A Milestone: Approval of CEUS for Diagnostic Liver Imaging in Adults and Children in the USA

The approval of microbubbles with the inert gas sulfur hexafluoride (SF₆) and a palmitic acid shell (SonoVue^®, Bracco Geneva, CH) for the diagnostic imaging of liver tumors in adults and children by the FDA in the United States represents a milestone for contrast-enhanced ultrasound (CEUS).

This warrants a look back at the history of the development of CEUS. The first publications based on echocardiographic observations of right ventricular contrast phenomena caused by tiny air bubbles following i. v. injection of indocyanine green appeared around 1970 [1] [2] [3]. A longer period of sporadic publications but no real progress then followed since, in contrast to X-ray methods, ultrasound works quite well without a contrast agent.

It is noteworthy that the foundations for further development were primarily laid in Europe. The development and approval (1991) of the contrast agent Echovist^® by a German contrast manufacturer for echocardiography unsuitable for passing through lungcapillaries [4] [5] resulted in the first extracardiac indications, e. g. for detecting retrovesical reflux and tubal patency, in the mid-1980 s [6] [7] [8]. The sensitivity of color Doppler was not able to compensate for the lack of an ultrasound contrast agent compared to CT with its obligatory contrast administration.

Studies of SHU 508 – microbubbles of air moderately stabilized with galactose and palmitic acid – began in 1990 [9] [10] [11] [12] [13] [14] [15] and the contrast agent was then introduced in 1995 in Germany as Levovist^®. The most important publications by Blomley, Cosgrove, Leen, and Albrecht are named here on a representative basis [16] [17] [18] [19] [20].

SHU 508 along with other US contrast agents provided impressive proof of the superiority of CEUS for the diagnosis of liver metastases. However, practical application remained complicated and required skill and technical know-how because of a lack of suitable software on US units [21] [22] [23] [24] [25]. The monograph regarding the use of contrast agent in the liver by Wermke and Gaßmann is impressive but unfortunately only available in German [26]. In addition to being applied in the heart and the liver, CEUS was first used in transcranial applications [27] and in vessels [28], the kidneys [29], and the breast [30]. Measurements at transit times were also of particular interest [31]. It was difficult to convince ultrasound device manufacturers of the need to adapt US units to US contrast agents and not vice versa.

The breakthrough came with low MI phase contrast inversion and the introduction of SonoVue^® in many European countries in 2001. This more stable US contrast agent is easy to use and is becoming indispensable in diagnostic imaging of the liver [32] [33] [34] [35] [36] [37] [38] [39] [40]. Studies have shown its excellent tolerability [41] and diagnostic reliability comparable to that of MDCT and MRI in the liver [42] [43]. Today it would be unimaginable to diagnose liver tumors without CEUS [44]. This also applies to very small lesions [45] [46].

EFSUMB published the first CEUS guidelines in 2004 [47] which have since been reissued and divided into hepatic [48] and extrahepatic applications [49]. The first recommendations regarding quantitative assessment have also been published [50].

The increasing scientific interest in CEUS is evident based on the greater number of PubMed hits for Echovist^® (ca. 130), Levovist^® (ca. 500) and SonoVue^® (ca. 1500) as well as on the fact that publications regarding CEUS comprise almost 20 % of UiM/EJU articles in the last 10 years. The number of CEUS articles in UiM/EJU continues to be high [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75].

In the clinical reality, CEUS has been able to become established alongside CT and MRI according to the saying “better is the enemy of good” [76] as the method of choice after B-mode ultrasound in the evaluation of liver tumor malignancy in Germany, where the technically challenging method is promoted. In the case of unclear CT and MRI findings, CEUS performed by an experienced examiner/clinician often provides the solution, particularly in the case of small lesions, and is the last resort before US-guided biopsy [45] [46]. However, there is a lack of competent CEUS examiners and Germany continues to be the world champion of X-ray examinations with no noticeable reverse trend. In almost every doctor’s office and hospital, ultrasound costs are by far not fully covered, resulting in an extremely high frequency of CT use with CT being available to everyone regardless of insurance status.

The USA is now in the starting position for CEUS. It will be exciting to see how the method will develop there. The FDA’s decision to approve sulfur hexafluoride (Lumason^® = SonoVue^®) should be considered against the background of the radiation exposure caused by CT examinations and the fact that MRI using gadolinium-containing contrast agents is no longer considered noninvasive because of nephrogenic systemic fibrosis (NSF) and the accumulation of the agent in the cerebrum. An essential point of the campaign regarding the avoidance of diagnostic radiation exposure triggered in the USA by the publications of Brenner et al. [77] [78] was that the agent was approved for use in the liver even for children [79] [80] – still off label in Europe – without additional comprehensive studies due to the available scientific results and the very low side effects profile of Lumason^® (= SonoVue^®). It is admittedly unclear why other indications (except the heart which has been approved since 2014) are excluded even though the microbubbles as a pure blood pool contrast agent can be diagnostically used in the entire vascular system and bed of all organs. To our knowledge, there is no such restriction on the approval of X-ray contrast agents.

Like echocardiography and emergency ultrasound, CEUS began in Europe but will probably only establish its final diagnostic value as a “reimport”.

This is a major opportunity to permanently define the role of Ultrasound as a highly valuable, patient-centered imaging method in the German health care system.

This may prompt some of our international readers to reflect upon the role of CEUS in their own countries.

Die Zulassung von Mikrobläschen mit Schwefelhexafluorid (SF₆), einem inerten Gas in Palmitinsäureschalen (SonoVue^®, Bracco Genf, CH), zur Lebertumordiagnostik bei Erwachsenen und Kindern durch die FDA in den USA wird einen Meilenstein für die Kontrastmittelsonografie (CEUS) darstellen.

Ein Rückblick auf die Entwicklung der Kontrastmittelsonografie (CEUS) ist daher sinnvoll. Die ersten Veröffentlichungen erfolgten um 1970 nach echokardiografischen Beobachtungen von rechtsventrikulären Kontrastphänomenen nach i.-v. Indocyanigrüninjektionen, die aufgeschüttelten winzigen Luftblasen geschuldet waren [1] [2] [3]. Es folgte eine längere Phase von vereinzelten Publikationen ohne in der Sache so recht weiter zu kommen, Ultraschalldiagnostik funktionierte im Gegensatz zu den Röntgenverfahren auch ohne Kontrastmittel sehr gut.

Es ist bemerkenswert, dass die Grundlagen für die weitere Entwicklung überwiegend in Europa erarbeitet wurden. Mit der Entwicklung des nicht lungengängigen Kontrastmittels (Echovist^®, Zulassung in Deutschland 1991), durch einen deutschen Kontrastmittelhersteller für die Echokardiografie [4] [5] ergaben sich ab Mitte der 80er-Jahre erste extrakardiale Indikationen [6] [7] [8], z. B. zum Nachweis des retrovesikalen Refluxes und der Tubendurchgängigkeit. Die Sensitivität des Farbdopplers vermochte das Fehlen eines Ultraschallkontrastmittels (USKM) gegenüber der übermächtigen CT mit obligatorischer KM-Gabe nicht zu kompensieren.

Die Anwendung von SHU 508 – bestehend aus mäßig mit Galactose und Palmitinsäure stabilisierten Mikrobläschen und „Berliner Luft“ im Innern – wurde ab 1990 untersucht [9] [10] [11] [12] [13] [14] [15] und 1995 als Levovist^® in Deutschland eingeführt. Stellvertretend seien hier die wichtigsten Publikationen von Blomley, Cosgrove, Leen und Albrecht genannt [16] [17] [18] [19] [20].

Mit SHU 508 und auch mit anderen USKM wurde die Überlegenheit der CEUS in der Diagnostik von Lebermetastasen eindrucksvoll belegt, die praktische Anwendung war noch umständlich und erforderte Geschick und technisches Know-how, weil die US-Geräte über keine geeignet Software verfügten [21] [22] [23] [24] [25]. Eindrucksvoll und leider nur in deutscher Sprache verfügbar ist die Monografie zur Kontrastmittelanwendung an der Leber von Wermke und Gaßmann [26]. Außer an Herz und Leber erfolgten die ersten Anwendungen transkraniell [27], an Gefäßen[28], Nieren [29] und Mamma [30], besonderes Interesse fanden auch Messungen zu Transitzeiten [31]. Nur mühsam konnten die Hersteller von Ultraschallgeräten überzeugt werden, dass die US-Geräte an die USKM angepasst werden müssen und nicht umgekehrt.

Der Durchbruch kam 2001 mit der Low MI Phasenkontrastinversionstechnik und der Einführung von SonoVue^® in vielen europäischen Ländern. Das stabilere USKM ist gut handhabbar und wird unverzichtbar in der Leberdiagnostik [32] [33] [34] [35] [36] [37] [38] [39] [40]. Studien haben die exzellente Verträglichkeit [41] ebenso wie vergleichbare diagnostische Zuverlässigkeit mit MDCT und MRI an der Leber belegt [42] [43]. Lebertumordiagnostik ohne CEUS ist nicht mehr vorstellbar [44] und das gilt auch für sehr kleine Läsionen [45] [46].

Bereits 2004 wurden von der EFSUMB die ersten Leitlinien zur CEUS publiziert [47] und mittlerweile erneut aufgelegt und wegen der wachsenden Zunahme in hepatische [48] und extrahepatische Anwendungen [49] getrennt. Weiter wurden erste Empfehlungen zur quantitativen Auswertung veröffentlicht [50].

Das steigende wissenschaftliche Interesse an CEUS lässt sich an der zunehmenden Frequenz der PubMed-Treffer für Echovist^® (ca. 130), Levovist^® (ca. 500) und SonoVue^® (ca. 1500) erkennen, ebenso daran, dass in den letzten 10 Jahren Publikationen zum Thema CEUS fast 20 % der UiM/EJU ausmachten. Der Anteil der CEUS-Beiträge ist auch in letzter Zeit in der UiM/EJU unverändert hoch [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75].

Betrachtet man jedoch die klinische Realität, so konnte sich CEUS gemäß unserem Sprichwort „das Bessere ist der Feind des Guten“ [76] in Deutschland – dort wo die technische anspruchsvolle Methode gepflegt wird – auf Augenhöhe mit CT und MRT sich in der Dignitätsbeurteilung von Lebertumoren als Methode der ersten Wahl nach der B-Bild-Sonografie durchsetzen. Bei ungeklärten CT- und MRT–Befunden ist der CEUS in der Hand des erfahrenen Untersuchers/Kliniker oft der Problemlöser v. a. bei kleinen Läsionen und letzte Instanz vor der US-geführten Biopsie [45] [46]. Allerdings fehlt es der CEUS an einer flächendeckenden Versorgung mit kompetenten Untersuchern, und nach wie vor ist Deutschland Röntgenweltmeister ohne erkennbaren Trend zur Umkehr. Der Einsatz der Sonografie in nahezu jeder ärztlichen Praxis und Klinik erfolgt ohne kostendeckende Honorierung und sorgt allerdings für eine extrem hohe CT-Frequenz (“3 – 5 Sonografiker füttern ein CT“) bei ubiquitärer Verfügbarkeit eines CT für jedermann unabhängig vom Versicherungsstatus.

Jetzt ist USA in der Startposition für CEUS. Es wird spannend, welche Entwicklung die CEUS in USA nehmen wird. Die Entscheidung der FDA zur Zulassung von Schwefelhexafluorid (Lumason^® = SonoVue^®) ist sicherlich vor dem Hintergrund der Strahlenbelastung durch CT-Untersuchungen zu sehen und der Tatsache, dass das MRT mit der Anwendung von gadoliniumhaltigen KM nicht nur wegen der nephrogene systemische Fibrose (NSF), sondern auch wegen der Ablagerung im Cerebrum seine Unschuld hinsichtlich Noninvasivität verloren hat. Die von der Veröffentlichung von Brenner et al. [77] [78] in den USA ausgelöste Kampagne zur Vermeidung von diagnostischer Strahlenbelastung war wesentlich, dass aufgrund der vorliegenden wissenschaftlichen Ergebnisse bei einem extrem niedrige NW-Profil von SonoVue^® selbst für Kinder [79] [80] – in Europa immer noch ein Off-lable-use – ohne weitere umfangreiche Studien an der Leber zugelassen wurde. Unlogisch bleibt freilich weshalb andere Indikationen (außer Herz, hier besteht in den USA eine Zulassung seit 2014) ausgenommen sind, wo sich die Mikrobläschen als reines Blood-pool-KM im gesamten Gefäßsystem und -bett aller Organe diagnostisch nutzen ließen. Eine solche Begrenzung der Zulassung existiert für Röntgen-KM u. W. nirgends.

Der CEUS hat, wie schon die Echokardiografie und die Notfallsonografie, ihren Ausgangspunkt in Europa genommen und wird vermutlich erneut, erst als „Reimport“ seinen endgültigen Stellenwert finden.

Dies ist eine weitere Riesenchance den hochqualifizierten Ultraschall in Deutschland als patientennahe Sonografie in unserem Gesundheitswesen adäquat zu verankern.

Ein jeder unserer internationalen Leser möge sich fragen, wie es in seinem Land um den CEUS bestellt ist.

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