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Intravenous vs Intraperitoneal Chemotherapy for Ovarian Cancer

Panelists: Bradley J. Monk, MD, University of Arizona and Creighton University School of Medicine at St. Joseph’s Hospital; Robert L. Coleman, MD, MD Anderson Cancer Center; Thomas Herzog, MD, University of Cincinnati; Kathleen N. Moore, MD, Stephenson Cancer Center; Angeles Alvarez Secord, MD, Duke University School of Medicine
Published: Tuesday, Feb 07, 2017


Transcript:

Bradley J. Monk, MD:
So, that’s surgery. Glad we got that solved. Let’s discuss something that also is very clear and has been definitively studied, intraperitoneal chemotherapy. We’re all familiar with the GOG-172 study, published in the New England Journal of Medicine by Deb Armstrong. I actually call that study, “dose-dense weekly IP therapy,” because it was dose intense, it was weekly, and it was intraperitoneal. The 3 things that they changed, there is an important difference that led to an NCI alert, PFS and OS difference. So, then you decided on a definitive trial, GOG-252.

Angeles Alvarez Secord, MD: First of all, it was a panel of experts at the Gynecologic Oncology Group, which we were all a part of, right? There are several great leaders in IP therapy, and I applaud them for all their efforts and their years. And this study was a little different in terms of the other studies. There are 3 arms: there’s a dose-dense IV arm with paclitaxel and carboplatin, there’s a dose-dense paclitaxel arm with IP carboplatin, and then the last arm was basically a modified GOG-172 with paclitaxel on day 1—a shorter duration of treatment—cisplatin/IP with a lower dose on day 2, and then you have day 8 of IP paclitaxel.

Bradley J. Monk, MD: So, a 3-arm trial, we all agreed on it. It was 2 arms IP. How did it work out?

Angeles Alvarez Secord, MD: Well, hang on, every arm also had bevacizumab, which was a decision that was made at the time. Was that your fault?

Bradley J. Monk, MD: No, bevacizumab’s a great drug.

Angeles Alvarez Secord, MD: It is a great drug, but I think one of the problems with these different arms they chose is they didn’t have the standard arm.

Bradley J. Monk, MD: What was the control?

Angeles Alvarez Secord, MD: There was no control arm. It was all these other arms.

Bradley J. Monk, MD: So, the control arm was dose-dense weekly paclitaxel and bevacizumab. Maybe that’s not the standard, but in the study that’s what was the standard.

Angeles Alvarez Secord, MD: That’s what the standard would be. There were 1560 women who participated in this study. That is a tremendous effort.

Bradley J. Monk, MD: Can you tell us about the difference in the arms? PFS and OS.

Thomas Herzog, MD: Endpoint maybe.

Angeles Alvarez Secord, MD: I’m getting there. They were the same. It was about 26 months for the standard of care arm, 28 months for the IP carboplatin arm, and the IP cisplatin arm was 27 months. So, that was all the same. The kicker here is really the toxicity. The toxicity was worse in that cisplatin-containing arm with more hypertension.

Bradley J. Monk, MD: IP was more toxic. That’s surprising.

Angeles Alvarez Secord, MD: Yes, cisplatin IP was more toxic when you combine with bevacizumab.

Bradley J. Monk, MD: So, what’s the conclusion to GOG-252? We have 3 arms…

Robert L. Coleman, MD: Wait, before you go on there, why don’t we talk about the eligibility? Because, I think that’s important. I think it’s important that we understand exactly who we’re treating, who are eligible for this study.

Angeles Alvarez Secord, MD: Well, it was patients with advanced-stage disease who were optimally debulked…

Bradley J. Monk, MD: Less than 1 cm.

Angeles Alvarez Secord, MD: Yes, less than 1 cm. What are you alluding to specifically?

Robert L. Coleman, MD: Mainly because when people look at data in all these different studies that we’re quoting, they’re all looking at those median time points. And so, even though they’re not supposed to, they all look to see how they rank up relative to each other.

Bradley J. Monk, MD: So, in this study, the R0s, they did better if they got IP?

Angeles Alvarez Secord, MD: No. They had a lot of R0s in this study. I think it was like, at least, 50%.

Bradley J. Monk, MD: And it still didn’t help.

Angeles Alvarez Secord, MD: But, listen to this, it’s a different group of patients than GOG-172 because if you look at the R0 group—I think it’s Chip Landen who wrote the study—the R0 group in the GOG-172 study had survival of over 70 months. It was outstanding. The PFS for this group was about 30 months across the board for the R0 patients. So, there’s something different about these patients, and it could be that we’re more aggressively debulking patients than we were in the past for GOG-172. And I’m not sure what it all exactly entails. Maybe bevacizumab is the greatest equalizer, so that could be a part of it, too.

Bradley J. Monk, MD: This is a serious discussion. A 1500-patient trial, given all its frailties, did not meet its primary endpoint. Does this answer the question of IP chemotherapy or do we still need to continue to debate it?

Kathleen N. Moore, MD: I don’t think it answers the question of IP chemotherapy. Unfortunately, we’ve learned a lot.

Bradley J. Monk, MD: What did we learn?

Kathleen N. Moore, MD: We’ve learned that a lot of the important stratification factors we know now—BRCA status, HRD status—none of those are included in this study.

Bradley J. Monk, MD: But, it’s randomized, they’re equal.

Kathleen N. Moore, MD: Well, I think we’ve learned from other ongoing studies that randomization actually doesn’t guarantee equal distribution of those important prognostic factors.

Bradley J. Monk, MD: You think the reason it’s negative is because there’s a randomization error?

Kathleen N. Moore, MD: I think we can’t confirm that we have equal groups, and, actually, this was brought up in an excellent ASCO discussion. I think we ask too many questions. I think that even though we think that the timing of paclitaxel, 3 versus 24 months, shouldn’t matter, it might matter here. The dose of cisplatin may be important. There were too many things changed. In GOG-252, we used less cisplatin. We used 3-hour paclitaxel. Those are both different than GOG-172, and we added bevacizumab and we didn’t stratify. I think it’s a great study. We did a great job. There were good data. The results are what they are, but they don’t answer a question.

Bradley J. Monk, MD: We did a great job. We had 1500 patients. We didn’t it answer any questions?

Angeles Alvarez Secord, MD: Brad, look at it this way. We have a trial in a contemporary setting. We achieved one of the highest progression-survival rates across the board.

Bradley J. Monk, MD: Yes.

Robert L. Coleman, MD: That’s right, across the board.

Angeles Alvarez Secord, MD: Besides the negative, I would emphasize the positive.

Bradley J. Monk, MD: And I’m not trying to pick at you, it’s just this is the end of the story. There will never be an American IP trial ever again.

Robert L. Coleman, MD: I was going to bring that up. So, the question about IP versus no IP, really the outstanding remaining trial is the iPocc trial.

Bradley J. Monk, MD: Which is a Japanese trial.

Robert L. Coleman, MD: That Keiichi Fujiwara is doing. In that particular trial, the only variable is the IP. It happens to be carboplatin and everybody is getting dose-dense which, as you know, in their patient population is important. But, I think it’s a good segue into GOG-262 because we talk about what’s the drug-drug interaction between these factors. And I think what Angeles mentioned is probably important, that there might be some equalizing factors that are catching one of the arms up that we missed because we did too many things at once. IP, adding the bevacizumab and weekly paclitaxel in GOG-262, didn’t seem to have the additive benefit we would have expected to see.

Bradley J. Monk, MD: Tom, tell us about GOG-262.

Thomas Herzog, MD: Well, let me go back to IP. I think that this is a very serious thing.

Bradley J. Monk, MD: It is, right.

Thomas Herzog, MD: A lot of people have dedicated their careers to this and so forth. But, I have to say we have to look at the community acceptance of IP going into this trial. It’s very, very low and there’s nothing about this trial that makes you want to continue to investigate IP. I think this is a big problem, and this was the opportunity for those who were the biggest believers in IP to get it right. And, for whatever reason—and it may be all the things that Katie just said and that Angeles just said in terms of we changed too many things—we reduced the dose. Maybe it was that the regimen from GOG-172 is superior. We don’t know, and, unfortunately, we didn’t have that as one of the arms. So, I think from a practical standpoint, it’s pretty bad.

Transcript Edited for Clarity
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Transcript:

Bradley J. Monk, MD:
So, that’s surgery. Glad we got that solved. Let’s discuss something that also is very clear and has been definitively studied, intraperitoneal chemotherapy. We’re all familiar with the GOG-172 study, published in the New England Journal of Medicine by Deb Armstrong. I actually call that study, “dose-dense weekly IP therapy,” because it was dose intense, it was weekly, and it was intraperitoneal. The 3 things that they changed, there is an important difference that led to an NCI alert, PFS and OS difference. So, then you decided on a definitive trial, GOG-252.

Angeles Alvarez Secord, MD: First of all, it was a panel of experts at the Gynecologic Oncology Group, which we were all a part of, right? There are several great leaders in IP therapy, and I applaud them for all their efforts and their years. And this study was a little different in terms of the other studies. There are 3 arms: there’s a dose-dense IV arm with paclitaxel and carboplatin, there’s a dose-dense paclitaxel arm with IP carboplatin, and then the last arm was basically a modified GOG-172 with paclitaxel on day 1—a shorter duration of treatment—cisplatin/IP with a lower dose on day 2, and then you have day 8 of IP paclitaxel.

Bradley J. Monk, MD: So, a 3-arm trial, we all agreed on it. It was 2 arms IP. How did it work out?

Angeles Alvarez Secord, MD: Well, hang on, every arm also had bevacizumab, which was a decision that was made at the time. Was that your fault?

Bradley J. Monk, MD: No, bevacizumab’s a great drug.

Angeles Alvarez Secord, MD: It is a great drug, but I think one of the problems with these different arms they chose is they didn’t have the standard arm.

Bradley J. Monk, MD: What was the control?

Angeles Alvarez Secord, MD: There was no control arm. It was all these other arms.

Bradley J. Monk, MD: So, the control arm was dose-dense weekly paclitaxel and bevacizumab. Maybe that’s not the standard, but in the study that’s what was the standard.

Angeles Alvarez Secord, MD: That’s what the standard would be. There were 1560 women who participated in this study. That is a tremendous effort.

Bradley J. Monk, MD: Can you tell us about the difference in the arms? PFS and OS.

Thomas Herzog, MD: Endpoint maybe.

Angeles Alvarez Secord, MD: I’m getting there. They were the same. It was about 26 months for the standard of care arm, 28 months for the IP carboplatin arm, and the IP cisplatin arm was 27 months. So, that was all the same. The kicker here is really the toxicity. The toxicity was worse in that cisplatin-containing arm with more hypertension.

Bradley J. Monk, MD: IP was more toxic. That’s surprising.

Angeles Alvarez Secord, MD: Yes, cisplatin IP was more toxic when you combine with bevacizumab.

Bradley J. Monk, MD: So, what’s the conclusion to GOG-252? We have 3 arms…

Robert L. Coleman, MD: Wait, before you go on there, why don’t we talk about the eligibility? Because, I think that’s important. I think it’s important that we understand exactly who we’re treating, who are eligible for this study.

Angeles Alvarez Secord, MD: Well, it was patients with advanced-stage disease who were optimally debulked…

Bradley J. Monk, MD: Less than 1 cm.

Angeles Alvarez Secord, MD: Yes, less than 1 cm. What are you alluding to specifically?

Robert L. Coleman, MD: Mainly because when people look at data in all these different studies that we’re quoting, they’re all looking at those median time points. And so, even though they’re not supposed to, they all look to see how they rank up relative to each other.

Bradley J. Monk, MD: So, in this study, the R0s, they did better if they got IP?

Angeles Alvarez Secord, MD: No. They had a lot of R0s in this study. I think it was like, at least, 50%.

Bradley J. Monk, MD: And it still didn’t help.

Angeles Alvarez Secord, MD: But, listen to this, it’s a different group of patients than GOG-172 because if you look at the R0 group—I think it’s Chip Landen who wrote the study—the R0 group in the GOG-172 study had survival of over 70 months. It was outstanding. The PFS for this group was about 30 months across the board for the R0 patients. So, there’s something different about these patients, and it could be that we’re more aggressively debulking patients than we were in the past for GOG-172. And I’m not sure what it all exactly entails. Maybe bevacizumab is the greatest equalizer, so that could be a part of it, too.

Bradley J. Monk, MD: This is a serious discussion. A 1500-patient trial, given all its frailties, did not meet its primary endpoint. Does this answer the question of IP chemotherapy or do we still need to continue to debate it?

Kathleen N. Moore, MD: I don’t think it answers the question of IP chemotherapy. Unfortunately, we’ve learned a lot.

Bradley J. Monk, MD: What did we learn?

Kathleen N. Moore, MD: We’ve learned that a lot of the important stratification factors we know now—BRCA status, HRD status—none of those are included in this study.

Bradley J. Monk, MD: But, it’s randomized, they’re equal.

Kathleen N. Moore, MD: Well, I think we’ve learned from other ongoing studies that randomization actually doesn’t guarantee equal distribution of those important prognostic factors.

Bradley J. Monk, MD: You think the reason it’s negative is because there’s a randomization error?

Kathleen N. Moore, MD: I think we can’t confirm that we have equal groups, and, actually, this was brought up in an excellent ASCO discussion. I think we ask too many questions. I think that even though we think that the timing of paclitaxel, 3 versus 24 months, shouldn’t matter, it might matter here. The dose of cisplatin may be important. There were too many things changed. In GOG-252, we used less cisplatin. We used 3-hour paclitaxel. Those are both different than GOG-172, and we added bevacizumab and we didn’t stratify. I think it’s a great study. We did a great job. There were good data. The results are what they are, but they don’t answer a question.

Bradley J. Monk, MD: We did a great job. We had 1500 patients. We didn’t it answer any questions?

Angeles Alvarez Secord, MD: Brad, look at it this way. We have a trial in a contemporary setting. We achieved one of the highest progression-survival rates across the board.

Bradley J. Monk, MD: Yes.

Robert L. Coleman, MD: That’s right, across the board.

Angeles Alvarez Secord, MD: Besides the negative, I would emphasize the positive.

Bradley J. Monk, MD: And I’m not trying to pick at you, it’s just this is the end of the story. There will never be an American IP trial ever again.

Robert L. Coleman, MD: I was going to bring that up. So, the question about IP versus no IP, really the outstanding remaining trial is the iPocc trial.

Bradley J. Monk, MD: Which is a Japanese trial.

Robert L. Coleman, MD: That Keiichi Fujiwara is doing. In that particular trial, the only variable is the IP. It happens to be carboplatin and everybody is getting dose-dense which, as you know, in their patient population is important. But, I think it’s a good segue into GOG-262 because we talk about what’s the drug-drug interaction between these factors. And I think what Angeles mentioned is probably important, that there might be some equalizing factors that are catching one of the arms up that we missed because we did too many things at once. IP, adding the bevacizumab and weekly paclitaxel in GOG-262, didn’t seem to have the additive benefit we would have expected to see.

Bradley J. Monk, MD: Tom, tell us about GOG-262.

Thomas Herzog, MD: Well, let me go back to IP. I think that this is a very serious thing.

Bradley J. Monk, MD: It is, right.

Thomas Herzog, MD: A lot of people have dedicated their careers to this and so forth. But, I have to say we have to look at the community acceptance of IP going into this trial. It’s very, very low and there’s nothing about this trial that makes you want to continue to investigate IP. I think this is a big problem, and this was the opportunity for those who were the biggest believers in IP to get it right. And, for whatever reason—and it may be all the things that Katie just said and that Angeles just said in terms of we changed too many things—we reduced the dose. Maybe it was that the regimen from GOG-172 is superior. We don’t know, and, unfortunately, we didn’t have that as one of the arms. So, I think from a practical standpoint, it’s pretty bad.

Transcript Edited for Clarity
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