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Duration of Adjuvant Therapy: CRC Subsets

Panelists: Johanna C. Bendell, MD, Sarah Cannon Research Institute; Cathy Eng, MD, FACP, The University of Texas MD Anderson Cancer Center; John L. Marshall, MD, The Ruesch Center for the Cure of GI Cancers ; Michael A. Morse, MD, Duke Cancer Institute; Dale R. Shepard, MD, PhD, FACP, Taussig Cancer Institute, Cleveland Clinic
Published: Thursday, Mar 01, 2018



Transcript: 

John L. Marshall, MD: In the Raleigh-Durham area, which is now the best retirement place in America, everybody that you take care of is over the age of 70. How do you manage an over 70-year-old patient differently? Let’s make this patient a stage 3, 72-year-old patient who is perfectly fit. This patient just came off of the tennis court.

Michael A. Morse, MD: Well, that’s the new age 60, now. I would definitely treat those people the same way in which we treat younger patients. I think it’s important to mention to them that there are data that suggest that under certain circumstances, there might not be a benefit from platinum-based therapy. Nonetheless, if that person is physiologically younger, can tolerate the therapy, and has a long-life expectancy ahead of them, he or she should be aware that there’s still a likely benefit.

John L. Marshall, MD: I hear you, but I keep coming back to the point that, in the study, those were the over 70-year-olds.

Michael A. Morse, MD: Absolutely.

John L. Marshall, MD: You had to have a good performance status. You had to be study eligible. It was a while ago, now. You’re right, people are living longer. I’m never really sure what to do with this patient. My inclination is to not give them the platinum and just to give them some fluoropyrimidine. Are you pro platinum?

Johanna C. Bendell, MD: I’m pro platinum, but this gives me a much better excuse to stop therapy if there’s any toxicity.

Cathy Eng, MD, FACP: I would agree. I’m pro platinum as well. I don’t think age really has a bearing. It’s really about how the patient looks and feels.

John L. Marshall, MD: How about if they are 82 years old? They just got off the tennis court.

Cathy Eng, MD, FACP: That may be the new age 70.

Dale R. Shepard, MD, PhD, FACP: I am also pro platinum. This is their physiologic age, not their actual age. I would start, but be quick to stop.

John L. Marshall, MD: All right. Let’s review the hardest topic, I think, in this area: duration of therapy. Cathy, you really did a fabulous job of helping to sort of set the tone after the presentation at last year’s American Society of Clinical Oncology (ASCO) meeting over the summer. It really sparked a whole lot of controversy regarding the right interpretation of the big data. Can you quickly review what was done? What were the findings? Tell us your take on it.

Cathy Eng, MD, FACP: I was asked to be a discussant on the pooled analysis of the IDEA trial. It was 6 large phase III trials. The primary endpoint was to determine if you could achieve the same disease-free survival, within a reasonable 95% confidence interval, by giving 3 months of oxaliplatin-based therapy versus 6 months. For the entire purpose of the meta-analysis, or the pooled analysis of these 6 trials, it did not fulfill its primary endpoint. I think that’s the take-home message, at the end of the day, regarding that analysis. Now, obviously, each of these trials can be interpreted individually. But for the purpose of the pooled analysis, it did not fulfill its primary endpoint.

John L. Marshall, MD: I’ll push back on the other and hear what other people think about this. I look at those curves, and I can’t draw anything in between some of them, particularly the lower-risk stage 3s. I’ve been showing those curves to patients, saying, “Is this worth an additional 3 months?” If anything, I’ve been adopting the stop of oxaliplatin at 3 months and maybe continuing 5-FU. What are you doing in practice?

Cathy Eng, MD, FACP: I do want to make sure that you understand that when you interpret that data (the low-risk versus the higher risk), that was a post-hoc analysis.

John L. Marshall, MD: Fair enough.

Cathy Eng, MD, FACP: I just want to make sure that people are aware of that.

John L. Marshall, MD: So, the question always is, is it worth exposing patients? The delta in neuropathy is something like a 20%, 25% grade 3 neuropathy difference. So, is that percentage—1 in 4 people getting grade 3 neuropathy—worth that delta, in terms of cure?

Cathy Eng, MD, FACP: Correct. But obviously, by giving less chemotherapy, you’re going to have less toxicities. That’s kind of a given.

John L. Marshall, MD: Absolutely. But do you get more advantage of going further? Other thoughts? I’d love to hear other people’s perspectives on this.

Johanna C. Bendell, MD: What struck me is the analysis of the lower-risk patients. For those lower-risk patients, I think you can do 3 months. I’ve been trying to push more of the capecitabine-based therapy. CAPEOX was very consistent across the trials. It really seemed to be better than FOLFOX. This is a big question mark, right? This is the largest data set that I think we’ve ever had comparing CAPEOX and infusional 5-FU. Is there something to that continuous dosing and having that continuous level of a fluoropyrimidine on board? Maybe. I’ve tended to do 3 months of CAPEOX for the lower-risk patients. In the higher-risk patients, we can do 3 months of oxaliplatin but maybe 6 months of the fluoropyrimidine.

John L. Marshall, MD: You keep the 5-FU going?

Johanna C. Bendell, MD: Yes.

John L. Marshall, MD: Michael?

Michael A. Morse, MD: No, I agree. I couldn’t add to that. I think it’s an individualized discussion, and it takes time, during each visit, to evaluate their neuropathy. I always warn people that the neuropathy sometimes happens after we’re finished.

Cathy Eng, MD, FACP: Yes, the rebound neuropathy.

John L. Marshall, MD: When we were participating in the study, too, the patients who got randomized to 3 months were often the more nervous patients. “Am I getting enough?” And so, having those patients come back and follow up, and being able to show them the results of the trial, has been fascinating. It’s funny to watch that with your patients in real time. Dale, how’s this going up in Cleveland?

Dale R. Shepard, MD, PhD, FACP: For the most part, we’re sort of adopting the same thing. In most of the patients that I approach, we’ll have the discussion. I usually shoot for 6 months in most patients, but I’m pretty quick to get rid of the oxaliplatin. As you mentioned, Mike, certainly the oxaliplatin effects can occur after you stop. So, you have to be really, really careful, particularly in low-risk patients. When they start to develop symptoms, I’m pretty fast to stop, particularly in older patients.

John L. Marshall, MD: How does this apply to other settings? I still really don’t know what to do if I’m giving neoadjuvant therapy to a rectal cancer patient. What do I do afterwards? There was a really nice little review in one of the ASCO publications, recently, that basically said that there isn’t any solid data that says to give chemotherapy post surgery. And now, I’ve got this 3-versus-6 thing. I’ve tended to give a few more months of treatment afterwards. What are you doing?

Johanna C. Bendell, MD: I tend not to mess with the curative setting. So, right now, I sort of keep it where we are. I do chemoradiation therapy up front. I do the surgery, and then do chemotherapy, out back. But certainly, people are pushing the edge of the envelope. They are not giving the chemotherapy out back, particularly in people who are clinical stage 2 before they go into the operating room. Then, we even have this data that are continuing to emerge that make me nervous, too, about not doing surgery for people who have a clinical complete response. It gives me the heebie-jeebies.

John L. Marshall, MD: It really makes me nervous.

Johanna C. Bendell, MD: Yes.

John L. Marshall, MD: I’m watching these people, particularly because they’re going to have an ostomy for life. I’m nervous. Pelvic disease is terrible. You don’t want to lose control.

Johanna C. Bendell, MD: Yes.

Cathy Eng, MD, FACP: I think you should keep your eyes out. There’s a couple of large Cooperative Group trials that are being proposed, and we’re reviewing them right now for that watch-and-wait scenario. Internationally, a lot of people are very interested—especially patients for organ preservation. So, we’re really trying to analyze that in an appropriate setting.

John L. Marshall, MD: Giving less is better.

Michael A. Morse, MD: Or the other trend is to give all of the therapy up front. The problem is, of course, that you may have overstaged the patient. They don’t need all of that. But that way they get all of their therapy and there’s no concern postoperatively.

John L. Marshall, MD: And the PROSPECT study is accruing very nicely. It’s got another couple hundred to go, and then we’ll be...

Cathy Eng, MD, FACP: Right, but PROSPECT is only for the mid- to high-line tumors. There’s the trial that’s for low-lying tumors.

John L. Marshall, MD: Very good. And so, less surgery. Sometimes, less radiation is being done and less long-term chemotherapy in the curative setting. We need permission. Your point on the discussion, on 3 versus 6 months, is that you trim how many more people will die because you didn’t give enough chemotherapy. Each of us might see 100 adjuvant patients in a year or two. So, if it’s 1% or 2%, that’s 1 or 2 people that we will meet with that will relapse. There’s no real marker there, right? There is nothing to really predict that the patient’s engaged in all of that.

Transcript Edited for Clarity 

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Transcript: 

John L. Marshall, MD: In the Raleigh-Durham area, which is now the best retirement place in America, everybody that you take care of is over the age of 70. How do you manage an over 70-year-old patient differently? Let’s make this patient a stage 3, 72-year-old patient who is perfectly fit. This patient just came off of the tennis court.

Michael A. Morse, MD: Well, that’s the new age 60, now. I would definitely treat those people the same way in which we treat younger patients. I think it’s important to mention to them that there are data that suggest that under certain circumstances, there might not be a benefit from platinum-based therapy. Nonetheless, if that person is physiologically younger, can tolerate the therapy, and has a long-life expectancy ahead of them, he or she should be aware that there’s still a likely benefit.

John L. Marshall, MD: I hear you, but I keep coming back to the point that, in the study, those were the over 70-year-olds.

Michael A. Morse, MD: Absolutely.

John L. Marshall, MD: You had to have a good performance status. You had to be study eligible. It was a while ago, now. You’re right, people are living longer. I’m never really sure what to do with this patient. My inclination is to not give them the platinum and just to give them some fluoropyrimidine. Are you pro platinum?

Johanna C. Bendell, MD: I’m pro platinum, but this gives me a much better excuse to stop therapy if there’s any toxicity.

Cathy Eng, MD, FACP: I would agree. I’m pro platinum as well. I don’t think age really has a bearing. It’s really about how the patient looks and feels.

John L. Marshall, MD: How about if they are 82 years old? They just got off the tennis court.

Cathy Eng, MD, FACP: That may be the new age 70.

Dale R. Shepard, MD, PhD, FACP: I am also pro platinum. This is their physiologic age, not their actual age. I would start, but be quick to stop.

John L. Marshall, MD: All right. Let’s review the hardest topic, I think, in this area: duration of therapy. Cathy, you really did a fabulous job of helping to sort of set the tone after the presentation at last year’s American Society of Clinical Oncology (ASCO) meeting over the summer. It really sparked a whole lot of controversy regarding the right interpretation of the big data. Can you quickly review what was done? What were the findings? Tell us your take on it.

Cathy Eng, MD, FACP: I was asked to be a discussant on the pooled analysis of the IDEA trial. It was 6 large phase III trials. The primary endpoint was to determine if you could achieve the same disease-free survival, within a reasonable 95% confidence interval, by giving 3 months of oxaliplatin-based therapy versus 6 months. For the entire purpose of the meta-analysis, or the pooled analysis of these 6 trials, it did not fulfill its primary endpoint. I think that’s the take-home message, at the end of the day, regarding that analysis. Now, obviously, each of these trials can be interpreted individually. But for the purpose of the pooled analysis, it did not fulfill its primary endpoint.

John L. Marshall, MD: I’ll push back on the other and hear what other people think about this. I look at those curves, and I can’t draw anything in between some of them, particularly the lower-risk stage 3s. I’ve been showing those curves to patients, saying, “Is this worth an additional 3 months?” If anything, I’ve been adopting the stop of oxaliplatin at 3 months and maybe continuing 5-FU. What are you doing in practice?

Cathy Eng, MD, FACP: I do want to make sure that you understand that when you interpret that data (the low-risk versus the higher risk), that was a post-hoc analysis.

John L. Marshall, MD: Fair enough.

Cathy Eng, MD, FACP: I just want to make sure that people are aware of that.

John L. Marshall, MD: So, the question always is, is it worth exposing patients? The delta in neuropathy is something like a 20%, 25% grade 3 neuropathy difference. So, is that percentage—1 in 4 people getting grade 3 neuropathy—worth that delta, in terms of cure?

Cathy Eng, MD, FACP: Correct. But obviously, by giving less chemotherapy, you’re going to have less toxicities. That’s kind of a given.

John L. Marshall, MD: Absolutely. But do you get more advantage of going further? Other thoughts? I’d love to hear other people’s perspectives on this.

Johanna C. Bendell, MD: What struck me is the analysis of the lower-risk patients. For those lower-risk patients, I think you can do 3 months. I’ve been trying to push more of the capecitabine-based therapy. CAPEOX was very consistent across the trials. It really seemed to be better than FOLFOX. This is a big question mark, right? This is the largest data set that I think we’ve ever had comparing CAPEOX and infusional 5-FU. Is there something to that continuous dosing and having that continuous level of a fluoropyrimidine on board? Maybe. I’ve tended to do 3 months of CAPEOX for the lower-risk patients. In the higher-risk patients, we can do 3 months of oxaliplatin but maybe 6 months of the fluoropyrimidine.

John L. Marshall, MD: You keep the 5-FU going?

Johanna C. Bendell, MD: Yes.

John L. Marshall, MD: Michael?

Michael A. Morse, MD: No, I agree. I couldn’t add to that. I think it’s an individualized discussion, and it takes time, during each visit, to evaluate their neuropathy. I always warn people that the neuropathy sometimes happens after we’re finished.

Cathy Eng, MD, FACP: Yes, the rebound neuropathy.

John L. Marshall, MD: When we were participating in the study, too, the patients who got randomized to 3 months were often the more nervous patients. “Am I getting enough?” And so, having those patients come back and follow up, and being able to show them the results of the trial, has been fascinating. It’s funny to watch that with your patients in real time. Dale, how’s this going up in Cleveland?

Dale R. Shepard, MD, PhD, FACP: For the most part, we’re sort of adopting the same thing. In most of the patients that I approach, we’ll have the discussion. I usually shoot for 6 months in most patients, but I’m pretty quick to get rid of the oxaliplatin. As you mentioned, Mike, certainly the oxaliplatin effects can occur after you stop. So, you have to be really, really careful, particularly in low-risk patients. When they start to develop symptoms, I’m pretty fast to stop, particularly in older patients.

John L. Marshall, MD: How does this apply to other settings? I still really don’t know what to do if I’m giving neoadjuvant therapy to a rectal cancer patient. What do I do afterwards? There was a really nice little review in one of the ASCO publications, recently, that basically said that there isn’t any solid data that says to give chemotherapy post surgery. And now, I’ve got this 3-versus-6 thing. I’ve tended to give a few more months of treatment afterwards. What are you doing?

Johanna C. Bendell, MD: I tend not to mess with the curative setting. So, right now, I sort of keep it where we are. I do chemoradiation therapy up front. I do the surgery, and then do chemotherapy, out back. But certainly, people are pushing the edge of the envelope. They are not giving the chemotherapy out back, particularly in people who are clinical stage 2 before they go into the operating room. Then, we even have this data that are continuing to emerge that make me nervous, too, about not doing surgery for people who have a clinical complete response. It gives me the heebie-jeebies.

John L. Marshall, MD: It really makes me nervous.

Johanna C. Bendell, MD: Yes.

John L. Marshall, MD: I’m watching these people, particularly because they’re going to have an ostomy for life. I’m nervous. Pelvic disease is terrible. You don’t want to lose control.

Johanna C. Bendell, MD: Yes.

Cathy Eng, MD, FACP: I think you should keep your eyes out. There’s a couple of large Cooperative Group trials that are being proposed, and we’re reviewing them right now for that watch-and-wait scenario. Internationally, a lot of people are very interested—especially patients for organ preservation. So, we’re really trying to analyze that in an appropriate setting.

John L. Marshall, MD: Giving less is better.

Michael A. Morse, MD: Or the other trend is to give all of the therapy up front. The problem is, of course, that you may have overstaged the patient. They don’t need all of that. But that way they get all of their therapy and there’s no concern postoperatively.

John L. Marshall, MD: And the PROSPECT study is accruing very nicely. It’s got another couple hundred to go, and then we’ll be...

Cathy Eng, MD, FACP: Right, but PROSPECT is only for the mid- to high-line tumors. There’s the trial that’s for low-lying tumors.

John L. Marshall, MD: Very good. And so, less surgery. Sometimes, less radiation is being done and less long-term chemotherapy in the curative setting. We need permission. Your point on the discussion, on 3 versus 6 months, is that you trim how many more people will die because you didn’t give enough chemotherapy. Each of us might see 100 adjuvant patients in a year or two. So, if it’s 1% or 2%, that’s 1 or 2 people that we will meet with that will relapse. There’s no real marker there, right? There is nothing to really predict that the patient’s engaged in all of that.

Transcript Edited for Clarity 
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