Validation of dynamic contrast-enhanced ultrasound in predicting outcomes of antiangiogenic therapy for solid tumors: the French multicenter support for innovative and expensive techniques study.

OBJECTIVES: Dynamic contrast-enhanced ultrasound (DCE-US) has been used in single-center studies to evaluate tumor response to antiangiogenic treatments: the change of area under the perfusion curve (AUC), a criterion linked to blood volume, was consistently correlated with the Response Evaluation Criteria in Solid Tumors response. The main objective here was to do a multicentric validation of the use of DCE-US to evaluate tumor response in different solid tumor types treated by several antiangiogenic agents. A secondary objective was to evaluate the costs of the procedure. MATERIALS AND METHODS: This prospective study included patients from 2007 to 2010 in 19 centers (8 teaching hospitals and 11 comprehensive cancer centers). All patients treated with antiangiogenic therapy were eligible. Dynamic contrast-enhanced ultrasound examinations were performed at baseline as well as on days 7, 15, 30, and 60. For each examination, a perfusion curve was recorded during 3 minutes after injection of a contrast agent. Change from baseline at each time point was estimated for each of 7 fitted criteria. The main end point was freedom from progression (FFP). Criterion/time-point combinations with the strongest correlation with FFP were analyzed further to estimate an optimal cutoff point. RESULTS: A total of 1968 DCE-US examinations in 539 patients were analyzed. The median follow-up was 1.65 years. Variations from baseline were significant at day 30 for several criteria, with AUC having the most significant association with FFP (P = 0.00002). Patients with a greater than 40% decrease in AUC at day 30 had better FFP (P = 0.005) and overall survival (P = 0.05). The mean cost of each DCE-US was 180&OV0556;, which corresponds to $250 using the current exchange rate. CONCLUSIONS: Dynamic contrast-enhanced ultrasound is a new functional imaging technique that provides a validated criterion, namely, the change of AUC from baseline to day 30, which is predictive of tumor progression in a large multicenter cohort. Because of its low cost, it should be considered in the routine evaluation of solid tumors treated with antiangiogenic therapy.

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.

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. DATA SOURCES: 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. REVIEW 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). LIMITATIONS: 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. STUDY REGISTRATION: PROSPERO: CRD42011001694. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Contrast-enhanced ultrasonography in the characterization of benign focal liver lesions: activity-based cost analysis.

PURPOSE: The aim of this study was to perform a cost analysis of contrast-enhanced ultrasonography (CEUS) in the study of benign focal liver lesions (BFLL) with indeterminate appearance on ultrasonography (US). MATERIALS AND METHODS: A decision model of patients with suspected BFLL on baseline US who subsequently underwent CEUS between 2002 and 2005 was constructed. We analysed the cost effectiveness of CEUS, considering whether or not computed tomography (CT) was necessary for the diagnosis. There were 398 patients with 213 angiomas, 41 focal nodular hyperplasias (FNH) and 154 pseudolesions (focal fatty sparing, focal fatty areas). Each patient underwent CEUS, and 98 of them were also studied by CT. All lesions were followed up. RESULTS: The cost of a single CEUS examination was 101.51 euros, and that of a single CT scan was 211.48 euros. For diagnosis of haemangiomas, we saved 1,406.97 euros in 2002, 5,315.22 euros in 2003, 10,317.78 euros in 2004 and 9,536.13 euros in 2005. For diagnosis of focal nodular hyperplasias, we saved 781.65 euros in 2003, 781.65 euros in 2004 and 1,406.97 euros in 2005. For diagnosis of pseudolesions, we saved 2,813.94 euros in 2002, 5,158.89 euros in 2003, 5,158.89 euros in 2004 and 4,220.91 euros in 2005. In the period 2002-2005, the introduction of CEUS allowed us to save a total of 47,055.33 euros in the diagnosis of benign focal hepatic liver lesions. CONCLUSIONS: This cost analysis shows that CEUS is the least expensive second-line modality after baseline US for the diagnosis of BFLL.

Economic assessment of contrast-enhanced ultrasonography for evaluation of focal liver lesions: a multicentre Italian experience.

BACKGROUND: The aim of this study was to evaluate the clinical and economic consequences of the introduction of contrast-enhanced ultrasonography (CEUS) into the diagnostic clinical algorithm for the characterization of incidental focal liver lesions (FLLs). METHODS: This prospective study enrolled 485 subjects at three hospitals in Italy. Two diagnostic algorithms were utilized: (1) a classic patient work-up, which included baseline US followed by a CT or MR examination, and (2) a new patient management scheme in which, following the baseline US, a CEUS examination was performed. For each pathway, both direct and indirect health costs for the National Health System (NHS) at two of the three hospitals involved in the study were calculated. Clinical outcome was measured in terms of number of cases correctly diagnosed, using contrast-enhanced CT/contrast-enhanced MR as the reference standard. RESULTS: CEUS correctly differentiated (benign vs. malignant) 559 of 575 lesions (97.2%), with a sensitivity of 98.1% and a specificity of 95.7%. Histological characterization was correct in 502 of 575 lesions (87%) with a sensitivity of 90.5% and a specificity of 85.4%. In terms of cost, the conventional diagnostic algorithm incurred for the NHS a total cost of Euro 134.576,60 vs. Euro 55.674,30 with CEUS, for a saving of Euro 78.902 (Euro 162 per patient). For the hospitals, the total cost was Euro 147.045 without CEUS vs Euro 61.979 with CEUS, for a saving of Euro 85.065,96 or Euro 175,39 per patient. CONCLUSION: The routine use of CEUS for the characterization of FLLs provides significant cost savings, both for the NHS and for the hospital.

Halogenated compounds and climate change: future emission levels and reduction costs.

OBJECTIVES: This work assesses the contribution to climate change resulting from emissions of the group of halogenated greenhouse gases. METHODS: A bottom-up emission model covering 22 technological sectors in four major regions is described. Emission estimates for 1996 and projection for 2010 and 2020 are presented. The costs for deep cuts into projected emission levels are calculated. RESULTS: The substances covered by this study have contributed emissions of 1100 +/- 800 MT CO2 equivalents per year in 1996. In terms of their relative contribution to emissions of CO2 equivalents, this corresponds to 3 +/- 2% of global emissions of all anthropogenic greenhouse gases. The wide range of uncertainty is due to the poorly quantified net global warming potential of the ozone depleting substances, which have an indirect cooling effect on climate through the destruction of stratospheric ozone. For annual emissions of HFCs, PFCs and SF6 (which are regulated under the Kyoto Protocol and for which global warming potentials are well defined), the relative contribution is projected to increase to 2% (600 MT CO2 eq.) of global greenhouse gas emissions by 2010. This trend is expected to continue, emissions are projected to grow to a contribution of roughly 3% (870 MT CO2 eq.) in 2020 compared to 0.9% (300 MT CO2 eq.) in 1996. For HFCs, PFCs and SF6, this study identifies global emission reduction potentials of 260 MT CO2 eq. per year in 2010 and 640 MT CO2 eq. per year in 2020 at below US$ 50 per ton. These values correspond to roughly 40% and 75% of projected emissions in 2010 and 2020, respectively.