Liver-Directed Therapy Could Shift First-Line Treatment for mCRC

Growing Treatment Paradigm in CRC

John L. Marshall, MD

If an overall survival advantage is found for patients receiving first-line FOLFOX6 with or without bevacizumab (Avastin) plus Yttrium-90 (Y-90) resin microspheres for liver metastatic colorectal cancer (mCRC), the field could see a significant shift in practice, says John L. Marshall, MD.

In an interview withTargeted Oncology, Marshall, chief of the Division of Hematology and Oncology at Medstar Georgetown University Hospital and director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers, reviewed findings of the phase III SIRFLOX trial, which was the first of 3 randomized controlled trials to explore Y-90 resin microspheres, and the potential impact from the remaining 2 trials, FOXFIRE, and FOXFIRE Global, which will be combined with SIRFLOX for an overall survival analysis that will contain 1103 patients.

Targeted Oncology:Can you give an overview of your talk on liver-directed therapy?

Marshall: In colorectal cancer, particularly mCRC, we've created this new subclass of patients with liver-dominant or liver-only metastatic colon cancer, and we’ve got all sort of tools and new, effective ways of managing that. Part of my thinking is should we begin to carve out really its own pathway, its own strategy for these kind of patients.

I really spent most of the time reviewing the knowledge that we have today. We have this belief that we should be giving chemotherapy around the time of a surgery for liver metasteses, and yet there really is no solid evidence that says that chemotherapy will add benefit to patients. So it doesn’t really have an “adjuvant” effect like we’d like it to have, meaning more people are cured if you give chemo than just doing surgery, and there really has only been shown a minor improvement in progression-free survival (PFS). So I actually believe personally that this is a different kind of animal, the surgery either cures patients or you have to treat them to progression, or at least wait until mets recur and manage it that way, just thinking of metastatic disease.

But then there’s this other group that has come out and these are liver-dominant patients who can’t have surgery, and it is this group where we have some new, exciting tools. Traditionally, we’ve been giving just chemotherapy until they drop. Well now, we’ve got more and more evidence that liver-directed therapy, whether that is chemotherapy, or the latest bell and whistle is called Y-90, Yttrium-90, where that’s injected can treat and control liver metastases for an extended period of time.

The primary study that I reviewed was the SIRFLOX study, and SIRFLOX randomized patients between FOLFOX6 plus bevacizumab (Avastin) versus FOLFOX6 and bevacizumab plus Y-90, right at the beginning, not when we normally have been using it as a salvage refractory therapy, but right at the beginning during the first cycle.

What this showed was, at least in the liver, there was a 12-month versus 20-month liver PFS, so big piece of change, almost 8 months improved outcome in terms of liver-specific PFS. There are 2 other studies that are coming before the overall survival analysis will be done.

The trick or the problem with this is that in this study patients were included who had extrahepatic disease, so they could have small volume lung disease, lymph nodes, that sort of thing, so the overall PFS was no different between the 2 arms. We’ll figure this out — does liver-dominant disease deserve up-front liver-directed therapy or not? We’ll know in for sure in about a year when the overall analysis is done.

The 2 additional studies are basically the same as the ones that have been done and will add enough patients and enough statistical power to tell us whether survival is positive.

Targeted Oncology:What can you tell us about Y-90? What do we know about it and what do we still need to know about it?

Marshall: Y-90 is really different. We think a lot of the times we’re injecting things into the liver, we’re doing it because it cuts off the blood supply. The liver is the only organ with 2 innies, it has an artery that goes in and a vein that goes in, and a vein that comes out. It turns out that the cancer likes to live on the artery and the liver is perfectly happy living off that vein. We take advantage of that by sneaking catheters in, interventional radiologists sneak in catheters and inject stuff. Our initial belief was that we are just choking the blood supply off to the tumor and that’s embolization, and then we said let’s throw a little chemo in there, and that’s chemoembolization.

Y-90 is actually different. It’s small particles, but those particles are bathed in radiation, Yttrium-90, and instead of it being sort of blood vessel choking, they just sort of hang up in the tumors and radiate inside out. Think of it as long-term, about a month-long of radiation, low-level radiation, delivered directly into the liver inside out. That’s important because it’s not embolic, it also means it’s a lot less toxic, there’s a lot less pain, nausea, fever, infection associated with it.

As oncologists we have to understand that mechanism because almost always when we radiate a GI cancer, we like to throw a little 5-fluorouracil (5-FU) in with it, so I almost always will use capecitabine for a month or so around the time of the injection of the Y-90 because I’m doing synchronous sensitization, so think of it as low-level chronic radiation, not embolism.

Now it does cause some liver hypertrophy so we know we want to do that sometimes to do liver resections, and so it’s not useless in that regard and so early Y-90 might convert some patients to resectable because of concomitant liver hypertrophy.

Targeted Oncology:What toxicities, if any, are there and when you add capecitabine with it, does it increase the likeliness of toxicities?

Marshall: So it’s generally a pretty safe procedure, so nowadays we're able to inject it through a radial artery, but typically it’s a groin artery, so they snake it up in there. It’s a procedure, you have anesthesia for, so there’s always that side effect. The treatment itself is usually very well tolerated, but people will complain of some fatigue or mild nausea, low-level fever for maybe a day or 2, or even longer, because remember we’re radiating over time, so they sometimes feel off a bit. I will say the majority of our patients that are going through this have very few side effects so they feel like nothing happened. You have to prepare your patient that it could and then expect and hope that it won’t be too bad.

The SIRFLOX study did regular dose chemo with it, so we know the safety is there, there’s a little bit more myelosuppression seen with it, a little bit more liver toxicity, a little more GI toxicity, but not through the roof, so it’s safe, in general. The worry I have is the more we’re using this early in the course, and now patients are going to live 2, 3, 4 years, what’s that going to do to their liver long-term? We know you can have liver resections, that’s OK, but do you get cirrhotic, do you get hypersplenism, do you get thrombocytopenia, because of the liver treatment up front, and I think our additional clinical trials will help teach us the answer to that.

Targeted Oncology:What are the next steps following this study?