Lipiodol—an effective imaging biomarker for chemoembolization of hepatocellular carcinoma

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Julius Chapiro (left) and Jeff Gershwin

Beyond embolization endpoints under fluoroscopic guidance, the introduction and standardisation of cone-beam CT imaging in the procedure room has allowed Lipiodol (Guerbet) to become a true imaging biomarker for therapeutic efficacy, write Julius Chapiro and Jean-Francois (Jeff) Geschwind.

Hepatocellular carcinoma is the second most common cause of cancer-related deaths worldwide and its incidence is continuing to grow at an alarming rate in Europe and the USA. The clinical management of patients with this disease has greatly evolved over the course of the last three decades. The progress in the field has been mainly driven by innovation in image guidance technology and drug delivery platforms, resulting in substantially improved clinical outcomes. These developments have allowed interventional oncologists to become the primary liaison for patients seeking therapy.

Most newly diagnosed patients cannot be treated by curative surgical therapy; oncologists also acknowledge that no systemic therapy has been shown to improve patient survival, with the notable exception of sorafenib that has conclusively been shown to improve survival in patients with advanced stage disease. In parallel, locoregional tumour therapies such as radiofrequency ablation and conventional transarterial chemoembolization (cTACE), have grown beyond their initial role as niche applications and have been fully incorporated into interdisciplinary guidelines and recommendations across the globe.

The data collected in the GIDEON (Global investigation of therapeutic decisions in hepatocellular carcinoma and of its treatment with sorafenib) registry, the largest observational registry completed in the field, suggest that nearly 50% of all patients with hepatocellular carcinoma undergo transarterial chemoembolization (cTACE) at some point after diagnosis. More importantly, the GIDEON registry reinvigorated the data from two older randomised controlled trials and once again established substantial survival benefits of cTACE over best supportive care. cTACE, a widely used longstanding technique among image-guided cancer therapies, takes advantage of the fact that hepatocellular carcinoma lesions draw their blood supply almost exclusively from the hepatic artery, whereas the remainder of the liver is supplied by the portal vein.

The most widely applied cTACE protocols involve selective intra-arterial infusion of a chemotherapeutic drug cocktail suspended in Lipiodol, an iodinated poppy seed oil–based medium, thereby creating an emulsion that sticks to the cancer cells. This step is followed by embolization of tumour feeding vessels with calibrated particles or gelatin sponge in order to protect the emulsion and prevent its separation, thereby keeping the chemotherapy within the tumour and maximising exposure time. Lipiodol has been widely considered as a unique agent which seems to be preferentially retained by the tumour tissue. While this agent has US FDA approval for imaging, it is not indicated for hepatocellular carcinoma treatment. However, in Europe and other parts of the world, Lipiodol is indicated both for the imaging and treatment of hepatocellular carcinoma. This oily medium works as an effective drug carrier, and tumour-seeking embolic agent, all at once. Most importantly, it is iodinated and can thus be easily visualised using any X-ray based imaging modality such as fluoroscopy or CT. This particular characteristic has become the key advantage with respect to identifying intra-procedural embolization endpoints.

Beyond embolization endpoints under fluoroscopic guidance, the introduction and standardisation of cone-beam CT imaging in the procedure room has allowed for Lipiodol to become a true imaging biomarker for therapeutic efficacy. As such, cross-sectional cone beam CT imaging provides immediate quantitative information on tumour coverage with Lipiodol oil, which can then be used as a key instrument to identify undertreated compartments of the target lesion with the catheter still in place. Such measurements have also been shown to closely correlate with tumour response, as measured on follow-up imaging, which usually occurs after one to two months after cTACE. This relationship establishes Lipiodol as an early indicator of therapeutic efficacy and allows for potential non-responders to be identified directly in the procedure room.

The conspicuity of ethidised oil also allows for an effective detection of non-target deposits, both within the liver and beyond, thus potentially gauging the extent of undesired toxicity. At the same time, Lipiodol causes no signal alteration on MR imaging and causes no interference with contrast-enhanced T1 sequences that are commonly used to assess tumour response. Despite all those benefits, Lipiodol has faced some challenges over the last decade and some practices have favoured the more recently introduced drug-eluting beads as the drug delivery vehicle of choice. However, TACE using drug-eluting beads (DEB-TACE) has yet to fulfill the promise of improved efficacy and its use has not translated into survival benefits for patients. Drug-eluting beads also lack the aforementioned imaging biomarker features of Lipiodol. It will thus be up to the interventional oncology community to resurrect and prospectively validate Lipiodol in the role it has played for almost 30 years ie, as a theranostic agent for the therapy of hepatocellular carcinoma.

Julius Chapiro is an associate researcher with the Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, USA. He has reported no disclosures pertaining to this article.

Jeff Geschwind is chairman, Department of Radiology and Biomedical Imaging and professor of Radiology and Oncology, Yale School of Medicine. Geschwind recieves grants from Philips, BTG, Boston Scientific, Guerbet and the National Institutes of Health. He is a consultant to Boston Scientific, BTG, Philips, Merck, Bristol-Myers Squibb, Guerbet, Terumo and Bayer.

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