A comprehensive review of liver-directed therapies available to aid in the management of biliary tract cancers.
Milind M. Javle, MD: I’m going to switch gears slightly. Dr Koay, and perhaps Dr Rocha as well, there are a variety of liver-directed therapies, and it’s quite confusing which way to go. There’s radioembolization, radiation therapy, radiofrequency ablation. Some places are also doing chemoembolization. How do we choose which is the appropriate modality? While we are focusing on targeted therapy and immunotherapy, I want to remind the audience that the treatment for these cancers is multidisciplinary, and even for nonresectable patients, there are a variety of liver-directed approaches that should be included. Dr Koay, you have published on this topic. How do you select from various therapies?
Eugene J. Koay, MD, PhD: Yes, thank you. It’s an area of controversy, is the bottom line. There are emerging data in multiple domains. I encourage my colleagues as well as my patients to think about it whenever they ask this question, should I do external beam radiation? This is in the setting of patients who are not surgical candidates. They’re unresectable, but they may have just liver-confined disease. The way I encourage them to think about it is, what is the safety of the treatment? Then also, what are the data that support the efficacy of the treatment? In that regard, it is a personalized decision because not everybody is going to be safe for all particular locoregional therapies. That can include external beam radiation, Y90 [yttrium-90 radioembolization], chemoembolization, radiofrequency ablation, HAI, the hepatic arterial infusion pump that Dr Rocha is studying, as well as others. You have to consider that patient-specific anatomy.
This goes back to the point about high-quality imaging and general clinical care of the patients. You need to understand how much liver you can spare; this takes from the surgical principles of making sure that there’s enough remnant liver that is going to be spared from your locoregional therapy. The liver is an essential organ, and so with external beam radiation, you have to make sure you’re going to spare enough functional healthy liver, or noninvolved liver, from the radiation adverse effects. The same goes for radioembolization with Y90, and any other local regional therapy to the liver. That’s the safety part. When it comes to efficacy, there are emerging data in all domains. With external beam radiation, there was a prospective phase 2 study among multiple institutions that published a local control rate of 94%, 2 years after the radiation, with a hypofractionated high-dose radiation regimen in 15 fractions. We were a part of that, and we’ve expanded on that.
Subsequently, we have offered this to a number of patients, as I mentioned earlier, looking at some of the molecular characteristics of these patients. There’s a lot of excitement about the role that radiotherapy may have for particularly patients with intrahepatic cholangiocarcinoma. In extrahepatic cholangiocarcinoma that is unresectable, we also have encouraging results there too. That is another area where it needs to have some multidisciplinary management. Those are areas where external beam may have some role. We need more clinical studies to begin to dissect how we identify the appropriate patients for that. I do think this goes back to all the topics we’ve already covered, some of the personalized anatomical considerations, some molecular considerations, whether they’re targetable or actionable as far as their mutational status is concerned.
When it comes to radioembolization, there has been a very nice phase 2 study that came out of Europe. This was also multi-institutional. It showed very encouraging results in patients who were unresectable. The response rate with radioembolization and chemotherapy was 39% in patients who were unresectable. There was a small population of those patients, about 40 patients, who got to go on to surgical resection. That is a very encouraging sign. It comes down to patient selection and understanding who might be on that borderline of not resection candidates vs resection candidates, and is there a possibility of downstaging of those patients?
The same thing goes for TACE [transarterial chemoembolization] as well as things like hepatic artery infusion, which Dr Rocha can speak about much more. I think it’s a wide-open field. This is where, again, multidisciplinary management is key. There needs to be a tumor board discussion to say, if this patient is indeed unresectable, what are some of the options we may have if we deliver this locoregional therapy for this patient? Is there an option for surgical resection if, say, the tumor regresses a bit away from this blood vessel or the bile duct? Or is it always going to be an unresectable case regardless of what happens? I think we have to take all those things into consideration, and that’s what guides us. There remains quite a lot we need to answer with future research.
Milind M. Javle, MD: Thank you, Dr Koay. I’ve learned working with Dr Koay, Christopher Crane, MD, and others at MD Anderson Cancer Center that often the setting is of critical importance. Liver-directed therapies are probably most effective in the setting of consolidation, or in the setting where the tumor is controlled with systemic therapy.
There was a very interesting abstract that I want to quote somewhat out of context, which was in HCC [hepatocellular carcinoma] presented yesterday at an oral session by Laura Dawson, MD. She showed that a single dose of 8 Gy was effective in palliating symptoms and improving survival in patients with HCC. While not all patients have access to the kind of sophisticated radiation oncology that Dr Koay offers, I think radiation oncology should be incorporated, radioembolization and other liver-directed therapy, in the multidisciplinary care of these patients. Dr Rocha, your institution has played a leading role in hepatic infusional therapies. Could you briefly comment on your experience and where you’re going with that?
Flavio G. Rocha, MD, FACS, FSSO: Absolutely. Thank you, Dr Javle. I would add to Dr Koay’s comments that sometimes local therapy also is there to control the disease in the liver. What happens sometimes with patients is they get in trouble because their liver starts failing. Again, even if there’s perhaps a small amount of disease outside the liver, if Dr Koay and his colleagues can control the disease in the liver, then we can prolong survival that way. As you mentioned, there are lots of ways to do this. We certainly have experience with hepatic artery infusion. It’s not a new technology, it’s been around for a while. The advantage there is that the pump, which is about the size of a hockey puck, is implanted surgically. The liver’s chemotherapy is directed at the hepatic artery. You get concentrated doses to the hepatic artery, and the advantage from a physiologic perspective is that the normal liver derives blood supply from the portal vein and the hepatic artery. Whereas tumors only derive their blood supply from the hepatic artery. That’s the therapeutic advantage. It can be used in combination with systemic therapy. The patients do need to be candidates for it from an anatomic perspective.
What I would add as far as indications is that we need to figure out the way to best do the treatment sequencing. That’s where a multidisciplinary discussion with Drs Koay and Shroff makes a difference. We have to know which therapy is not going to burn bridges so that the patients can be candidates for multiple lines of therapy. The other advantage of radioembolization as well is that it can treat the tumor and also cause hypertrophy. We use it for a dual function, particularly for those patients who are maybe borderline resectable and can get to surgery if we can get a bit of response and a bit of growth in their livers. Again, I want to highlight how important it is to have these discussions as a group and not in a vacuum.
Milind M. Javle, MD: The message I’m getting from the group here is that for liver-directed therapies, a multidisciplinary approach is critical. But applying them in a careful, methodical way is equally critical. We see patients who get multiple episodes of radioembolization and come in with a cirrhotic liver, for instance, without appropriate dosimetry like they do in radiation oncology. Unfortunately, despite a lot of talent in this field, we don’t have level 1 evidence such as phase 3 trials. Perhaps that might not happen anytime soon because this is not a common disease. We have to tap into local expertise and not hesitate to refer these patients to centers of excellence, and really be judicious in terms of administration of these therapies so that we do not burn any bridges.
Transcript edited for clarity.