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Targeting VEGF in Advanced Ovarian Cancer

Panelists: Bradley J. Monk, MD, FACS, FACOG, Arizona Oncology Practice of US Oncology; Oliver Dorigo, MD, PhD, Stanford University Medical Center; Thomas Herzog, MD, University of Cincinnati Cancer Institute; Kathleen Moore, MD, Stephenson Cancer Center; Leslie M. Randall, MD, MAS, University of California, Irvine
Published: Wednesday, Aug 22, 2018



Transcript: 

Bradley J. Monk, MD, FACS, FACOG: Now that we have taken and done a surgery in whatever setting, let’s talk about frontline chemotherapy. Again, this is our optimal opportunity to impact survival. Oliver, what’s the community standard for frontline chemotherapy in newly diagnosed stage 3 and stage 4 cancer? It’s a simple question. I know you’re going to give me a complicated answer, but it’s a simple question. What’s the community standard?

Oliver Dorigo, MD, PhD: The community standard is that it’s a simple answer. It’s intravenous carboplatin/Taxol every 3 weeks for 6 cycles.

Bradley J. Monk, MD, FACS, FACOG: Thank you very much. Paclitaxel and carboplatin—OK. Leslie, in your practice, what percentage of patients get intravenous carboplatin and paclitaxel every 3 weeks? One hundred percent? No way. What percentage actually get that?

Leslie M. Randall, MD, MAS: The percentage who are not on a clinical trial.

Bradley J. Monk, MD, FACS, FACOG: That’s what I’m getting at.

Leslie M. Randall, MD, MAS: It’s about 20%, 30%.

Bradley J. Monk, MD, FACS, FACOG: Is there any role for a dose-dense weekly regimen, where paclitaxel is given weekly? You can give more of it. Obviously, there is a Japanese trial that suggested that was superior. But when bevacizumab was in the mix, in American patients, it wasn’t. Is there any role, in today’s world, for dose-dense weekly paclitaxel and every 3-week carboplatin?

Thomas Herzog, MD: Well, if you take the Japanese data and look at the subgroup analysis from GOG 262, and the 14% or so patients who did not receive bevacizumab—it was a post hoc analysis—it did show that the dose-dense did better. So, if you’re not using bevacizumab, you might need to be doing dose-dense therapy.

Bradley J. Monk, MD, FACS, FACOG: Have you heard of ICON8? Are you familiar with ICON8?

Kathleen Moore, MD: I believed that data until I saw ICON8.

Bradley J. Monk, MD, FACS, FACOG: Tell them what that is.

Kathleen Moore, MD: ICON8 was a randomized phase III trial of frontline chemotherapy with standard 3-week dosing, standard dose-dense dosing.

Bradley J. Monk, MD, FACS, FACOG: No bevacizumab.

Kathleen Moore, MD: No bevacizumab. And then weekly paclitaxel and weekly carboplatin, which came out of the MITO-7 trial.

Bradley J. Monk, MD, FACS, FACOG: In a third arm.

Kathleen Moore, MD: In a third arm. There was absolutely no difference in the progression-free survival between the 3 arms. And we know the toxicity differences with the weekly administration.

Bradley J. Monk, MD, FACS, FACOG: The argument is that ICON8 has not been published. Until it’s published, it’s difficult to impact the NCCN guidelines. It will be published. I’m here to tell you that it will be published soon. But I think the community standard remains to be every 3-week carboplatin/paclitaxel.

There was a study that was published in 2011 called GOG-0218. That study added bevacizumab. Bevacizumab, carboplatin, and paclitaxel, like you said, Tom, every 3 weeks, has been labeled around the world. At the 2018 ASCO Annual Meeting, the final overall survival data was presented. GOG-0218 published in 2011 in the New England Journal of Medicine. What did the updated final overall survival show?

Leslie M. Randall, MD, MAS: The final overall survival shows no difference in outcome between the 3 groups—randomized to the standard carboplatin and Taxol every 3 weeks with or without bevacizumab, and then a third arm that added a bevacizumab maintenance strategy that showed a progression-free survival advantage for the maintenance strategy but no overall survival advantage among any of the arms. Interestingly and consistently between the sister trial, ICON7 in Europe, GOG-0218 does show, and is hypothesis-generating, an overall survival advantage in the high-risk population. In the trials, this population was considered to be stage 3 suboptimal or stage 4.

Bradley J. Monk, MD, FACS, FACOG: A 10-month overall survival in stage IV patients if bevacizumab is added?

Leslie M. Randall, MD, MAS: Correct.

Bradley J. Monk, MD, FACS, FACOG: Is that true? Do you believe that? Katie, do you believe that if you use bevacizumab in stage IV patients that they are going to live longer?

Kathleen Moore, MD: Yes.

Bradley J. Monk, MD, FACS, FACOG: Oliver?

Oliver Dorigo, MD, PhD: Well, we see it again in 2018. We saw it in the high-risk group in ICON7, and that’s exactly how I practice.

Kathleen Moore, MD: Yes.

Bradley J. Monk, MD, FACS, FACOG: Tom?

Thomas Herzog, MD: I think that data is real, and it is reassuring that it showed results in 2 phase III trials, despite cutting the bevacizumab in half and going with a shorter maintenance.

Bradley J. Monk, MD, FACS, FACOG: GOG-0218 has been filed with the FDA. The action date is in late June 2018. It will likely get approved. We’ve heard nothing to the contrary. Is bevacizumab only for patients with high-risk disease? There were no complete resections in the study—no R0s in that study. So, the group is already a high-risk population but not the highest risk. Does this mean that in our practice we should maybe restrict the use to only the stage 4 patients, or those with large volume, residual disease? What do you think?

Kathleen Moore, MD: I actually don’t think so. I absolutely would want to use it in the high-risk setting, but the studies were positive. ICON7 was positive. GOG-0218 was positive.

Bradley J. Monk, MD, FACS, FACOG: And it’s positive for 6 months of progression-free survival.

Kathleen Moore, MD: That’s a benefit. And so, again, it’s shared decision making with the patient. When you’re setting them up for their therapy, they may not want to do that. But truthfully, I don’t know any reason why I would not offer bevacizumab to an advanced-stage patient who is undergoing adjuvant chemotherapy.

Bradley J. Monk, MD, FACS, FACOG: Leslie, we were talking off camera. You said that the neoadjuvant group is high-risk.

Leslie M. Randall, MD, MAS: Exactly.

Bradley J. Monk, MD, FACS, FACOG: Does that mean that we should use bevacizumab in the setting of neoadjuvant chemotherapy too?

Leslie M. Randall, MD, MAS: I think they should absolutely be considered as high-risk. Interestingly, this trial was done around 2009, when we didn’t really give neoadjuvant chemotherapy. And so, neoadjuvant therapy was not considered in this trial. But those patients, especially in the United States, are your highest-risk patients, and they would qualify under these indications.

Bradley J. Monk, MD, FACS, FACOG: So, if you’re going to use bevacizumab with neoadjuvant therapy, you’re going to give a little before the surgery and after the surgery, or just as maintenance? How are you going to integrate the drug? As Leslie said, the study was done in an era when neoadjuvant chemotherapy wasn’t common. How do you integrate bevacizumab into frontline treatment?

Thomas Herzog, MD: Technically, you’re a bit restricted because of the surgery. You lose cycle 3. You’re probably going to omit it because you’re going to be doing surgery within 28 days. And you may lose cycle 4 as well because you usually don’t like to give it during wound healing for another 28 days. And so, we’ll stick to that answer.

Bradley J. Monk, MD, FACS, FACOG: I think that’s fine. Oliver, there’s another overall survival final endpoint with another anti-VEGF agent—oral pazopanib. Tell us what that showed, in terms of the final overall survival rates.

Oliver Dorigo, MD, PhD: Pazopanib is an interesting agent because it targets a lot of the VEGF receptor kinases. It has been studied for a long time as a maintenance strategy after successful frontline treatment of advanced epithelial ovarian cancer. And yet the first (in 2014) didn’t show an increase in progression-free survival. We have now seen data that confirm this. And they don’t show an increase in overall survival. Pazopanib is not a drug that is easily tolerated. We see a lot of side effects. I think, Brad, that this has to be considered as a negative trial.

Bradley J. Monk, MD, FACS, FACOG: It certainly didn’t lead to regulatory approval.

Oliver Dorigo, MD, PhD: Yes, I agree.

Transcript Edited for Clarity

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Transcript: 

Bradley J. Monk, MD, FACS, FACOG: Now that we have taken and done a surgery in whatever setting, let’s talk about frontline chemotherapy. Again, this is our optimal opportunity to impact survival. Oliver, what’s the community standard for frontline chemotherapy in newly diagnosed stage 3 and stage 4 cancer? It’s a simple question. I know you’re going to give me a complicated answer, but it’s a simple question. What’s the community standard?

Oliver Dorigo, MD, PhD: The community standard is that it’s a simple answer. It’s intravenous carboplatin/Taxol every 3 weeks for 6 cycles.

Bradley J. Monk, MD, FACS, FACOG: Thank you very much. Paclitaxel and carboplatin—OK. Leslie, in your practice, what percentage of patients get intravenous carboplatin and paclitaxel every 3 weeks? One hundred percent? No way. What percentage actually get that?

Leslie M. Randall, MD, MAS: The percentage who are not on a clinical trial.

Bradley J. Monk, MD, FACS, FACOG: That’s what I’m getting at.

Leslie M. Randall, MD, MAS: It’s about 20%, 30%.

Bradley J. Monk, MD, FACS, FACOG: Is there any role for a dose-dense weekly regimen, where paclitaxel is given weekly? You can give more of it. Obviously, there is a Japanese trial that suggested that was superior. But when bevacizumab was in the mix, in American patients, it wasn’t. Is there any role, in today’s world, for dose-dense weekly paclitaxel and every 3-week carboplatin?

Thomas Herzog, MD: Well, if you take the Japanese data and look at the subgroup analysis from GOG 262, and the 14% or so patients who did not receive bevacizumab—it was a post hoc analysis—it did show that the dose-dense did better. So, if you’re not using bevacizumab, you might need to be doing dose-dense therapy.

Bradley J. Monk, MD, FACS, FACOG: Have you heard of ICON8? Are you familiar with ICON8?

Kathleen Moore, MD: I believed that data until I saw ICON8.

Bradley J. Monk, MD, FACS, FACOG: Tell them what that is.

Kathleen Moore, MD: ICON8 was a randomized phase III trial of frontline chemotherapy with standard 3-week dosing, standard dose-dense dosing.

Bradley J. Monk, MD, FACS, FACOG: No bevacizumab.

Kathleen Moore, MD: No bevacizumab. And then weekly paclitaxel and weekly carboplatin, which came out of the MITO-7 trial.

Bradley J. Monk, MD, FACS, FACOG: In a third arm.

Kathleen Moore, MD: In a third arm. There was absolutely no difference in the progression-free survival between the 3 arms. And we know the toxicity differences with the weekly administration.

Bradley J. Monk, MD, FACS, FACOG: The argument is that ICON8 has not been published. Until it’s published, it’s difficult to impact the NCCN guidelines. It will be published. I’m here to tell you that it will be published soon. But I think the community standard remains to be every 3-week carboplatin/paclitaxel.

There was a study that was published in 2011 called GOG-0218. That study added bevacizumab. Bevacizumab, carboplatin, and paclitaxel, like you said, Tom, every 3 weeks, has been labeled around the world. At the 2018 ASCO Annual Meeting, the final overall survival data was presented. GOG-0218 published in 2011 in the New England Journal of Medicine. What did the updated final overall survival show?

Leslie M. Randall, MD, MAS: The final overall survival shows no difference in outcome between the 3 groups—randomized to the standard carboplatin and Taxol every 3 weeks with or without bevacizumab, and then a third arm that added a bevacizumab maintenance strategy that showed a progression-free survival advantage for the maintenance strategy but no overall survival advantage among any of the arms. Interestingly and consistently between the sister trial, ICON7 in Europe, GOG-0218 does show, and is hypothesis-generating, an overall survival advantage in the high-risk population. In the trials, this population was considered to be stage 3 suboptimal or stage 4.

Bradley J. Monk, MD, FACS, FACOG: A 10-month overall survival in stage IV patients if bevacizumab is added?

Leslie M. Randall, MD, MAS: Correct.

Bradley J. Monk, MD, FACS, FACOG: Is that true? Do you believe that? Katie, do you believe that if you use bevacizumab in stage IV patients that they are going to live longer?

Kathleen Moore, MD: Yes.

Bradley J. Monk, MD, FACS, FACOG: Oliver?

Oliver Dorigo, MD, PhD: Well, we see it again in 2018. We saw it in the high-risk group in ICON7, and that’s exactly how I practice.

Kathleen Moore, MD: Yes.

Bradley J. Monk, MD, FACS, FACOG: Tom?

Thomas Herzog, MD: I think that data is real, and it is reassuring that it showed results in 2 phase III trials, despite cutting the bevacizumab in half and going with a shorter maintenance.

Bradley J. Monk, MD, FACS, FACOG: GOG-0218 has been filed with the FDA. The action date is in late June 2018. It will likely get approved. We’ve heard nothing to the contrary. Is bevacizumab only for patients with high-risk disease? There were no complete resections in the study—no R0s in that study. So, the group is already a high-risk population but not the highest risk. Does this mean that in our practice we should maybe restrict the use to only the stage 4 patients, or those with large volume, residual disease? What do you think?

Kathleen Moore, MD: I actually don’t think so. I absolutely would want to use it in the high-risk setting, but the studies were positive. ICON7 was positive. GOG-0218 was positive.

Bradley J. Monk, MD, FACS, FACOG: And it’s positive for 6 months of progression-free survival.

Kathleen Moore, MD: That’s a benefit. And so, again, it’s shared decision making with the patient. When you’re setting them up for their therapy, they may not want to do that. But truthfully, I don’t know any reason why I would not offer bevacizumab to an advanced-stage patient who is undergoing adjuvant chemotherapy.

Bradley J. Monk, MD, FACS, FACOG: Leslie, we were talking off camera. You said that the neoadjuvant group is high-risk.

Leslie M. Randall, MD, MAS: Exactly.

Bradley J. Monk, MD, FACS, FACOG: Does that mean that we should use bevacizumab in the setting of neoadjuvant chemotherapy too?

Leslie M. Randall, MD, MAS: I think they should absolutely be considered as high-risk. Interestingly, this trial was done around 2009, when we didn’t really give neoadjuvant chemotherapy. And so, neoadjuvant therapy was not considered in this trial. But those patients, especially in the United States, are your highest-risk patients, and they would qualify under these indications.

Bradley J. Monk, MD, FACS, FACOG: So, if you’re going to use bevacizumab with neoadjuvant therapy, you’re going to give a little before the surgery and after the surgery, or just as maintenance? How are you going to integrate the drug? As Leslie said, the study was done in an era when neoadjuvant chemotherapy wasn’t common. How do you integrate bevacizumab into frontline treatment?

Thomas Herzog, MD: Technically, you’re a bit restricted because of the surgery. You lose cycle 3. You’re probably going to omit it because you’re going to be doing surgery within 28 days. And you may lose cycle 4 as well because you usually don’t like to give it during wound healing for another 28 days. And so, we’ll stick to that answer.

Bradley J. Monk, MD, FACS, FACOG: I think that’s fine. Oliver, there’s another overall survival final endpoint with another anti-VEGF agent—oral pazopanib. Tell us what that showed, in terms of the final overall survival rates.

Oliver Dorigo, MD, PhD: Pazopanib is an interesting agent because it targets a lot of the VEGF receptor kinases. It has been studied for a long time as a maintenance strategy after successful frontline treatment of advanced epithelial ovarian cancer. And yet the first (in 2014) didn’t show an increase in progression-free survival. We have now seen data that confirm this. And they don’t show an increase in overall survival. Pazopanib is not a drug that is easily tolerated. We see a lot of side effects. I think, Brad, that this has to be considered as a negative trial.

Bradley J. Monk, MD, FACS, FACOG: It certainly didn’t lead to regulatory approval.

Oliver Dorigo, MD, PhD: Yes, I agree.

Transcript Edited for Clarity
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