Contrast Material–enhanced Abdominal USExaminations with DMP 115 (DEFINITY) ProvidesAdditional Diagnostic Information with Potential

for Changes in Patient Management1

M.L. Rosenberg, MD, A.P. Carpenter, PhD, and the Phase III DEFINITY Clinical Investigators

RATIONALE AND OBJECTIVES

Ultrasound imaging has attained a prominent place inliver and kidney studies because of its availability, lowcost, patient comfort, and acceptability as well as the lackof radiation exposure. Despite its many positive features,however, limitations still exist. Image quality may be de-graded by large body habitus or excessive bowel gas.Moreover, many liver or kidney diseases can have similarappearances in ultrasound imaging, or pathology may bepresent that is isoechoic with surrounding normal tissue.For example, the presence of malignancy in the liver canbe masked by chronic changes resulting from cirrhosis orhepatitis (1). In addition, the differentiation of malignantfrom benign solid masses in a reliable fashion is problem-atic (1).

The recent advances in ultrasound contrast agents mayhelp address some of the challenges that face non–con-trast material–enhanced abdominal ultrasound examina-tions. It has been suggested that ultrasound contrastagents may allow better detection of malignancies versusbenign tissue changes (2) or as a general aid in the inter-pretation of pathology (3). Furthermore, techniques suchas Doppler imaging of microsphere cavitation from con-trast agents that have an extended retention in the liverhave been shown to improve the conspicuity of occult

metastases (4). These flash echo or stimulated acousticimaging techniques have the limitation of exhibiting onlytransient response whereby the contrast enhancement isnot observed after a few frames of imaging (5). Recently,ultrasound contrast agents have also been assessed for thecontinuous gray scale fundamental and/or harmonic imag-ing of liver pathology as a means to retain the dynamicinformation of ultrasound imaging and to allow for themore complete assessment of the whole organ (6,7).

To examine the clinical utility of a perfluorocarbon-based ultrasound contrast agent, DMP 115, (DEFINITY;DuPont Pharmaceuticals, Billerica, Mass), in abdominalultrasound examinations, clinical trials have been con-ducted to compare the diagnostic information of the con-trast material–enhanced examination to the baseline non–contrast material–enhanced examination.

Two phase III multicenter trials were conducted todetermine the efficacy of DMP 115 for contrast enhance-ment of abdominal ultrasound examinations of suspectedliver or kidney pathology. Among other end points, thesetrials examined the potential for contrast-material en-hanced examinations to provide additional diagnostic in-formation that would result in changes in patient manage-ment relative to the standard, unenhanced, abdominal ul-trasound examination.

MATERIALS AND METHODS

DMP 115 is a liposome-encapsulated microsphere sus-pension containing perfluoropropane microspheres with anapproximate mean number diameter of 1.5�m and a con-centration of�1 � 108 microspheres/mL. Slow bolus

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1 From the DuPont Merck Pharmaceutical Co, 331 Treble Cove Rd, Bil-lerica, MA 01862. Address correspondence to M.L.R.

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administrations of 10�L/kg DMP 115 were given to pa-tients enrolled at 20 investigational centers. Contrastagent and non-contrast agent images were acquired infundamental and/or harmonic imaging modes. Two hun-dred nine (209) subjects with suspected liver or kidneypathology were enrolled in these trials.

RESULTS

The on-site (institutional) reading of DMP 115 imagesdemonstrated that additional diagnostic information wasobtained in 83.3% of subjects enrolled across both trialswhen compared to non–contrast material–enhanced ex-aminations (Table 1). The subjects with suspected liverpathology showed additional diagnostic information in81.1% of cases, whereas subjects with suspected renalpathology demonstrated that 86.8% of cases had increaseddiagnostic information (Tables 2, 3).

For those patients who had additional diagnostic infor-mation provided by the contrast material-enhanced ultra-sound examination, the percentage of patients for whom achange in patient management would be recommendedbased on the DMP 115 ultrasound study was 46% for allpatients and 53%/41% for kidney/liver subjects, respec-

Table 1Percentage of Patients with Additional Diagnostic Informationfrom the DMP 115 Ultrasound Study, Institutional Read—AllPatients (Trials DMP 115-009 and -010)

Trial N% Patients with

Additional Information 95% CI

DMP 115-009 107 83.2* 74.4, 88.6DMP 115-010 96 83.3* 74.0, 88.9Combined 203 83.3* 77.2, 87.5

Note.—For blinded read and institutional read, DMP 115dose � 10 �L/kg. N � sample size; CI � confidence interval.*Indicates the percentage of patients with additional diagnostic

information is statistically significantly greater than 50% (P � .01).

Table 2Percentage of Patients with Additional Diagnostic Informationfrom the DMP 115 Ultrasound Study—Patients withSuspected Liver Pathology (Trials DMP 115-009 and -010)

Trial and Reader N% Patients with

Additional Information 95% CI

DMP 115-009Institutional Read 66 77.3* 65.0, 84.9

DMP 115-010Institutional Read 61 85.2* 73.3, 91.1

CombinedInstitutional Read 127 81.1* 73.0, 86.5

Note.—DMP 115 dose � 10 �L/kg. N � sample size; CI �confidence interval.*Indicates the percentage of patients with additional diagnostic

information is statistically significantly greater than 50% (P � .01).

Table 3Percentage of Patients with Additional Diagnostic Informationfrom the DMP 115 Ultrasound Study—Patients withSuspected Kidney Pathology (Trials DMP 115-009 and -010)

Trial and Reader N% Patients with

Additional Information 95% CI

DMP 115-009Institutional Read 41 92.7† 79.0, 95.9

DMP 115-010Institutional Read 35 80.0† 62.5, 88.4

CombinedInstitutional Read 76 86.8† 76.7, 91.9

Note.—DMP 115 dose � 10 �L/kg. N � sample size; CI �confidence interval.*Indicates the percentage of patients with additional diagnostic

information is statistically significantly greater than 50% (P � .05).†Indicates the percentage of patients with additional diagnostic

information is statistically significantly greater than 50% (P � .01).

Table 4Percentage of Patients (Overall and by Organ) with Changein Patient Management Based on Additional DiagnosticInformation Provided by the DMP 115 Ultrasound Study:Institutional Read—By Trial and Combined (Trials DMP115-009 and -010)

Trial andPopulation

Change in Patient Management

N% Patients

with Outcome* 95% CI

DMP 115-009All Patients 89 50.6 39.8, 60.2Liver 51 43.1 29.6, 55.9Kidney 38 60.5 43.4, 73.1

DMP 115-010All Patients 80 40.0 29.4, 50.4Liver 52 38.5 25.6, 51.2Kidney 28 42.9 25.0, 59.4

CombinedAll Patients 169 45.6 38.0, 52.8Liver 103 40.8 31.3, 50.0Kidney 66 53.0 40.4, 63.8

Note.—DMP 115 dose � 10 �L/kg. N � sample size; CI �confidence interval.*Percentage of patients for whom management change would

be recommended based on additional diagnostic information fromDMP 115 administration.

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tively (Table 4). The most common change in patientmanagement noted by study investigators due to the addi-tion of contrast agent was that 23% of patients who hadadditional diagnostic information were judged to not needadditional diagnostic examinations. Other patient manage-ment alterations that would have been recommendedbased on the DMP 115 contrast agent study vs the non-contrast agent examination were: alteration in diagnosticworkup (7%), alteration in biopsy strategy (7%), changein patient therapy (3%), and alteration in surgical strategy(3%).

CONCLUSION

The addition of contrast agent enhancement with DMP115 to standard gray-scale abdominal ultrasound examina-tions provided both additional diagnostic information andthe potential for substantive changes in patient manage-ment in a large fraction of the suspected liver and kidneypathology population enrolled in these phase III trials.

REFERENCES

1. Blum L, Kurtz AB. Liver. In: Goldberg BB, ed. Textbook of abdominalultrasound. Philadelphia, Pa: Williams & Wilkins, 1993; 81–95.

2. Cosgrove DO, Blomley MJK. Evaluation of tumors using echo-enhanc-ing agents. In: Goldberg BB, ed. Ultrasound contrast agents. London,England: Martin Dunitz, 1997; 159–168.

3. Albrecht T, Hoffman CW, Blomley MJK, Cosgrove DO. Transit timestudies and harmonic imaging of the liver. Presented at the 1st AnnualSymposium on Ultrasound Contrast for Radiological Diagnosis, To-ronto, Canada, October 1998.

4. Blomley MJ, Albrecht, T, Cosgrove DO, et al. Improved imaging of livermetastases with stimulated acoustic emission in the late phase of en-hancement with the US contrast agent SHU 508A: early experience.Radiology 1999; 210:409–416.

5. Kamiyama N, Moriyasu F, Mine Y, Goto Y. Analysis of flash echo fromcontrast agent for designing optimal ultrasound diagnostic systems.Ultrasound Med Biol 1999; 25:411–420.

6. Kono Y, Moriyasu F, Mine Y, et al. Gray-scale second harmonic imag-ing of the liver with galactose-based microbubbles. Invest Radiol 1997;32:120–125.

7. Forsberg F, Goldberg BB, Liu JB, Merton DA, Rawool NM. On the fea-sibility of real-time, in vivo harmonic imaging with proteinaceous micro-spheres. J Ultrasound Med 1996; 15:853–860.

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