Dr. Manish Shah (Host): Welcome to Weill Cornell Medicine CancerCast: Conversations About New Developments in Medicine, Cancer Care, and Research. I'm your host, Dr. Manish Shah. And today, we'll be talking about minimally invasive liver cancer treatments and techniques. Our guest today is Dr. Juan Rocca. Dr. Rocca is the Surgical director of the Weill Cornell Liver Cancer Program and an attending surgeon in the Division of Liver Transplantation and Hepatobiliary Surgery at New-York Presbyterian Weill Cornell Medicine.

He is a recognized leader in minimally invasive liver surgery and has been an early adopter of laparoscopic techniques, robotic surgery, and most recently histotripsy, a non-invasive technology for liver tumor ablation. Thank you so much for joining.

Dr. Juan Rocca: Thank you for having me, Manish. And I'm glad that we can discuss what we do here at Cornell.

Dr. Manish Shah: Let's just start off with some background. Tell us a little bit about why the liver is so important and, maybe from a cancer perspective, how central it is in terms of metastatic disease.

Dr. Juan Rocca: So, I usually tell my patients that the liver is like a giant factory. It does many different things in the body. But first, it facilitates digestion of nutrients by making bile. The bile is like a soap that helps digest the food that is in the gut. And then, all those nutrients are being broken down in the gut, go through the blood, into the liver.

And the liver processes all these nutrients to make proteins, to make hormones, cholesterol, which is very important for the brain, tissue regeneration, clotting factors, and is a big regulator of all the body metabolism. So, it has, I would, say almost infinite functions. It's extremely important for sustaining life, and it works 24/7.

Dr. Manish Shah: For almost every organ in the body, there's an arterial blood supply, and then the venous blood supply takes blood away from the organ back to the heart. The liver is unique in that there's an arterial blood supply that feeds the liver, but there's also a blood supply of the portal system, which is taking blood from the intestines into the liver, right?

And so, all the nutrients from the intestines and things like that also go to the liver. So in some respects, there's almost two arterial supplies and then one venous supply back to the heart.

Dr. Juan Rocca: That's right. And that's why it makes it a very special organ. Not only in terms of physiology or how it works, but also when it comes to cancer. But yes, the arterial blood delivers oxygen to all the tissues, including the intestines. And when the intestine absorbs the food, instead of returning the blood directly to the heart, returns the blood to the liver through the portal system.

So, the portal system is like a highway system where you deliver all the needs of a factory to really process and create new products. And at the same time, it's a place where if you have a cancer in the digestive system, it can deliver cancer cells into the liver and create metastasis.

Dr. Manish Shah: let's talk about cancer So, the liver can have cancers that start in the liver. Those are mostly liver cancer or hepatocellular cancer or cholangiocarcinoma. These are bile ducts that are in the liver that can originate. Are those cancers predominantly supplied by the arterial blood supply or the portal venous blood supply?

And then, is that different for metastases that go to the liver?

Dr. Juan Rocca: So, the two primary liver cancers, the two most frequent ones are hepatocellular carcinoma, which it's arising from the liver cells, and then the cholangiocarcinoma that arises from the biliary cells or the cholangiocytes. And they're supplied mostly by arterial supply, but they also depend a little bit on portal supply, but mostly by arterial supply.

And liver metastases or tumors that are not from the liver, but the cells are traveling through blood, through the portal system into the liver, they have a different type of blood supply. they have a cord that is not so vascular and then the liver is surrounding it with some mostly arterial supply.

And that is what sometimes lets us give some treatments through the arterial system into the liver, to really decrease the size of this metastasis.

Dr. Manish Shah: So, both primary liver tumors, whether it's a paracellular or cholangiocarcinoma or secondary liver tumors, tumors that spread to the liver from another organ are both generally supplied by the arterial system. And that allows for us to have an ability to give directed therapy by the arterial system and to preferentially attack those tumors, whereas sparing maybe some of the liver parenchyma, because the liver also has a portal venous supply, which has nutrients and oxygen.

Dr. Juan Rocca: That's correct. And that's one of the keys for the development of the transarterial therapies, as you mentioned, which are key on the management of not only primary liver tumors, hepatocellular cancer and cholangiocarcinoma, but also metastasis.

Dr. Manish Shah: In the last few years, immunotherapy has been revolutionary in terms of being able to treat some cancers like melanoma or microsatellite instable colon cancer, And what's really emerging is that the liver, if there are metastases to the liver, they can actually lead to some kind of immune resistance. So, not only is the liver really critical in terms of making all the proteins and coagulation factors and things like that, but it also is critical in directing systemic immunity that can affect the ability of immunotherapy to work.

So, it really is kind of a central organ in terms of cancer. it metabolizes drugs, so it metabolizes chemotherapy and it can affect also the efficacy of immunotherapy. So, I think that's really quite fascinating. And so for me, Dr. Rocca, that means that you're going to be very busy because this is really complicated.

Dr. Juan Rocca: Yes. Clearly, in the last few years, with the new systemic therapies that are beyond chemotherapy, but the immunotherapy and targeted therapies, surgeons have been busier, not less busy because it's allowing us to treat with surgery cancers that we couldn't imagine that we would be able to treat before.

Dr. Manish Shah: Let's talk about the different things that can be done for tumors that are in the liver, the panoply of different options so that people know that it's really quite complicated. let's start with surgical techniques. So, the different surgeries that could be done to address liver metastases,

Dr. Juan Rocca: the classic liver surgery has always been open, a traditional liver surgery. You know, the liver, it's like a big sponge that holds significant amount of blood and blood vessels going through it at high pressure and low pressure artery, portal vein and the hepatic veins. So, it's a very complex organ if we have to cut a piece of it.

It is a kind complex operation, no matter how much liver you're removing, always, you need to be prepared to deal with bleeding and need to control bleeding during the operation. So, that's one of the key issues. Any liver surgery, no matter how you approach it, will have the risk of bleeding during the operation or immediately after.

And then, the other thing that we cut is bile duct, right? So, these bile ducts, when we cut them, we put stitches, we clip them, we seal them with different techniques, but they can eventually open up and leak. And the bile is like olive oil. It is very sneaky.

It doesn't have a clotting factor like the blood. So, the blood when it clots, it's seals. But the bile, when it starts leaking, you need to really direct that leak. And it takes a few days to a few weeks to resolve. So, that's one of the downsides of liver surgery.

One is bleeding, the other one is bile leak. And then, infections or, in extreme cases where we remove too much liver, you can have liver failure, or sometimes until the liver grows back, which is another quality of the liver, you can cut up to 70% of the liver, and that remaining 30% can grow back very quickly in actually six to eight weeks.

But during that period where it's growing back, your immune defenses can be low, your metabolic functions may not be very well supplied. You go through a period of vulnerability where you are more prone to infections, and metabolic dysfunction. So, it's important to consider those three main things: bleeding, bile leak and liver failure.

That's for any type of liver operation. Of course, the larger amount of liver, the higher the risk of any of these three complications.

Dr. Manish Shah: And then, there's robotic surgery, which is something you specialize in.

Dr. Juan Rocca: That's right. So, that is part of what we call minimally invasive surgery. Minimally invasive surgery has been around for decades now; first, with laparoscopy, and probably everybody's familiar with the laparoscopic gallbladder surgery, which is surgery through small keyholes, instead of making a big incision. And we put instruments through those small keyholes to perform the operation.

Now, robotic surgery has the same principle than laparoscopic surgery, is surgery through keyholes. But the instruments that we are introducing through those keyholes are still commanded by the surgeons. It's not the robot that is commanding the instruments, but they are articulated and they're like mini hands inside the body, so we can perform pretty much any maneuver that we do in traditional open surgery, we can do it minimally invasively.

And that allows us to still be minimally invasively, like a gallbladder surgery, but to perform much more complex operations like liver surgery, including liver transplantation nowadays.

Dr. Manish Shah: That's incredible. Let's talk about transplantation because that's, I think, the most extreme form of surgery where you're replacing the liver with someone else's liver. Can you talk about that? I think the main question might be a donor liver versus the other types of transplants that are available.

Dr. Juan Rocca: Liver transplantation, for the purpose of cancer surgery, is a good solution when the cancer is not in one spot of the liver, but in many different spots. Trying to remove all these cancer spots becomes impossible. So then, the rational here, instead of cutting pieces of the liver, is to cut the entire liver out with the disease, and then replace that liver with a normal liver from either a deceased donor or a living donor.

A deceased donor will typically donate the entire liver, or whole liver. And a living donor will typically donate part of the liver, which could be 30%, 50%, or up to 70% of a normal liver. So, those are the two main sources of liver transplantation.

Dr. Manish Shah: when you do a directed donor, you take the entire liver of the person that you're doing the operation on and replacing it with a portion of someone else's liver. Is that right?

Dr. Juan Rocca: That's correct. That's living donor liver transplant. We remove the entire liver on the recipient, but then we remove a part of the liver on the donor. And we split the liver literally in two. But there are different proportions of volumes on the donor and the recipient, but the concept is that we transplant only a piece of the liver to the recipient, but that piece of the liver will grow back in a matter of six to eight weeks, almost to 90% of the original volume.

Dr. Manish Shah: Oh, that's incredible. We're doing liver transplant not only for cirrhosis, which is kind of liver. But also, often for patients that have cancer that spread to liver, but has disease that's limited only to liver. And those cancers include neuroendocrine cancer, cholangiocarcinoma, colorectal cancer. Any others on the list? I think that the diseases that we can transplant are increasing, right?

Dr. Juan Rocca: Yes, that's a great point. So, originally, we used to do liver transplantation for liver cancer only on primary cancer of the liver, and this was mainly for hepatocellular cancer. And the reason why we did that was because we couldn't do surgery on those livers because the liver had cirrhosis.

And so, cirrhosis, it's a condition on the liver where the liver would not be able to regenerate after the surgery and would go into liver failure. So, the rationale was to just remove the entire liver and give you a new liver to remove the tumor because the liver could not tolerate an operation.

That's for primary liver cancer. Then, the liver transplantation starts addressing other types of cancers in the liver that were from metastasis. And these were like, for example, neuroendocrine tumors, which are very slow-growing tumors and can take decades for the tumor really to get out of control. But it invades the liver in multiple sides of the liver and surgery cannot address all the tumors, and the tumor is only in the liver and nowhere else, then you could remove the entire liver and replace the liver with a transplant.

And it made sense because neuroendocrine tumor was very slow growing. What is new now is that, for metastasis, we are doing liver transplant for colorectal liver metastasis. This is colorectal cancer that has metastasis to the liver. And the benchmark for survival after liver transplant is about 80% at five years for primary liver cancer.

And now, the colorectal liver metastasis is given a five-year survival of 60-80%, depending on the case selection. So, it's getting very close and that's why transplantation is being allowed for this disease.

Dr. Manish Shah: it's really been transformative, the advances in liver surgery and the application of more aggressive liver surgery, including transplant for cancer care. Let's shift for the next few minutes to talk about the different kind of ablative techniques. Conceptually, the way I think of it is that liver surgery removes the cancer from the liver or the entire liver.

If there's too much cancer in the liver, ablative techniques kill the tumor that's in the liver by different methodologies. Is that right?

Dr. Juan Rocca: That's right. So, the original ablation techniques were temperature-based. The concept was to insert a needle into the tumor and raise temperature that would pretty much cook the tissue and denaturalize it. And those cells, the good ones and the bad ones that were in that area, would die from high temperature.

And so, the initial way to do this was radiofrequency, then it was moving to microwave technology, which is the one that is being used most frequently, microwave ablation. This could be done at the time of an operation. You can remove some tumors and ablate other ones, or it can be done without an operation, through the skin under imaging guidance with ultrasound or CAT scan.

And typically, this is being done by our colleagues, the interventional radiologists. But we have been working together with this type of technology because sometimes we do these same procedures during an operation. So, that's what we call typically ablation, which is either radiofrequency or microablation. And now, there's a new competing, technology, which instead of using high temperature to kill the tissue, is using an ultrasound-based technology.

This is called histotrypsy, instead of creating high temperature in the area, what it does is by ultrasound waves, it creates like shock waves that create a kind of a scissors type of mechanical force that liquefies the tissue in that spot, it breaks down the cells and creates like a liquid of it without viable cells.

And that's called histotripsy, which it has the advantage it does not require any sort of Incision or needle to go into the body. It can be done extracorporeally like radiation does. And right now, we're doing different types of trials to test how good histotripsy is compared to the existing technologies that have been around for about 20 years now.

Dr. Manish Shah: There's been a lot of interest with histotripsy it's exciting to be able to kill tumors based on ultrasound wave technology as opposed to heat. Because as you mentioned, the main excitement is that it's what we call a no-cut kind of technique to try to ablate the tumors. And then, there are other ways to direct treatment to the liver, such as radioembolization, which is where we inject small little beads that are tagged with radioactivity and they are delivered to the site of the tumor.

And that's where we take advantage of the arterial blood supply to these tumors. And then, there's also transarterial chemotherapy or chemoembolization where we deliver chemotherapy directly to the tumor as well. And then, there are even other techniques such as external beam radiation or SBRT, which is stereotactic body radiation.

There's so many different techniques. And maybe what we should think about is how are these decisions made between all the different options. And we had our tumor board this morning, maybe you could describe that a little bit,

Dr. Juan Rocca: i'm glad that you brought up the concept of tumor board and multidisciplinary care. And I think the key of all this is really to look at each patient and what type of tumor they have, the location, how it's responded to chemotherapy or immunotherapy. And from there, come up with the best method to remove that tumor from the liver.

It could be with open surgery. It could be with robotic surgery, minimal invasive surgery. It could be with ablation, a microwave ablation. It could histotripsy, it could be radiation, it could be transarterial embolization, either with radiation beads or chemotherapy directly or radiation therapy. So, it's really important that we try to allocate the best tool for each particular case, rather than trying to only work with one tool.

And that's the value of multidisciplinary tumor board, where we have radiologists, oncologists, liver surgeons, interventional radiologist and hepatologist. So, that's the key.

Dr. Manish Shah: So for our listeners, the features that are critical in terms of helping guide this decision will be, and I'm just going to list a few of them. And then, you'll tell me how many more there are, which are probably more, but I think it's the number of liver lesions and the relative location to a blood vessel or to the bile duct.

And then, the performance status or the function of the liver, and then also what other treatment options there are available to give the best outcome. Those are, I think, some of the key ones, but are there others that you would think of?

Dr. Juan Rocca: Maybe we can bring a couple of examples to illustrate what you just said. for example, if someone has a decent sized tumor, let's say the size of a softball, okay? But it is in an area of the liver that, by cutting half of the liver, it can be removed safely without compromising the oncologic outcomes because we can remove the entire tumor out.

And the patient is in good shape and is fit for tolerating operation, well, that's the goal. We are removing the entire tumor without leaving tumor behind. And that's the goal of bringing someone without evidence of disease, or what we call NED. So, that's the most straightforward discussion. On the other end, the patient has multiple tumors in the liver at both sides of the liver.

It's what we call multifocal, multiple sites, and bilobar, in both sides. So, multifocal bilobar disease becomes a very challenging situation for a surgeon, because it's hard to cut out multiple sites of the liver without compromising the oncologic outcome. We probably are going to be leaving something behind. And that is where either we think about transplantation, if that is the case, we've removed the entire liver with all the tumor burden.

But there are many patients that are not in a situation that can receive a transplant for different reasons, they may be too old. They may have other conditions. Maybe the type of biology of the tumor doesn't allow us to consider transplantation safely. So then, you need to consider other treatments that are non-surgical and delivering treatment through the blood vessels of the liver is a very smart way to deal with this.

This is the transarterial therapies or ablation that has shown that ablation, for example, is equivalent to surgery when tumors are under three centimeters, at least for colorectal liver metastasis. So, anytime depending on the location we decide to do ablation or delivery with transarterial therapy, or sometimes, when we don't have a good option, external gene radiation is the way to go.

Dr. Manish Shah: Those are important examples, and we see this every day. So, I think the number of lesions in their location within the liver, if they're all localized on one side where a resection makes sense, then I think that would be the preferred way. But if they are deep in the liver or isolated, then maybe more local regional treatments are the best approach.

What about histotripsy? So, let's focus on that a little bit. I think what's unique about histotripsy is that the shock waves that you were describing, they can liquefy the tumor. But relatively, they don't damage the bile ducts or the blood vessels. So, this might be very unique technology that's good for tumors that are next to these bile ducts or blood vessels.

Is that fair?

Dr. Juan Rocca: Yes. We are studying this better, but that's the concept. The frequency of the ultrasound waves create cavitation. And that cavitation may destroy the liver cells and the tumor cells, but may not destroy the blood vessels or the bile ducts that have high collagen on them. So, that's a good way to selectively destroy the cells that you want to destroy and preserve the scaffolding of the liver for the main blood vessels or the bile duct.

And sometimes the cells on the scaffolding get killed, but then the scaffolding allows cells to regenerate there. So, it's a very interesting effect of lithotripsy, which allows to preserve the most important structures of the liver while eliminating the cancer cells. And this is something that slowly we are becoming a bit more encouraged to treat lesions that are more central.

Initially, we were only treating lesions that were more peripheral. And we have had success in showing that blood vessels in treated areas with histotripsy regenerate very quickly. And they continue giving blood to the liver.

Dr. Manish Shah: So, the collagen scaffold allows for the correct blood vessels or bile ducts to regenerate in the area. And we selectively kill the cancer cells and they don't regenerate. We don't have long-term data, right? But that's the hope.

Dr. Juan Rocca: Yes, exactly. So far, it is something we need to prove over time that it's sustained, and we need to bring more patients to trials to really confirm that. But that's a very important concept.

Dr. Manish Shah: Surgery has been part of our practice for decades. And so, we do long-term data on the survival of patients after a successful surgery, whether it's a cholangiocarcinoma or a liver cancer. And then, there's less data, but still quite a bit of data on the older liver-directed therapies like ablated techniques or radioembolization.

And the most recent technology is the histotripsy. It's only been available, I believe, since January of '24 or something like that. 'So, not even two years. And so, the long-term data are just not available. So, it's very possible that histotripsy works really well and is another excellent way for us to control cancer.

But over time, we may find that this liquification of the tumor bed may be 99.9% successful. But that 0.01% of cells, if they recur in some patients, then that may not be the best option and we may be more selective. So, I guess my point is that, as we get more data, the indications for histotripsy versus the other local regional treatments might be tweaked a little bit.

So that way, we can give patients the best chance of a best outcome.

Dr. Juan Rocca: Yes, you're absolutely right. And that's why it's so important to conduct studies because imagine the number of different situations of tumors, depending on the location, the biology of the tumor, we really need to dissect out all these little details to see where histotripsy is better than other therapies that have shown over time to be very effective.

It may be that's for some certain type of tumors works better than for others, despite the same location. We still don't have that long-term followup data to answer that question.

Dr. Manish Shah: Well, this has really been terrific. Are there any other exciting areas of research regarding liver-directed therapies or cancer in the liver that you're excited about or are on the horizon?

Dr. Juan Rocca: With every technique that we use as surgeons, we are always conducting studies to see if they're effective or not. Of course, our main driver of innovation in what we do in liver surgery is robotic surgery right now. And what we're trying to show is that by having a minimally invasive surgery, or that having complex operations on the liver with minimal invasive surgery, allowing a faster recovery of the cancer patient that allows the cancer patient to continue other treatments like chemotherapy or immunotherapy in a more streamlined fashion than with traditional surgery, that you would have to probably wait a couple of months to recover, to go back to your medications.

And that can allow a better long-term survival, or better long-term control of the disease by disrupting less the main oncologic treatment, which usually is a systemic treatment. It's not just local. Think it's important to acknowledge that, for most of the cancer treatments, surgery is a way to control part of the disease.

But when the disease is metastatic, you really need to control the disease in the blood, and that's what we are looking into.

Dr. Manish Shah: And this actually is a great segue to another key takeaway, which is that, with all these new technologies, both in terms of local treatments as well as our ability to treat cancers better with targeted therapies and immunotherapy, you have become busier, not less busy. And that's because you're able to offer care to more people, which I think is really quite remarkable.

Dr. Juan Rocca: Exactly. in the past, surgeons would only treat early cancers that were early enough that could be removed with surgery completely. And now, we are treating any type of stage of cancer because, after having chemotherapy, immunotherapy, targeted therapies, those tumors can be reduced to a size that we can consider a safe operation and an eradication of the tumor.

So, it's actually broadening our practice. And also, we are starting to understand that the surgical practice is one component of the oncologic care of a patient, and it's not all of it.

Dr. Manish Shah: Yeah, I think that really highlights a theme that we have here on CancerCast, that cancer care has become diverse and complicated, and patients are best served by a multidisciplinary team approach. I think the disciplines that we can offer really provide a unique ability to give individualized care to patients.

And it's something that we strive for.

Dr. Juan Rocca: Yeah, I couldn't agree with that more.

Dr. Manish Shah: Well, Juan, thank you so much for your time today. To our listeners, you can download, subscribe, rate, and review CancerCast on Apple Podcast, Spotify, YouTube or online at weillcornell.org. We also encourage you to write to us at cancercast@med.cornell.edu with questions, comments, and topics you'd like to hear us cover in the future.

That's it for CancerCast: Conversations About New Developments in Medicine, Cancer Care and Research. I'm Dr. Manish Shah. Thanks for listening.

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