SonoVue (sulphur hexafluoride microbubbles) – contrast agent for contrast-enhanced ultrasound imaging of the liver

The diagnostics advisory committee reviewed the evidence on the clinical and cost effectiveness of contrast-enhanced ultrasound with SonoVue and noted that the technology was assessed in 3 clinical indications, in adults, when unenhanced ultrasound is inconclusive:

• characterising incidentally detected focal liver unrelated to the clinical indication for which the imaging was requested

• investigating potential liver metastases in people with colorectal cancer

• characterising focal liver lesions identified through monitoring of people with cirrhosis.

In general, the committee noted that most of the studies identified in the systematic review of clinical effectiveness were of diagnostic test accuracy and that the quality assessment of these studies, using QUADAS 2, highlighted significant limitations in the data. In particular, there was a 'high' risk of bias rating for the 'patient selection' domain from the use of a retrospective study design or from inappropriate exclusions of particular patient groups (for example, exclusion of people with a low probability of malignancy).

The committee thought that the large retrospective safety study of contrast-enhanced ultrasound with SonoVue in abdominal imaging showed that the safety profile of SonoVue was comparable to, if not better than, contrast-enhanced CT and contrast enhanced MRI.

The committee also considered the impact of the use of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), as a newer 'combined' vascular and hepatocyte-specific contrast agent for MRI. The external assessment group noted that, although most of the evidence for MRI was based on older contrast agents (such as SPIO), a study of people with cirrhosis by Blondin et al. (2011) did not suggest that the accuracy of Gd-EOB-DTPA was significantly different to that of contrast-enhanced ultrasound. Blondin et al. showed that sensitivity estimates were similar and high (more than 90%) for both contrast-enhanced ultrasound and Gd-EOB-DTPA contrast-enhanced MRI. Specificity appeared lower for contrast-enhanced ultrasound than for Gd-EOB-DTPA contrast-enhanced MRI, but the small number of people with benign lesions in this study resulted in high imprecision in specificity estimates: 50% (95% confidence interval [CI] 42 to 88%) for contrast-enhanced ultrasound and 83% (95% CI 36 to 100%) for Gd-EOB-DTPA contrast-enhanced MRI.

The committee considered contrast-enhanced ultrasound with SonoVue for characterising incidentally detected focal liver lesions and noted that, in liver imaging, this clinical indication would likely be the most common application of the technology. The committee noted that the base-case analysis showed clinically insignificant increases in effectiveness for contrast-enhanced ultrasound compared with contrast-enhanced CT and MRI (incremental QALYs for contrast-enhanced ultrasound compared with contrast-enhanced CT were 0.00016, and for contrast-enhanced ultrasound compared with contrast-enhanced MRI, 0.0026). Moreover, there were cost decreases with contrast-enhanced ultrasound (£52 compared with contrast-enhanced CT, and £131 compared with contrast-enhanced MRI). Thus contrast-enhanced ultrasound with SonoVue dominated the comparators. Probabilistic sensitivity analysis revealed that there was little uncertainty about the cost effectiveness of contrast-enhanced ultrasound compared with the other 2 imaging techniques. Additional analyses did not lead to significant changes in the incremental costs and effectiveness of contrast-enhanced ultrasound compared with contrast-enhanced CT or contrast-enhanced MRI. Therefore, the committee concluded that it could recommend contrast-enhanced ultrasound with SonoVue for characterising incidentally detected focal liver lesions.

The committee considered contrast-enhanced ultrasound with SonoVue for investigating potential liver metastases in people with colorectal cancer and noted that NICE's guideline on colorectal cancer recommends the use of CT in staging of colorectal cancer, which includes the identification of liver metastases. Therefore, the use of contrast-enhanced ultrasound with SonoVue would only be applicable in a small number of cases (for example, if contrast-enhanced CT is not clinically appropriate, is not accessible, is not acceptable to the person, or is inconclusive). The committee considered the economic analysis performed by the external assessment group and noted that the base-case analysis showed that contrast-enhanced CT was cost effective; however, contrast-enhanced ultrasound with SonoVue generated equal benefits and was only £1 more costly. The committee considered a range of additional analyses performed by the external assessment group. In the base-case analysis it was assumed that people who were incorrectly diagnosed with liver metastases (false-positives) would receive biopsy and the incorrect diagnosis would be discovered before treatment. If this is not assumed, then people could receive unnecessary treatment and the lower specificity of contrast-enhanced ultrasound resulted in increased costs and reduced effectiveness. Contrast-enhanced MRI with gadolinium dominates all other tests under this assumption. The committee discussed that although the diagnostic pathway varies depending on the clinical scenario, most people would be unlikely to receive unnecessary treatment. This is because the multidisciplinary team would probably seek assurance (from further imaging or a watch and wait strategy) before starting treatment. Direct biopsies of liver metastases may make the metastases inoperable, so they are unlikely to be performed. Therefore, the committee recommended the use of contrast-enhanced ultrasound with SonoVue for investigating potential liver metastases from colorectal cancer, when contrast-enhanced CT is not clinically appropriate, is not accessible or is not acceptable to the person.

The committee considered the applicability of the colorectal cancer analysis to metastases from other primary cancers. It concluded that the data for diagnostic accuracy are equally applicable to liver metastases from other primary cancers (because the liver is being imaged in all cases). Although the treatment of metastases may vary by type of primary cancer, the committee did not consider that this would affect the cost effectiveness of SonoVue sufficiently for it to modify its decision not to limit its recommendations to potential liver metastases from colorectal cancer.

The committee considered contrast-enhanced ultrasound with SonoVue for characterising focal liver lesions identified through monitoring people with cirrhosis. The committee considered the economic analysis performed by the external assessment group and noted that the base-case analysis showed that contrast-enhanced ultrasound with SonoVue was cost effective. The committee felt that the clinical evidence base was weaker for this indication, as noted in the diagnostics assessment report.

The committee considered several circumstances that would result in contrast-enhanced ultrasound being less cost effective. First, the modelling assumed that all people with diagnoses of hepatocellular carcinoma on characterisation scans, regardless of modality, would have subsequent scans with CT or MRI for treatment planning. The committee heard from experts that although lesions characterised with contrast-enhanced ultrasound would need subsequent CT or MRI scans, focal liver lesions characterised with CT or MRI would not usually need a second scan. The external assessment group determined that the extra scans did not add significantly to the overall cost and would not affect the overall cost effectiveness.

The committee also noted that in the base case, a high proportion of people who had an initial unenhanced ultrasound were assumed to have inconclusive scans (43%, from data supplied by the manufacturer of SonoVue). The committee noted that it was difficult for the external assessment group to ascertain accurate estimates for this parameter in people with cirrhosis because of variation in the definition of 'inconclusive' in the studies and clinical practice. The committee heard from clinical experts that this estimate did not reflect clinical practice and that inconclusive scans normally occur in a much lower proportion of people (10% to 15%) who then need further imaging to characterise their lesion(s). The external assessment group reviewed data submitted by the manufacturer and concluded that the percentage of inconclusive unenhanced scans in people with cirrhosis could not be calculated from these data for a variety of reasons, particularly because the data contained estimates that encompassed both non-diagnostic and diagnostic images, and the use of contrast-enhanced ultrasound rather than unenhanced ultrasound in the studies. The committee concluded that the percentage of inconclusive unenhanced ultrasound scans was likely to be nearer 10% to 15%. At this level, contrast-enhanced MRI with gadolinium was more effective than contrast-enhanced ultrasound and had an ICER of £16,100 per QALY gained. Therefore, contrast-enhanced ultrasound was not a cost-effective option under this circumstance. Contrast-enhanced CT was dominated by contrast-enhanced ultrasound with a 10% to 15% rate of inconclusive scans. Given the uncertainty in the estimate of the prevalence of inconclusive unenhanced ultrasound scans, particularly in people with cirrhosis, and given that the optimal diagnostic strategy depends on this estimate, the committee recommended further research on this issue (see section 7).

The committee discussed the pressures on MRI departments in the NHS, many of which faced substantially greater demand for MRI than current capacity could supply. It was thought that, from anecdotal evidence, approximately 5.5% of people who would otherwise have been referred for an MRI scan did not have one, either because it was not available or not clinically appropriate (for example, those with a pacemaker) or because they would not tolerate a scan. The committee recommended the use of contrast-enhanced ultrasound with SonoVue for people who would not or could not receive a contrast-enhanced MRI scan.

The committee also considered whether patient preferences might impact on the selection of imaging modality. Given that contrast-enhanced ultrasound is less expensive than CT or MRI, the small improvements in health-related quality of life arising from CT and particularly MRI might be outweighed by a personal preference for ultrasound over the other modalities. No data on patient preferences were identified by the external assessment group's systematic review. The committee recommended research on patient preferences, and their impact on quality of life, for contrast-enhanced ultrasound and other imaging modalities and whether there are likely differences between contrast-enhanced ultrasound and the other imaging modalities (see section 7).

The committee discussed the level of training needed to perform a contrast-enhanced ultrasound. It was noted that an appropriate level of operator experience was needed to be able to successfully perform contrast-enhanced ultrasound and that currently there was a shortage in appropriately trained sonographers. The committee concluded that it would be desirable to develop a clinical support framework for sharing and discussing experiences of contrast-enhanced ultrasound. Moreover, NHS departments offering contrast-enhanced ultrasound for liver imaging should review whether they have appropriately trained staff and offer training if necessary by using, for example, the minimum training guidelines provided by the EFSUMB.

The committee noted that the economic analysis was based on the assumption that the contrast-enhanced ultrasound scan would be performed in the same appointment as the unenhanced ultrasound scan. Although alternative scenarios exploring the need to book an additional outpatient appointment (in 50% and 67% of cases) were assessed by the external assessment group, this did not affect the results of the economic analysis. The committee stated that there were significant benefits from having contrast-enhanced ultrasound performed in the same appointment as the unenhanced ultrasound scan, including patient convenience and the potential for reducing anxiety by ruling out a malignant lesion sooner. Also, savings from reducing the number of appointments are likely. In the committee's view the potential benefit of reducing anxiety by rapidly ruling out malignancy would be a significant advantage compared with the other imaging modalities and is a consequence of being able to perform contrast-enhanced ultrasound during the same appointment. In the committee's view performing contrast-enhanced ultrasound in the same appointment as unenhanced ultrasound was the optimal model of service delivery.

The committee considered possible equality impacts. It noted that although obesity may be a general barrier to the use of ultrasound in some people, its impact on image quality on an individual basis is unpredictable. The committee concluded that the recommendations would be unlikely to disadvantage those with obesity or protected groups.