Karen Brown, MD, FSIR, presented on bland embolization this year at the Symposium on Clinical Interventional Oncology (CIO) in Miami, Florida. Dr. Brown is Interventional Radiology Section Chief at the University of Utah in Salt Lake City, and her CIO presentation covered the rationale for embolization with particles/microspheres alone, and how survival and complication outcomes for patients are the same as with other therapies.
What developments led to the current practice of bland embolization?
Hepatic embolization began in the 1970s and early 1980s, before the days of sophisticated liver surgery. At that time, the idea was to kill a liver tumor by taking away its blood supply. Surgeons would find a large tumor that could not be resected, and they would ligate the artery as a method of treatment, hoping to make the tumor necrotic. However, the tumor would eventually return. The treatment strategy then evolved to occluding the blood supply to the tumor percutaneously rather than taking the patient to the operating room for surgery. Interventional therapies were evolving and the thought was to work with a catheter to occlude the tumor vessels. The patient outcomes were decent, with fewer complications, and seemed better than what other limited options were available at that time.
It remained difficult to completely kill the tumor, and efforts were made to improve response. Lipiodol was added since it was noted to be taken up by liver tumor. Subsequently lipiodol was mixed with chemotherapy with the intention of carrying the chemotherapy to the tumor, despite the fact that the chemotherapeutic agents did not dissolve in the lipiodol. The chemotherapy could wash out of the targeted area resulting in development of side effects, such as hair loss, similar to those seen with systemic chemotherapy.
More recently, drug-eluting beads have been used to deliver chemotherapy directly to a tumor. Pharmacokinetic studies have shown that microspheres remain in the tumor and elute the chemotherapy, typically doxorubicin, into the tissue over a period of hours to days. Blood-level measurements of doxorubicin are very low after treatment with drug-eluting beads, and patients rarely experience side effects such as neutropenia or hair loss.
However, myself and some others, believe that the most important factor in killing the tumor is ischemia rather than chemotherapy, as hepatocellular carcinoma (HCC) is resistant to most chemotherapeutic agents. I believe that penetrating the tumor and blocking the microvasculature can create better ischemia and thereby kill the tumor. This concept led to a randomized trial that was published in 2016.1 In this trial, embolization with a microsphere that was not loaded with a drug was compared with a drug-eluting microsphere. That study demonstrated that there was no difference in any outcome between the two methods.
What types of particles are used for various tumor sizes?
We generally prefer to use the smallest size particles possible. However, the as tumors grow, the blood supply becomes more prominent. One of the hallmarks of malignancy is that tumors become vascularized.
With HCC, as the tumors become bigger, their vascular supply often becomes hypervascular. If small particles are used on tumors that are 10 cm or larger, it is possible that the particles could pass through the venous side and be shunted to the lungs. It is a known complication of embolization that patients can die of respiratory failure in this manner. With that in mind, if I am working with a small tumor (less than 3 cm) that is beginning to evolve its vascular supply, then I would tend to use very small particles that are very tightly calibrated.
If I am working with a tumor that is 1.5-2 cm or less, then I will almost always use 40 micron particles. I know that 40 micron particles will penetrate into the tumor neo-vascularity, and that although there are many vessels, the vessels are still small, and there is little risk of shunting through them. As tumors approach 10 cm, I would not use 40 micron or 75 micron particles. I tend to go up a step to the 100-300 micron range. The overall idea is to use the smallest particle that will penetrate into the intratumoral vessels without being so small that the particle passes through into the systemic circulation and shunts into the lungs.
In terms of current options available, Embozene (Boston Scientific) makes one of the most tightly calibrated protocols and has both 40 and 75 micron particles. Those are the smallest and most tightly calibrated non-drug-eluting particles on the market. There are also particles by Embosphere (Merit Medical), and other manufacturers that come in various size ranges.
Are there any procedural protocols that are important to highlight?
Patients receive a prophylactic dose of antibiotics prior to embolization because the procedure involves creating necrotic tissue and puncturing the skin. It is important to ensure that bacteria are unable to thrive in the tumor and turn it into an abscess. Patients also receive a dose of anti-emetic medication pre-operatively.
Post-operatively, patients may experience post-embolization syndrome. This syndrome consists of symptoms such as pain, fever, nausea, and vomiting. I give patients dexamethasone intra-operatively, as well as ketorolac, a nonsteroidal anti-inflammatory (NSAID) agent. The ketorolac is delivered intravenously during the procedure and then is continued around-the-clock for as long as the patient is in the hospital. The majority of patients go home the day after the procedure.
Do you use anesthesia for the procedure?
If a multifocal tumor or an entire lobe is being treated, then the anesthesia is not as critical to success. Personally, I prefer anesthesia for all of my cases. If patients are uncomfortable, it can be difficult to obtain high quality images that clearly display all the vessels supplying the tumor. When treating a smaller solitary tumor, especially if it is a watershed area between two segments of the liver, one could miss a vessel if not using anesthesia and if the patient is unable to breath-hold. If you cannot see the vessel, then you cannot treat the vessel, and the patient will have a recurrence of cancer.
What are some reasons why modalities other than bland embolization are chosen?
Sometimes Y-90 is preferred. Patients have almost no symptoms within a day or two of embolization with Y-90, though they may develop delayed symptoms or side effects. Overall, Y-90 is well tolerated and is an outpatient procedure that does not require an overnight stay in the hospital. Y-90 is quite expensive, perhaps more so than when using other embolization methods, even after taking into account the cost of the overnight hospital stay. Although Y-90 is very popular among practitioners, it is important to keep in mind that survival outcomes are the same as for bland embolization, with the exception of a prolonged thrombotic thrombocytopenic purpura, which is particularly important for patients on the transplant list. Y-90 is also known to contribute to deterioration of liver function in the long-term.
Transarterial chemoembolization (TACE) is also an option for many patients. There are some cost differences that may make TACE somewhat more expensive than bland embolization. A downside of TACE is that the patient is exposed to potential toxicities through chemotherapy in the bloodstream, and there appears to be a higher incidence of post-embolization vessel occlusion.
All these modalities should be viewed as tools in the interventional oncology toolbox. I think we sometimes tend to gravitate towards one type of embolization, whether TACE or bland or Y-90, and choose that type in all circumstances. There are specific situations where one modality may be the best choice, and there are specific indications that would lead me to choose Y-90 over bland embolization. My hope is that other interventional oncologists may come to be more open-minded about the role of bland embolization.
What do you hope that colleagues will take away from your presentation?
I want to emphasize that there is no difference in outcome between bland embolization and any other trans-arterial treatment method in terms of response, survival or complications. The key difference is that there is more post embolization syndrome with bland embolization than what is seen with Y90 or drug-eluting beads, although similar to what is seen with conventional TACE. I believe that there is less injury to the non-tumor bearing liver with bland embolization than with either chemoembolization or radioembolization. When treating liver cancer, it is important to balance two diseases—the underlying liver disease, and the tumor. A toxic treatment might kill 100% of the tumor, but if the treatment is too toxic, it might result in progression of the underlying liver disease and ultimately death from liver failure. We need to remain focused on the overall outcome for the patient.
1. Brown KT, Do RK, Gonen M, et al. Randomized trial of hepatic artery embolization for hepatocellular carcinoma using doxorubicin-eluting microspheres compared with embolization with microspheres alone. J Clin Oncol. 2016;34(17):2046-53.