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Management of Regional Colorectal Cancer Metastases

Panelists: John L. Marshall, MD, Georgetown University; Bert H. ONeil, MD, Indiana University School of Medicine; Marwan Fakih, MD, City of Hope Comprehensive Care Center; Gabriela Chiorean, MD, University of Washington School of Medicine; Wells A. Messersmith, MD, FACP, University of Colorado Cancer Center
Published: Thursday, Sep 20, 2018



Transcript: 

John L. Marshall, MD: Quickly, gang, let’s cover the sort of very complex world. There is no book to read; you’ve got to figure it out on your own. How do you deal with patients with regional metastases where your goal is lofty and maybe even curative in nature? And we’ve got pretty good data around liver disease, but we’re talking about peritoneal disease now and other modalities. Marwan, how’s it handled at your place in terms of deciding how to manage these patients?

Marwan Fakih, MD: For liver disease, I have to say at our center, we’re blessed to have the ability to have pumps. So, we have been using hepatic arterial infusions in high-risk patients.

John L. Marshall, MD: You’re 1 of the 4 places on the planet that’s doing that.

Marwan Fakih, MD: We’re one of the few places.

John L. Marshall, MD: Anybody else doing that?

Gabriela Chiorean, MD: I’m sending patients to New York.

John L. Marshall, MD: We send them…there’s a train that takes them to New York.

Marwan Fakih, MD: So, for the regional disease, I think that’s probably a 3-hour session, because what is regional disease? It is potentially resectable. Is it resectable now? Is it high-risk of recurrence? What is your risk stratification for recurrence here? What’s your CRS score? And so, all of these factor in to what you want to do for the patient. But if we’re talking about regional disease adjuvant therapy, we do kind of discuss these in a multidisciplinary setting. If it’s liver only—we think the patient has a very high rate of recurrence in the liver, such as 4 or more lesions—we are considering some of those patients for hepatic arterial infusion placement.

John L. Marshall, MD: You’re impressively consistent because you’re bracing the right- and the left-sided EGFR survival advantage, FOLFIRINOX survival advantage, and infusion pump survival advantage. They’re all a pain, and they’re tough to manage, and they require a lot, but you’re really going for that OS, where I think the rest of us are saying, “Well, it’s just hard; it’s complex, and it would require major changes.” And I know you guys have seen the fact that they stopped making these infusion pumps.

Marwan Fakih, MD: Right.

John L. Marshall, MD: So, we have to, for those folks who are still doing that, figure out how to do it. Is there any patient who really should get Y-90?

Wells A. Messersmith, MD, FACP: So, the short answer is maybe. By the way…

John L. Marshall, MD: I’m going to go to somebody else; come on.

Wells A. Messersmith, MD, FACP: I live in the West, so all these comments about the wild, wild West—I’ll let them fly. So, I think, first of all, you have SIR-Spheres; they’re low-dose radiation regional. And there are the FOXFIRE and SIRFLOX trials, which are essentially negative.

John L. Marshall, MD: Frontline.

Wells A. Messersmith, MD, FACP: Frontline. So, that definitely dropped off our use of those in the frontline setting.

John L. Marshall, MD: Do you believe the right-sided subgroup on that?

Wells A. Messersmith, MD, FACP: Again, I think it’s hypothesis generated. I’d want to see something prospective. TheraSphere, which is a high-dose, very targeted radioembolization technique, those trials are ongoing. There’s a second-line trial that we’re participating in, and we’re still on occasion doing that. I will say that over the past 18 years of doing this, the ability to resect lesions has become much more, in terms of really worrying more about the future liver remnant, what you’re left with rather than what you had to begin with; portal vein immobilization allowing the other side of the liver—for instance, hypertrophy and a greater future liver remnant. So, we’re certainly more aggressive about resections than we were before. But our radioembolization rates have dropped considerably since the publication of those trials, just following the data.

John L. Marshall, MD: Yes. I think we use them a lot in the refractory space in liver-dominant disease. Particularly, a lot of us are phase I-ers up here. You see that patient from outside—a lot of disease in the liver—while you’re waiting on the slot or you need a new biopsy to prove a marker. You go to IR, you get a little biopsy, you get a little Y-90, and then 4 weeks later, you’re good to go. Are you all playing that game?

Wells A. Messersmith, MD, FACP: Well, it’s just interesting that we work in an industry where we buy a Lexus and we’re just not sure if it works. If I turn the key, it might not work at all, and you’re just going to get out and walk away.

John L. Marshall, MD: Tesla.

Wells A. Messersmith, MD, FACP: Yes, exactly.

John L. Marshall, MD: If only it were a Lexus.

Wells A. Messersmith, MD, FACP: So, I think we just have to keep that in mind, that there’s only enough money in the till, and these things are really expensive.

John L. Marshall, MD: In my world, I come from HIPEC-ville where Sugarbaker started the business in the Washington, DC, region. So, we’re very heavy-handed. I’ll defer to you guys to set me straight a little bit. Gabriela, do you think there’s a role in colon cancer for HIPEC? Do you send patients sometimes for that?

Gabriela Chiorean, MD: I actually do. So, for those select patients who don’t have visceral disease—they have peritoneal carcinomatosis—I typically start out with systemic chemotherapy, but I do want them evaluated serially by a surgeon expert in cytoreductive surgery and HIPEC. And more often than not, I’m being told the patient is not a good candidate; the burden of disease is too high. Oftentimes I say, “Let’s wait for 6 months, do a laparoscopy, and look at their burden of disease.” I would say very few patients are good candidates for HIPEC, but those that are, I would not hesitate to refer them.

John L. Marshall, MD: Counter to that anybody? Is there a case to be made?

Marwan Fakih, MD: We actually offer HIPEC in our center, as well, but we’re quite selective. I think we’re all waiting for the data to see, how much does the hyperthermic chemotherapy add to the cytoreduction? I think that’s a very important question. This is not in any way an easy procedure. It takes about 2 to 3 months for patients to recover fully. They have significant discomfort in the abdomen that continues for about 8 weeks or more. It’s not easy to go back on chemotherapy. So, I think it’s important to look at the carcinomatosis score in those patients and just limit it to the patients where the data have shown that you’d make a dent. I have to say, the cure rate is going to be very, very, very low. And what you’re doing with this procedure is, you’re just moving; you’re basically improving survival, maybe. And at the same time, I think it may have palliative role, because these patients will die with bowel obstruction. And if you are able to delay bowel obstruction by preventing progressive sarcomatosis, that might by itself may be an important endpoint.

John L. Marshall, MD: Yes, I think his imaging has gotten better, surgeons have gotten better, and recovery is improved. I would say with R-CHOP, they seem to recover a little bit better than you described from these big surgeries. We’ve gone away from surgery as a curative modality, although you try it when you can, to one that’s just resetting the clock.

Marwan Fakih, MD: Resetting the clock, exactly.

John L. Marshall, MD: Back to no evidence of disease and if the surgery is feasible, and this is true whether it’s Y-90 or stereotactic radiation or RFA: We’re playing a lot of Whac-A-Mole out there. Is everybody doing that? That’s where we are. So, the question I have for you guys is: OK, now what? They come back and they’re stage 4, no evidence of disease, maybe got some preoperative chemotherapy—what do you do now? They have a very high risk of relapse in the 80% or more range—what do you do now?

Wells A. Messersmith, MD, FACP: I don’t send them to you, because I don’t have to give maintenance capecitabine.

John L. Marshall, MD: Come on. So, what do you give them? You don’t give them FOLFIRI, I trust.

Wells A. Messersmith, MD, FACP: So, for these folks, absolutely. Most of these folks are, like you said, a highly selected patient population, right?

John L. Marshall, MD: There are more and more of them, right? More and more of these people.

Wells A. Messersmith, MD, FACP: Absolutely. But most of them have gotten at least 6 months of therapy, sometimes 12. And I agree with you. The curves often don’t flatten. But we don’t have chemotherapy curves that have 60% 5-year survival, plain and simple. So, what I often tell patients is, like you said, that you’re kind of resetting the clocks. It’s probably going to come back. I have seen some patients cured. It’s probably going to come back. But, boy, you can have 3, 4 years off chemotherapy. So, in my mind, half the point of doing the surgery is to get off chemotherapy for a while, stop seeing me, stop the co-pay, stop all the stuff with chemotherapy and just kind of give them a break. But we don’t have data. I think you can also make a cogent argument for some type of maintenance approach given the high relapse rate. And it’s a great question.

John L. Marshall, MD: No, I’m not trying to advocate for it necessarily, but I’m lost; I don’t know what to do. And what I am seeing is a lot of people giving another 6 months of FOLFOX or FOLFIRI, which I don’t give them, because I don’t think it’s going to have the adjuvant effect that they’re going for.

Marwan Fakih, MD: So, what we’re seeing, John, is basically a shift also in a higher-risk population undergoing that procedure. And I think those are the patients who are relapsing very quickly. And I think in those patients, one should certainly, if you are doing the procedure, think about maintaining those patients on chemotherapy. And perhaps we should start stratifying our patients a little bit better as to “OK, if you’ve only got 2 peritoneal implants and I’ve resected them, and I’ve done HIPEC, what’s the point of keeping you on chemotherapy for good?”

Wells A. Messersmith, MD, FACP: That’s a great point. And our surgeons won’t do it, and by the way, this is not something you want to dabble in. These really have to be done full time. But unless they can get a CC0—so, complete resection of all disease—they really try not to do it. And I often feel badly when I see a second opinion. Someone has had a CC2—visible disease left behind—what have you really done for that patient?

John L. Marshall, MD: Yes. It’s a really great discussion and a difficult situation, and it’s very hard to write down what the right answer is. And I think that makes it also very hard to design trials because they’re so variable, the kinds of patients who end up stage 4, no evidence of disease.

Wells A. Messersmith, MD, FACP: I’ve quoted you before to my patients saying there are kneelers and there are standers. You either believe or you don’t you believe.

Transcript Edited for Clarity 

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Transcript: 

John L. Marshall, MD: Quickly, gang, let’s cover the sort of very complex world. There is no book to read; you’ve got to figure it out on your own. How do you deal with patients with regional metastases where your goal is lofty and maybe even curative in nature? And we’ve got pretty good data around liver disease, but we’re talking about peritoneal disease now and other modalities. Marwan, how’s it handled at your place in terms of deciding how to manage these patients?

Marwan Fakih, MD: For liver disease, I have to say at our center, we’re blessed to have the ability to have pumps. So, we have been using hepatic arterial infusions in high-risk patients.

John L. Marshall, MD: You’re 1 of the 4 places on the planet that’s doing that.

Marwan Fakih, MD: We’re one of the few places.

John L. Marshall, MD: Anybody else doing that?

Gabriela Chiorean, MD: I’m sending patients to New York.

John L. Marshall, MD: We send them…there’s a train that takes them to New York.

Marwan Fakih, MD: So, for the regional disease, I think that’s probably a 3-hour session, because what is regional disease? It is potentially resectable. Is it resectable now? Is it high-risk of recurrence? What is your risk stratification for recurrence here? What’s your CRS score? And so, all of these factor in to what you want to do for the patient. But if we’re talking about regional disease adjuvant therapy, we do kind of discuss these in a multidisciplinary setting. If it’s liver only—we think the patient has a very high rate of recurrence in the liver, such as 4 or more lesions—we are considering some of those patients for hepatic arterial infusion placement.

John L. Marshall, MD: You’re impressively consistent because you’re bracing the right- and the left-sided EGFR survival advantage, FOLFIRINOX survival advantage, and infusion pump survival advantage. They’re all a pain, and they’re tough to manage, and they require a lot, but you’re really going for that OS, where I think the rest of us are saying, “Well, it’s just hard; it’s complex, and it would require major changes.” And I know you guys have seen the fact that they stopped making these infusion pumps.

Marwan Fakih, MD: Right.

John L. Marshall, MD: So, we have to, for those folks who are still doing that, figure out how to do it. Is there any patient who really should get Y-90?

Wells A. Messersmith, MD, FACP: So, the short answer is maybe. By the way…

John L. Marshall, MD: I’m going to go to somebody else; come on.

Wells A. Messersmith, MD, FACP: I live in the West, so all these comments about the wild, wild West—I’ll let them fly. So, I think, first of all, you have SIR-Spheres; they’re low-dose radiation regional. And there are the FOXFIRE and SIRFLOX trials, which are essentially negative.

John L. Marshall, MD: Frontline.

Wells A. Messersmith, MD, FACP: Frontline. So, that definitely dropped off our use of those in the frontline setting.

John L. Marshall, MD: Do you believe the right-sided subgroup on that?

Wells A. Messersmith, MD, FACP: Again, I think it’s hypothesis generated. I’d want to see something prospective. TheraSphere, which is a high-dose, very targeted radioembolization technique, those trials are ongoing. There’s a second-line trial that we’re participating in, and we’re still on occasion doing that. I will say that over the past 18 years of doing this, the ability to resect lesions has become much more, in terms of really worrying more about the future liver remnant, what you’re left with rather than what you had to begin with; portal vein immobilization allowing the other side of the liver—for instance, hypertrophy and a greater future liver remnant. So, we’re certainly more aggressive about resections than we were before. But our radioembolization rates have dropped considerably since the publication of those trials, just following the data.

John L. Marshall, MD: Yes. I think we use them a lot in the refractory space in liver-dominant disease. Particularly, a lot of us are phase I-ers up here. You see that patient from outside—a lot of disease in the liver—while you’re waiting on the slot or you need a new biopsy to prove a marker. You go to IR, you get a little biopsy, you get a little Y-90, and then 4 weeks later, you’re good to go. Are you all playing that game?

Wells A. Messersmith, MD, FACP: Well, it’s just interesting that we work in an industry where we buy a Lexus and we’re just not sure if it works. If I turn the key, it might not work at all, and you’re just going to get out and walk away.

John L. Marshall, MD: Tesla.

Wells A. Messersmith, MD, FACP: Yes, exactly.

John L. Marshall, MD: If only it were a Lexus.

Wells A. Messersmith, MD, FACP: So, I think we just have to keep that in mind, that there’s only enough money in the till, and these things are really expensive.

John L. Marshall, MD: In my world, I come from HIPEC-ville where Sugarbaker started the business in the Washington, DC, region. So, we’re very heavy-handed. I’ll defer to you guys to set me straight a little bit. Gabriela, do you think there’s a role in colon cancer for HIPEC? Do you send patients sometimes for that?

Gabriela Chiorean, MD: I actually do. So, for those select patients who don’t have visceral disease—they have peritoneal carcinomatosis—I typically start out with systemic chemotherapy, but I do want them evaluated serially by a surgeon expert in cytoreductive surgery and HIPEC. And more often than not, I’m being told the patient is not a good candidate; the burden of disease is too high. Oftentimes I say, “Let’s wait for 6 months, do a laparoscopy, and look at their burden of disease.” I would say very few patients are good candidates for HIPEC, but those that are, I would not hesitate to refer them.

John L. Marshall, MD: Counter to that anybody? Is there a case to be made?

Marwan Fakih, MD: We actually offer HIPEC in our center, as well, but we’re quite selective. I think we’re all waiting for the data to see, how much does the hyperthermic chemotherapy add to the cytoreduction? I think that’s a very important question. This is not in any way an easy procedure. It takes about 2 to 3 months for patients to recover fully. They have significant discomfort in the abdomen that continues for about 8 weeks or more. It’s not easy to go back on chemotherapy. So, I think it’s important to look at the carcinomatosis score in those patients and just limit it to the patients where the data have shown that you’d make a dent. I have to say, the cure rate is going to be very, very, very low. And what you’re doing with this procedure is, you’re just moving; you’re basically improving survival, maybe. And at the same time, I think it may have palliative role, because these patients will die with bowel obstruction. And if you are able to delay bowel obstruction by preventing progressive sarcomatosis, that might by itself may be an important endpoint.

John L. Marshall, MD: Yes, I think his imaging has gotten better, surgeons have gotten better, and recovery is improved. I would say with R-CHOP, they seem to recover a little bit better than you described from these big surgeries. We’ve gone away from surgery as a curative modality, although you try it when you can, to one that’s just resetting the clock.

Marwan Fakih, MD: Resetting the clock, exactly.

John L. Marshall, MD: Back to no evidence of disease and if the surgery is feasible, and this is true whether it’s Y-90 or stereotactic radiation or RFA: We’re playing a lot of Whac-A-Mole out there. Is everybody doing that? That’s where we are. So, the question I have for you guys is: OK, now what? They come back and they’re stage 4, no evidence of disease, maybe got some preoperative chemotherapy—what do you do now? They have a very high risk of relapse in the 80% or more range—what do you do now?

Wells A. Messersmith, MD, FACP: I don’t send them to you, because I don’t have to give maintenance capecitabine.

John L. Marshall, MD: Come on. So, what do you give them? You don’t give them FOLFIRI, I trust.

Wells A. Messersmith, MD, FACP: So, for these folks, absolutely. Most of these folks are, like you said, a highly selected patient population, right?

John L. Marshall, MD: There are more and more of them, right? More and more of these people.

Wells A. Messersmith, MD, FACP: Absolutely. But most of them have gotten at least 6 months of therapy, sometimes 12. And I agree with you. The curves often don’t flatten. But we don’t have chemotherapy curves that have 60% 5-year survival, plain and simple. So, what I often tell patients is, like you said, that you’re kind of resetting the clocks. It’s probably going to come back. I have seen some patients cured. It’s probably going to come back. But, boy, you can have 3, 4 years off chemotherapy. So, in my mind, half the point of doing the surgery is to get off chemotherapy for a while, stop seeing me, stop the co-pay, stop all the stuff with chemotherapy and just kind of give them a break. But we don’t have data. I think you can also make a cogent argument for some type of maintenance approach given the high relapse rate. And it’s a great question.

John L. Marshall, MD: No, I’m not trying to advocate for it necessarily, but I’m lost; I don’t know what to do. And what I am seeing is a lot of people giving another 6 months of FOLFOX or FOLFIRI, which I don’t give them, because I don’t think it’s going to have the adjuvant effect that they’re going for.

Marwan Fakih, MD: So, what we’re seeing, John, is basically a shift also in a higher-risk population undergoing that procedure. And I think those are the patients who are relapsing very quickly. And I think in those patients, one should certainly, if you are doing the procedure, think about maintaining those patients on chemotherapy. And perhaps we should start stratifying our patients a little bit better as to “OK, if you’ve only got 2 peritoneal implants and I’ve resected them, and I’ve done HIPEC, what’s the point of keeping you on chemotherapy for good?”

Wells A. Messersmith, MD, FACP: That’s a great point. And our surgeons won’t do it, and by the way, this is not something you want to dabble in. These really have to be done full time. But unless they can get a CC0—so, complete resection of all disease—they really try not to do it. And I often feel badly when I see a second opinion. Someone has had a CC2—visible disease left behind—what have you really done for that patient?

John L. Marshall, MD: Yes. It’s a really great discussion and a difficult situation, and it’s very hard to write down what the right answer is. And I think that makes it also very hard to design trials because they’re so variable, the kinds of patients who end up stage 4, no evidence of disease.

Wells A. Messersmith, MD, FACP: I’ve quoted you before to my patients saying there are kneelers and there are standers. You either believe or you don’t you believe.

Transcript Edited for Clarity 
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