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Dose-Dense Chemotherapy for Ovarian Cancer; Adding Bevacizumab

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: Friday, Feb 10, 2017


Transcript:

Bradley J. Monk, MD:
And so, GOG-262, the trial published last summer of 2016 in the New England Journal of Medicine, was a study of dose-dense, weekly. When paclitaxel is given weekly, we can give more of it. We can give 80 mg/m² a week, 80 x 3 is 240; that’s more than 175 mg/m². So, no breaks. The dose of paclitaxel is 80 mg/m² every week, with carboplatin every 3 weeks. Again, that was supposed to be the confirmatory trial—the Japanese trial that you mentioned—but it also was negative. And people have said, like you have suggested in GOG-252, that bevacizumab was the equalizer.

Thomas Herzog, MD: Well, it was a suboptimal population—first of all, stage III/IV—and you had 14.8 months PFS in the group that received the dose-dense, versus 14.3 months. Not different, and short because of your population being suboptimal—almost 700 patients in this trial. Certainly, one of the things that you look at is, again, the bevacizumab issue. And so, in this particular trial, it was not assigned whether you would get bevacizumab. It was physician and patient choice, and, as it turns out, about 84% or more chose to go on to bevacizumab.

So, the overall result showed no difference. However, if you look at that smaller group—about 16% of the patients—you see that there was a difference, about 14.2 versus 10.3. Hazard ratio was fairly impressive. It was 0.59, so a significant difference for those that got the dose-dense, favoring the dose-dense, which supports the Japanese data in those that do not have bevacizumab at the time frontline therapy. The dose-dense is more efficacious.

Bradley J. Monk, MD: Thank you, Tom. That’s really important. So, does that define, now, the chemotherapy standard in the frontline treatment of ovarian cancer? It’s a subset analysis, but it confirms the Japanese experience that the standard treatment is weekly paclitaxel, dose-dense, with carboplatin every 3 weeks. I’d like to hear the panelists’ opinion of what you think your go-to chemotherapy regimen is frontline. That’s a very practical question.

Angeles Alvarez Secord, MD: Let’s just be clear. In terms of a standard arm for a clinical trial, I think that makes sense. In terms of a standard of care when you’re treating a patient, I think there’s more than one standard in how you can treat patients with ovarian cancer.

Thomas Herzog, MD: Yes, it’s a standard.

Bradley J. Monk, MD: What percent of patients do you think get dose-dense weekly paclitaxel in North Carolina?

Angeles Alvarez Secord, MD: I do not know that frequency. I’ll tell you, we serve a fairly large area. We have patients that are coming from far away, and it’s not convenient for them to come every week. Sometimes you can arrange for them to have some of their treatments by a local physician closer to them, but even that can’t always be easy. For some patients, they prefer the convenience of a Q3 week regimen. Some patients will come weekly for their treatments. I do discuss the incorporation of bevacizumab into their regimen, but that’s for select patients.

Bradley J. Monk, MD: Sure, when it’s given every 3 weeks.

Angeles Alvarez Secord, MD: Yes.

Bradley J. Monk, MD: Rob, what do you think?

Robert L. Coleman, MD: I would say that in our center, it’s very similar. In fact, even in Houston, if the patients are in the periphery—and we have, where our clinics are in the periphery—they’ll be more likely to get dose-dense than if they come actually in town because it’s just where the referral practices are. But, there is one thing I want to mention because it’s important in the patient population and why I keep going back to that. If you go back to GOG-111, which is when paclitaxel and cisplatin was brought into the frontline setting, the median PFS in suboptimal patients was 18 months. But, in this study, GOG-262—it was the same patient population, suboptimal, in that same infusion, although we used carboplatin and then 3-hour paclitaxel—it was 10 months. Bradley J. Monk, MD: I think it’s part of the assessment. In that era, we were not doing CT scans at this stage.

Robert L. Coleman, MD: But, 8 months’ difference?

Angeles Alvarez Secord, MD: I don’t think it’s just that. I think you have to look at what studies were open, and that study was open. It’s like, “Ah, she’s suboptimal.”

Robert L. Coleman, MD: Exactly, that’s what I’m saying. There are inherent factors even in the randomized trials.

Thomas Herzog, MD: We’ve seen that over time, right? We saw that with GOG-111.

Robert L. Coleman, MD: I just want to caution. When we start looking at…

Bradley J. Monk, MD: Cross-trial comparison.

Robert L. Coleman, MD: Yes, absolutely.

Bradley J. Monk, MD: That’s interesting. So, I think we can agree that many patients—I’m not sure I can say most—get dose-dense weekly; AUC (area under the curve) probably is a 6 if carboplatin is given every 3 weeks, paclitaxel 80 mg/m², no break. Bevacizumab is still an option. Katie, is bevacizumab used? Tell me what your thoughts are of frontline bevacizumab, because you heard that it ruined GOG-262 and it ruined GOG-252 because it’s this great drug. If it’s such a great drug, maybe we should add it to Q3 week chemotherapy. Remember, when it’s added weekly, it doesn’t really help. But, I might prefer to get Q3 week chemotherapy with bevacizumab than weekly.

Kathleen N. Moore, MD: Sure, and we have a positive trial supporting that. We have GOG-218. That’s a positive trial. It met its primary endpoint and has supporting data from Europe and ICON7. So, we have a positive trial to support that. Unfortunately, it’s not listed as an indication in the United States, so some providers can use it. Some providers can justify its use in high-risk patients, stage IV in suboptimal patients, per the ICON7 and actually GOG-218’s sub-analyses.

Bradley J. Monk, MD: Stage IV patients with high-volume residual disease in a subset live longer with frontline bevacizumab, and with ascites, which is 85% of the patients.

Kathleen N. Moore, MD: Yes. So, I think when we have data to support that use, it’s unfortunately not equally available to patients in the United States because it doesn’t have an FDA indication. Were it available to me, I would absolutely discuss it with patients, but it’s not something that we’re actually able to use at my site.

Bradley J. Monk, MD: So, that’s a good summary of frontline. We really debated. We discussed neoadjuvant chemotherapy. We really beat IP chemotherapy back and forth. Now we talked about dose-dense weekly and then adding bevacizumab.

Transcript Edited for Clarity
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Transcript:

Bradley J. Monk, MD:
And so, GOG-262, the trial published last summer of 2016 in the New England Journal of Medicine, was a study of dose-dense, weekly. When paclitaxel is given weekly, we can give more of it. We can give 80 mg/m² a week, 80 x 3 is 240; that’s more than 175 mg/m². So, no breaks. The dose of paclitaxel is 80 mg/m² every week, with carboplatin every 3 weeks. Again, that was supposed to be the confirmatory trial—the Japanese trial that you mentioned—but it also was negative. And people have said, like you have suggested in GOG-252, that bevacizumab was the equalizer.

Thomas Herzog, MD: Well, it was a suboptimal population—first of all, stage III/IV—and you had 14.8 months PFS in the group that received the dose-dense, versus 14.3 months. Not different, and short because of your population being suboptimal—almost 700 patients in this trial. Certainly, one of the things that you look at is, again, the bevacizumab issue. And so, in this particular trial, it was not assigned whether you would get bevacizumab. It was physician and patient choice, and, as it turns out, about 84% or more chose to go on to bevacizumab.

So, the overall result showed no difference. However, if you look at that smaller group—about 16% of the patients—you see that there was a difference, about 14.2 versus 10.3. Hazard ratio was fairly impressive. It was 0.59, so a significant difference for those that got the dose-dense, favoring the dose-dense, which supports the Japanese data in those that do not have bevacizumab at the time frontline therapy. The dose-dense is more efficacious.

Bradley J. Monk, MD: Thank you, Tom. That’s really important. So, does that define, now, the chemotherapy standard in the frontline treatment of ovarian cancer? It’s a subset analysis, but it confirms the Japanese experience that the standard treatment is weekly paclitaxel, dose-dense, with carboplatin every 3 weeks. I’d like to hear the panelists’ opinion of what you think your go-to chemotherapy regimen is frontline. That’s a very practical question.

Angeles Alvarez Secord, MD: Let’s just be clear. In terms of a standard arm for a clinical trial, I think that makes sense. In terms of a standard of care when you’re treating a patient, I think there’s more than one standard in how you can treat patients with ovarian cancer.

Thomas Herzog, MD: Yes, it’s a standard.

Bradley J. Monk, MD: What percent of patients do you think get dose-dense weekly paclitaxel in North Carolina?

Angeles Alvarez Secord, MD: I do not know that frequency. I’ll tell you, we serve a fairly large area. We have patients that are coming from far away, and it’s not convenient for them to come every week. Sometimes you can arrange for them to have some of their treatments by a local physician closer to them, but even that can’t always be easy. For some patients, they prefer the convenience of a Q3 week regimen. Some patients will come weekly for their treatments. I do discuss the incorporation of bevacizumab into their regimen, but that’s for select patients.

Bradley J. Monk, MD: Sure, when it’s given every 3 weeks.

Angeles Alvarez Secord, MD: Yes.

Bradley J. Monk, MD: Rob, what do you think?

Robert L. Coleman, MD: I would say that in our center, it’s very similar. In fact, even in Houston, if the patients are in the periphery—and we have, where our clinics are in the periphery—they’ll be more likely to get dose-dense than if they come actually in town because it’s just where the referral practices are. But, there is one thing I want to mention because it’s important in the patient population and why I keep going back to that. If you go back to GOG-111, which is when paclitaxel and cisplatin was brought into the frontline setting, the median PFS in suboptimal patients was 18 months. But, in this study, GOG-262—it was the same patient population, suboptimal, in that same infusion, although we used carboplatin and then 3-hour paclitaxel—it was 10 months. Bradley J. Monk, MD: I think it’s part of the assessment. In that era, we were not doing CT scans at this stage.

Robert L. Coleman, MD: But, 8 months’ difference?

Angeles Alvarez Secord, MD: I don’t think it’s just that. I think you have to look at what studies were open, and that study was open. It’s like, “Ah, she’s suboptimal.”

Robert L. Coleman, MD: Exactly, that’s what I’m saying. There are inherent factors even in the randomized trials.

Thomas Herzog, MD: We’ve seen that over time, right? We saw that with GOG-111.

Robert L. Coleman, MD: I just want to caution. When we start looking at…

Bradley J. Monk, MD: Cross-trial comparison.

Robert L. Coleman, MD: Yes, absolutely.

Bradley J. Monk, MD: That’s interesting. So, I think we can agree that many patients—I’m not sure I can say most—get dose-dense weekly; AUC (area under the curve) probably is a 6 if carboplatin is given every 3 weeks, paclitaxel 80 mg/m², no break. Bevacizumab is still an option. Katie, is bevacizumab used? Tell me what your thoughts are of frontline bevacizumab, because you heard that it ruined GOG-262 and it ruined GOG-252 because it’s this great drug. If it’s such a great drug, maybe we should add it to Q3 week chemotherapy. Remember, when it’s added weekly, it doesn’t really help. But, I might prefer to get Q3 week chemotherapy with bevacizumab than weekly.

Kathleen N. Moore, MD: Sure, and we have a positive trial supporting that. We have GOG-218. That’s a positive trial. It met its primary endpoint and has supporting data from Europe and ICON7. So, we have a positive trial to support that. Unfortunately, it’s not listed as an indication in the United States, so some providers can use it. Some providers can justify its use in high-risk patients, stage IV in suboptimal patients, per the ICON7 and actually GOG-218’s sub-analyses.

Bradley J. Monk, MD: Stage IV patients with high-volume residual disease in a subset live longer with frontline bevacizumab, and with ascites, which is 85% of the patients.

Kathleen N. Moore, MD: Yes. So, I think when we have data to support that use, it’s unfortunately not equally available to patients in the United States because it doesn’t have an FDA indication. Were it available to me, I would absolutely discuss it with patients, but it’s not something that we’re actually able to use at my site.

Bradley J. Monk, MD: So, that’s a good summary of frontline. We really debated. We discussed neoadjuvant chemotherapy. We really beat IP chemotherapy back and forth. Now we talked about dose-dense weekly and then adding bevacizumab.

Transcript Edited for Clarity
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