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First-line Targeted Therapies in Metastatic CRC

Insights From:Alan P. Venook, MD, University of California
Published Online: Thursday, Jul 21, 2016



Transcript:

Alan P. Venook, MD:
Metastatic colorectal cancer is unique in that you can cure patients even after the disease is metastasized. So, the first questions we ask are: What’s the goal? Can we cure this patient? Who can we cure? Well, we’re surprised. You can cure patients you wouldn’t have thought you could cure. But patients with a single metastasis, or a long time between their primary and the metastatic disease, there are a couple of criteria that would put the patient in good shape with vis-à-vis the chance of being cured.

Again, a single metastasis could be a huge metastasis, but just one is much better in terms of curability than three 2-mm metastases because of the way the biology is playing out. I think the goals of therapy should govern everything else we do. In my view, if I have a patient who comes in with a small liver metastasis, let’s say their primary cancer’s in place, you have to decide, do you leave the primary in place? These are the decisions you make.

If you think you can cure the patient, our approach would be, for example, to start right away with chemotherapy, leave the primary in place, treat with chemotherapy, and see how the cancer behaves. What’s the biology of the cancer? Even if you could remove the cancer right off the bat, we don’t do that. Give chemotherapy, let’s see what the disease is doing, and then take it from there. There’s stylistic and learned people who would disagree with some of these issues, but my belief is you want to. It’s all about the biology. If the cancer isn’t amenable to it, you’re not going to cure the patient. So, what we always try to do is buy some time, get a sense of where the disease is going, and then make our decisions.

I often bristle at it. One of the scenarios that I’m most unhappy with are patients with colon cancer and metastatic disease who are seen by the surgeon, and the surgeon immediately takes the patient to the OR to take out the primary. You lose 6 or 8 weeks while the patient’s recovering. We need that to change, for example. And so I think the idea that many, if almost any, patients need treatment tomorrow is really probably not the case.

Every patient is different. So, for example, a patient who’s a pianist, I probably wouldn’t use oxaliplatin early on because the patient might get a neuropathy. A patient who has hypertension or who has had recent stroke, I wouldn’t use bevacizumab. All of these are obvious factors. I don’t think it’s one-size-fits-all, although my approach is almost always to not start with FOLFOX, and I’m an outlier in that regard. I use FOLFIRI as a backbone. The reason is, on average, we look for our first line of treatment to get us the most mileage, to get in the most treatment. And you’ll only get 7 or 8 doses of oxaliplatin into the average patient before they develop a neuropathy. It doesn’t make sense to me to start a treatment which you’re going to want it to do the heavy lifting and you’re going to know you’re going to stop in 3 or 4 months.

So, that informs the chemotherapy; FOLFIRI and FOLFOX are equivalent. In somebody with Crohn’s disease or bad diarrhea, I might not use irinotecan. In somebody with Gilbert’s syndrome, which is a metabolic abnormality that about 10% of the population have, it affects the bilirubin metabolism. Irinotecan is not a good choice for those patients.

But chemotherapy is one item that the antibodies, I really believe it’s what are the goals of treatment. If you have a resectable patient who’s KRAS wild-type, you might think you’d use cetuximab. The problem is there’s a study that specifically looked at that, a new study called EPIC, and the patients did worse when they got cetuximab.

With bevacizumab, it doesn’t really make a big difference in the rate, the degree of response. And if you use bevacizumab, you have to wait 6 or 8 weeks after the last dose. So, in a patient who I think is curable today but I want to wait and see how the biology is going to behave, I won’t use a biologic. I’ll use chemotherapy for two or four cycles, and then we’ll make a decision. But I’d emphasize that for every patient there’s some nuances and some differences. If when you take the primary out, what do you do about a rectal cancer? All of those things. Again, to me though, what you dare not miss is the opportunity to cure the disease. And to know if you can do that, you have to get a sense of how the disease is behaving.

Transcript Edited for Clarity
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Transcript:

Alan P. Venook, MD:
Metastatic colorectal cancer is unique in that you can cure patients even after the disease is metastasized. So, the first questions we ask are: What’s the goal? Can we cure this patient? Who can we cure? Well, we’re surprised. You can cure patients you wouldn’t have thought you could cure. But patients with a single metastasis, or a long time between their primary and the metastatic disease, there are a couple of criteria that would put the patient in good shape with vis-à-vis the chance of being cured.

Again, a single metastasis could be a huge metastasis, but just one is much better in terms of curability than three 2-mm metastases because of the way the biology is playing out. I think the goals of therapy should govern everything else we do. In my view, if I have a patient who comes in with a small liver metastasis, let’s say their primary cancer’s in place, you have to decide, do you leave the primary in place? These are the decisions you make.

If you think you can cure the patient, our approach would be, for example, to start right away with chemotherapy, leave the primary in place, treat with chemotherapy, and see how the cancer behaves. What’s the biology of the cancer? Even if you could remove the cancer right off the bat, we don’t do that. Give chemotherapy, let’s see what the disease is doing, and then take it from there. There’s stylistic and learned people who would disagree with some of these issues, but my belief is you want to. It’s all about the biology. If the cancer isn’t amenable to it, you’re not going to cure the patient. So, what we always try to do is buy some time, get a sense of where the disease is going, and then make our decisions.

I often bristle at it. One of the scenarios that I’m most unhappy with are patients with colon cancer and metastatic disease who are seen by the surgeon, and the surgeon immediately takes the patient to the OR to take out the primary. You lose 6 or 8 weeks while the patient’s recovering. We need that to change, for example. And so I think the idea that many, if almost any, patients need treatment tomorrow is really probably not the case.

Every patient is different. So, for example, a patient who’s a pianist, I probably wouldn’t use oxaliplatin early on because the patient might get a neuropathy. A patient who has hypertension or who has had recent stroke, I wouldn’t use bevacizumab. All of these are obvious factors. I don’t think it’s one-size-fits-all, although my approach is almost always to not start with FOLFOX, and I’m an outlier in that regard. I use FOLFIRI as a backbone. The reason is, on average, we look for our first line of treatment to get us the most mileage, to get in the most treatment. And you’ll only get 7 or 8 doses of oxaliplatin into the average patient before they develop a neuropathy. It doesn’t make sense to me to start a treatment which you’re going to want it to do the heavy lifting and you’re going to know you’re going to stop in 3 or 4 months.

So, that informs the chemotherapy; FOLFIRI and FOLFOX are equivalent. In somebody with Crohn’s disease or bad diarrhea, I might not use irinotecan. In somebody with Gilbert’s syndrome, which is a metabolic abnormality that about 10% of the population have, it affects the bilirubin metabolism. Irinotecan is not a good choice for those patients.

But chemotherapy is one item that the antibodies, I really believe it’s what are the goals of treatment. If you have a resectable patient who’s KRAS wild-type, you might think you’d use cetuximab. The problem is there’s a study that specifically looked at that, a new study called EPIC, and the patients did worse when they got cetuximab.

With bevacizumab, it doesn’t really make a big difference in the rate, the degree of response. And if you use bevacizumab, you have to wait 6 or 8 weeks after the last dose. So, in a patient who I think is curable today but I want to wait and see how the biology is going to behave, I won’t use a biologic. I’ll use chemotherapy for two or four cycles, and then we’ll make a decision. But I’d emphasize that for every patient there’s some nuances and some differences. If when you take the primary out, what do you do about a rectal cancer? All of those things. Again, to me though, what you dare not miss is the opportunity to cure the disease. And to know if you can do that, you have to get a sense of how the disease is behaving.

Transcript Edited for Clarity
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