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Treatment Options for High-Risk Stage II Colon Cancer

Panelists: Johanna C. Bendell,MD, Sarah Cannon Research Institute; Dirk Arnold, MD, PhD, KTB Klinik fur Tumorbiologie GmbH & Co. KG ; Heinz-Josef Lenz, MD, FACP, USC Center for Molecular Pathway and Drug Discovery; Zev A. Wainberg, MD, UCLA Medical Center
Published: Sunday, Dec 02, 2018



Transcript: 

Johanna C. Bendell, MD: Now, would you argue that [based on what] we’ve seen for the high-risk stage II population, we treat them differently than a regular-risk, stage II [patient], right? So, regular risk, stage II, we treat with fluorouracil [5-FU] therapy. We don’t add the oxaliplatin [Eloxatin] in, right? But in the high-risk, stage II population, we’ve seen that oxaliplatin and fluorouracil [are] used.

Dirk Arnold, MD, PhD: It’s decreasing, isn’t it, do you think? So, my personal feeling says we are decreasingly using oxaliplatin in, however, stage II.

Johanna C. Bendell, MD: Even in high-risk stage II?

Dirk Arnold, MD, PhD: Yes, we’ll say. We have analyzed now the MOSAIC trial with a longer follow-up. We have seen that there’s zero effect [on] overall survival, whether we use oxaliplatin in high-risk, stage II or not. So, the overall survival curve is exactly the same.

Zev A. Wainberg, MD: And that’s a good point. Also, if you look at the use of adjuvant chemotherapy in the United States, certainly in the United States, in so-called low-risk T3N0, the use of adjuvant capecitabine [Xeloda] has gone down quite a bit over the last 10 years. Meaning the discussion that you’re supposed to have with the patient about the pros and cons of adjuvant therap. There’s some data that support adjuvant therapy but there’s a lot of data to suggest that the number needed to treat is so high that a lot of oncologists veered away from it. The use has gone down and that’s interesting because the tendency is to try to do less, perhaps in these patients who are so likely to be cured from their cancer otherwise. With respect to T4 disease, I think there’s pretty good evidence that those folks do have, obviously, a prognosis that’s not that different from, certainly, N1 disease, so they should be treated with some chemotherapy. The big debate, as Dirk is saying, is, should they get oxaliplatin or not or should we just leave it alone with fluoropyrimidine?

Heinz-Josef Lenz, MD, FACP: And should we do 6 months of 5-FU or 3 months of FOLFOX [folinic acid, fluorouracil, oxaliplatin]? So, it’s getting more complicated, not less.

Johanna C. Bendell, MD: If we’re guiding somebody who’s watching this, what do we want to tell them? In stage II, what do we use? What are the molecular tests they need to get? MSI [microsatellite instability] for sure, right? Because that will guide you toward chemotherapy versus no chemotherapy. Recurrent score, Dirk?

Dirk Arnold, MD, PhD: Well, yes. I’m not sure whether we… [whether] the recurrence could really help us. But I think the risk factor should be clear and insufficient lymph node count or examination is clearly, it’s number one, and perforation obstruction is clearly number two. And I think all the others don’t really matter.

Johanna C. Bendell, MD: Yes. Zev?

Zev A. Wainberg, MD: I use recurrent score extremely infrequently.

Johanna C. Bendell, MD: Infrequently.

Zev A. Wainberg, MD: It’s the rare patient who I use it for, because it doesn’t stratify the patients with to the extent that you need, it doesn’t really help you. And it certainly doesn’t help predict the benefit of chemotherapy. It’s a prognostic score that has a very narrow prognostic guidance. So, I’m also not a big user of that particular test.

Johanna C. Bendell, MD: So, MSI, and then, clinically, knowing how many lymph nodes were removed and if that patient was a T4, and that might guide you toward treatment for the stage II [patients].

Heinz-Josef Lenz, MD, FACP: Obstruction.

Johanna C. Bendell, MD: Obstruction and perforation.

Heinz-Josef Lenz, MD, FACP: The typical classical sectors we know from the guidelines.

Johanna C. Bendell, MD: And then we would do either a fluorouracil or a fluoropyrimidine or fluoropyrimidine plus oxaliplatin, depending on which side of the coin you are sitting on.

Heinz-Josef Lenz, MD, FACP: FOLFOX, no?

Zev A. Wainberg, MD: I don’t know. I personally, very infrequently, would use FOLFOX in stage II colon cancer. Like Dirk, I look at that data, and I’m not that compelled by the high-risk stage II population within the MOSAIC [trial] and updated analysis. It all depends on how many risks. I think these are the kind of things where you look at the patient and you say, well, they have T4 and poorly differentiated histology and bad lympho-vascular invasion. And if they have a number of risk factors that within stage II categorize them as at more higher risk, then I think certainly these are the things we should weigh.

Heinz-Josef Lenz, MD, FACP: Then you use FOLFOX for 6 months or XELOX [capecitabine (Xeloda), oxaliplatin] for 3 months?

Zev A. Wainberg, MD: Well that’s the next topic.

Dirk Arnold, MD, PhD: But this gives some confidence, and I would like to echo what Zev was saying. I think it’s difficult to justify 6 months of oxaliplatin-based treatment in stage II disease nowadays. I think that’s, for me, very likely overtreatment if it was not a really poor candidate.

Johanna C. Bendell, MD: Because we also have to remember, for patients that we’re curing, it’s not only the long-term neuropathy which can be debilitating, but also from MOSAIC, we saw a chance of leukemia happening years down the road from having received the platinum therapy. So, it’s not a decision that we want to take lightly.

Really quickly while we’re still talking a bit about markers of risk of recurrence: Heinz, we talked a little bit... you mentioned circulating tumor cells. We’ve seen some data. What’s the data that we’re seeing? Is it ready for primetime?

Heinz-Josef Lenz, MD, FACP: I’m not sure if it’s ready for primetime. But the data are very, very exciting and I think promising for the future. Based on [these] data, phase III clinical trials are ongoing in the US where you either test for circulating tumor DNA for stage II disease, using the circulating tumor DNA for escalating, not de-escalating treatment options. So, when you’re positive, you’re randomized to chemotherapy versus no chemotherapy, and the other ones are observed like we just discussed.

Now, we have to realize the frequency of positive liquid biopsy in stage II, around 8%, based on publication; in stage III, about 20%. Now, if, when you look at [these] data, these positive carriers of certain DNA have an extremely high risk of recurrence; basically almost everyone recurs. So, it’s a very, very high risk factor, which potentially identifies the patients who recur and certainly should get aggressive treatment, and not 5-FU alone, and [are good candidates] for FOLFOX treatment. I think what is missing information is, how many times can FOLFOX get rid of the circulating DNA?

How many patients can clear it under treatment? Because basically, this is minimal metastatic disease. Is FOLFOX enough? Should we escalate it up to treatment like metastatic disease? These are all questions we don’t know. And I think, until then, we will have to figure out stage III disease and clearance with adjuvant in a better way. But these trials or these projects are ongoing.

Johanna C. Bendell, MD: So now we’ve got stage II figured, sort of.

Transcript Edited for Clarity 

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Transcript: 

Johanna C. Bendell, MD: Now, would you argue that [based on what] we’ve seen for the high-risk stage II population, we treat them differently than a regular-risk, stage II [patient], right? So, regular risk, stage II, we treat with fluorouracil [5-FU] therapy. We don’t add the oxaliplatin [Eloxatin] in, right? But in the high-risk, stage II population, we’ve seen that oxaliplatin and fluorouracil [are] used.

Dirk Arnold, MD, PhD: It’s decreasing, isn’t it, do you think? So, my personal feeling says we are decreasingly using oxaliplatin in, however, stage II.

Johanna C. Bendell, MD: Even in high-risk stage II?

Dirk Arnold, MD, PhD: Yes, we’ll say. We have analyzed now the MOSAIC trial with a longer follow-up. We have seen that there’s zero effect [on] overall survival, whether we use oxaliplatin in high-risk, stage II or not. So, the overall survival curve is exactly the same.

Zev A. Wainberg, MD: And that’s a good point. Also, if you look at the use of adjuvant chemotherapy in the United States, certainly in the United States, in so-called low-risk T3N0, the use of adjuvant capecitabine [Xeloda] has gone down quite a bit over the last 10 years. Meaning the discussion that you’re supposed to have with the patient about the pros and cons of adjuvant therap. There’s some data that support adjuvant therapy but there’s a lot of data to suggest that the number needed to treat is so high that a lot of oncologists veered away from it. The use has gone down and that’s interesting because the tendency is to try to do less, perhaps in these patients who are so likely to be cured from their cancer otherwise. With respect to T4 disease, I think there’s pretty good evidence that those folks do have, obviously, a prognosis that’s not that different from, certainly, N1 disease, so they should be treated with some chemotherapy. The big debate, as Dirk is saying, is, should they get oxaliplatin or not or should we just leave it alone with fluoropyrimidine?

Heinz-Josef Lenz, MD, FACP: And should we do 6 months of 5-FU or 3 months of FOLFOX [folinic acid, fluorouracil, oxaliplatin]? So, it’s getting more complicated, not less.

Johanna C. Bendell, MD: If we’re guiding somebody who’s watching this, what do we want to tell them? In stage II, what do we use? What are the molecular tests they need to get? MSI [microsatellite instability] for sure, right? Because that will guide you toward chemotherapy versus no chemotherapy. Recurrent score, Dirk?

Dirk Arnold, MD, PhD: Well, yes. I’m not sure whether we… [whether] the recurrence could really help us. But I think the risk factor should be clear and insufficient lymph node count or examination is clearly, it’s number one, and perforation obstruction is clearly number two. And I think all the others don’t really matter.

Johanna C. Bendell, MD: Yes. Zev?

Zev A. Wainberg, MD: I use recurrent score extremely infrequently.

Johanna C. Bendell, MD: Infrequently.

Zev A. Wainberg, MD: It’s the rare patient who I use it for, because it doesn’t stratify the patients with to the extent that you need, it doesn’t really help you. And it certainly doesn’t help predict the benefit of chemotherapy. It’s a prognostic score that has a very narrow prognostic guidance. So, I’m also not a big user of that particular test.

Johanna C. Bendell, MD: So, MSI, and then, clinically, knowing how many lymph nodes were removed and if that patient was a T4, and that might guide you toward treatment for the stage II [patients].

Heinz-Josef Lenz, MD, FACP: Obstruction.

Johanna C. Bendell, MD: Obstruction and perforation.

Heinz-Josef Lenz, MD, FACP: The typical classical sectors we know from the guidelines.

Johanna C. Bendell, MD: And then we would do either a fluorouracil or a fluoropyrimidine or fluoropyrimidine plus oxaliplatin, depending on which side of the coin you are sitting on.

Heinz-Josef Lenz, MD, FACP: FOLFOX, no?

Zev A. Wainberg, MD: I don’t know. I personally, very infrequently, would use FOLFOX in stage II colon cancer. Like Dirk, I look at that data, and I’m not that compelled by the high-risk stage II population within the MOSAIC [trial] and updated analysis. It all depends on how many risks. I think these are the kind of things where you look at the patient and you say, well, they have T4 and poorly differentiated histology and bad lympho-vascular invasion. And if they have a number of risk factors that within stage II categorize them as at more higher risk, then I think certainly these are the things we should weigh.

Heinz-Josef Lenz, MD, FACP: Then you use FOLFOX for 6 months or XELOX [capecitabine (Xeloda), oxaliplatin] for 3 months?

Zev A. Wainberg, MD: Well that’s the next topic.

Dirk Arnold, MD, PhD: But this gives some confidence, and I would like to echo what Zev was saying. I think it’s difficult to justify 6 months of oxaliplatin-based treatment in stage II disease nowadays. I think that’s, for me, very likely overtreatment if it was not a really poor candidate.

Johanna C. Bendell, MD: Because we also have to remember, for patients that we’re curing, it’s not only the long-term neuropathy which can be debilitating, but also from MOSAIC, we saw a chance of leukemia happening years down the road from having received the platinum therapy. So, it’s not a decision that we want to take lightly.

Really quickly while we’re still talking a bit about markers of risk of recurrence: Heinz, we talked a little bit... you mentioned circulating tumor cells. We’ve seen some data. What’s the data that we’re seeing? Is it ready for primetime?

Heinz-Josef Lenz, MD, FACP: I’m not sure if it’s ready for primetime. But the data are very, very exciting and I think promising for the future. Based on [these] data, phase III clinical trials are ongoing in the US where you either test for circulating tumor DNA for stage II disease, using the circulating tumor DNA for escalating, not de-escalating treatment options. So, when you’re positive, you’re randomized to chemotherapy versus no chemotherapy, and the other ones are observed like we just discussed.

Now, we have to realize the frequency of positive liquid biopsy in stage II, around 8%, based on publication; in stage III, about 20%. Now, if, when you look at [these] data, these positive carriers of certain DNA have an extremely high risk of recurrence; basically almost everyone recurs. So, it’s a very, very high risk factor, which potentially identifies the patients who recur and certainly should get aggressive treatment, and not 5-FU alone, and [are good candidates] for FOLFOX treatment. I think what is missing information is, how many times can FOLFOX get rid of the circulating DNA?

How many patients can clear it under treatment? Because basically, this is minimal metastatic disease. Is FOLFOX enough? Should we escalate it up to treatment like metastatic disease? These are all questions we don’t know. And I think, until then, we will have to figure out stage III disease and clearance with adjuvant in a better way. But these trials or these projects are ongoing.

Johanna C. Bendell, MD: So now we’ve got stage II figured, sort of.

Transcript Edited for Clarity 
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