By Michael C Soulen
Debates were a popular format at the World Conference on Interventional Oncology (WCIO; Chicago, Illinois, USA, 14–17 June) and at many interventional radiology meetings in recent years. A recurring theme has been alternative embolotherapies for hepatic malignancies: bland embolization vs. chemoembolization, oil vs. drug-eluting beads, chemoembolization vs. yttrium. Of course, if there were level one evidence to support a particular practice, there would not be much of a debate! The popularity of this theme is a sign of the lack of clear cut best practice in what is a large and developing part of many interventional radiology practices. These debates provide a lively platform for purported expert doctors to become spin doctors.
What evidence do we have to guide us in the day-to-day care of our patients?
In the 1980s and 1990s, Lipiodol was observed to be selectively taken up and retained in hepatocellular carcinomas, and to serve as a carrier for dissolved or emulsified chemotherapeutic drugs. Iodized oil retention was proven in resection studies to be an imaging biomarker for tumour necrosis, and this imaging marker was predictive of patient survival. In 2002, two randomised trials of chemoembolization with doxorubicin, Lipiodol, and particulate embolics performed in Europe and Asia both showed improved survival compared to best supportive care. Chemoembolization with Lipiodol, an anthracycline, and particulates became the de facto standard of care for unresectable hepatocellular carcinomas.
What happened to plain old bland embolization?
In fact, the European randomised trial of chemoembolization had a bland embolization arm that performed almost as well! The trial was stopped at the point when survival in the chemoembolization arm became significantly better than the control arm, with a hazard ratio of 0.47 (0.25-0.91), p=0.02. The bland group had identical 3-year survival, with a hazard ratio of 0.57 (0.31-1.04), p=0.07 compared to the control group, on the verge of statistical significance and indistinguishable from the performance of the chemoembolization arm.
Clinical trials enrol early-stage, low risk patients with Childs A liver function. In real life practice, the majority of chemoembolized patients have more advanced disease. Although bland and Lipiodol-chemoembolization have never been compared prospectively in advanced hepatocellular carcinomas, large series from major cancer centres in the USA treating a complex mix of hepatocellular carcinoma patients also show identical survival outcomes.
This gets to one of the core controversies in chemoembolization: is the primary mode of action ischaemic cell death from embolization, or is it cytotoxic drug delivery? The similar outcomes between bland and chemoembolization argue for the former. The drug-eluting bead embolic platforms are betting on the latter.
Embolic microspheres that can carry therapeutic payloads are a logical leap forward in targeted therapy. Loaded microspheres improve local delivery and decrease systemic leak of drug compared to oily emulsions. Microspheres open the door for delivery of novel therapeutics, such as viruses, genes, antimetabolites, and alternative drugs too toxic when given systemically.
For better or worse, the early clinical studies with drug-eluting beads focused on delivery of doxorubicin to hepatocellular carcinomas. Since Lipiodol chemoembolization already delivers lethal levels of doxorubicin to hepatocellular carcinomas, and the additional therapeutic benefit from adding doxorubicin is marginal anyway, it is not surprising that prospective trials to date have shown identical outcomes with doxorubicin-drug-eluting beads, oily chemoembolization, and bland embolization in hepatocellular carcinomas. The ongoing HiQuality randomised trial of doxorubicin-drug-eluting beads vs. doxorubicin-Lipiodol in advanced hepatocellular carcinomas, sponsored by Merit Medical, will help elucidate this further.
The other hot alternative is radioembolization with yttrium-90 microspheres. This, slower, gentler approach to embolotherapy is better tolerated than ischaemic techniques, with a similar safety profile. There are no prospective trials of Y-90 radioembolization compared to other embolotherapies. A published series reporting long-term survival show similar outcomes with Y-90 to chemoembolization for hepatocellular carcinomas, cholangiocarcinoma, and liver metastases.
So does it matter which embolotherapy you choose?
For the average patient, probably not. In practice, I provide new patients with detailed information on chemoembolization and radioembolization, and let the patient decide which to do first-line.
That being said, no patient is average. There are plenty of circumstances where personalised care dictates a specific treatment plan. Use of chemotherapeutic drugs may be contraindicated in patients with cardiac, haematological, or renal insufficiency. Toxicities from post-embolization syndrome make chemoembolization less desirable for the elderly, debilitated, and patients with caretaker roles, who tolerate radioembolization better. Treating via extrahepatic collaterals is safer with bland embolization when non-target tissues are at risk. Patients with biliary stents or surgery are at high risk for liver abscess following chemoembolization; radioembolization appears to be safer in this setting.
Michael C Soulen is a professor of Radiology and Surgery at the Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA, and chairman of the WCIO Board of Directors.
