of cirrhosis and the characterisation of incidentally detected FLLs, with similar costs and effects for the detection of liver metastases from CRC. Further research is needed to compare the effects of different imaging modalities (SonoVue CEUS, CECT, CEMRI) on therapeutic planning, treatment and clinical outcomes. Future test accuracy studies should provide standardised definitions of a positive imaging test, and compare all three imaging modalities in the same patient group.
  
  
  BACKGROUND
  PROSPERO: CRD42011001694.
  
  
  BACKGROUND
  The National Institute for Health Research Health Technology Assessment programme.
authors.affiliation: Kleijnen Systematic Reviews Ltd, York, UK. marie@systematic-reviews.com
authors.forename: M
authors.initials: M
authors.lastname: Westwood
authors.forename: M
authors.initials: M
authors.lastname: Joore
authors.forename: J
authors.initials: J
authors.lastname: Grutters
authors.forename: K
authors.initials: K
authors.lastname: Redekop
authors.forename: N
authors.initials: N
authors.lastname: Armstrong
authors.forename: K
authors.initials: K
authors.lastname: Lee
authors.forename: V
authors.initials: V
authors.lastname: Gloy
authors.forename: H
authors.initials: H
authors.lastname: Raatz
authors.forename: K
authors.initials: K
authors.lastname: Misso
authors.forename: J
authors.initials: J
authors.lastname: Severens
authors.forename: J
authors.initials: J
authors.lastname: Kleijnen
mesh_terms: D003287:Contrast Media; D003362:Cost-Benefit Analysis; D006801:Humans; D008099:Liver / Q000000981:diagnostic imaging; D008103:Liver Cirrhosis / Q000175:diagnosis / Q000473:pathology; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D045423:Microbubbles; D009362:Neoplasm Metastasis; D010743:Phospholipids / Q000191:economics*; D019057:Quality-Adjusted Life Years; D013459:Sulfur Hexafluoride / Q000191:economics*; D013673:Technology Assessment, Biomedical; D014057:Tomography, X-Ray Computed; D014463:Ultrasonography
chemical_list: D003287:Contrast Media; D010743:Phospholipids; C420843:contrast agent BR1; D013459:Sulfur Hexafluoride