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Factors in Choice of Treatment for Recurrent Ovarian Cancer

Panelists: Bradley J. Monk, MD, FACS, FACOG, University of Arizona and Creighton University; Michael J. Birrer, MD, PhD The University of Alabama at Birmingham; Ursula A. Matulonis, MD, Harvard Medical School
Published: Saturday, Dec 22, 2018



Transcript: 

Bradley J. Monk, MD: All right, well let’s transition to recurrent epithelial ovarian cancer. Although there are only about 24,000 cases, the death rate remains high. Fortunately, the survival rate though is relatively long, and I’ve tried to [give the] message that the prevalence is 10 times the incidence. So, if it’s somewhere around 24,000 per year, there’s more than 200,000 women fighting in the recurrent setting. And so, what happens is that they’re diagnosed in the advanced stage. Unfortunately, recurrences are common, and then they get treated over and over again. So, I want us to begin by outlining the factors that predict or inform what that treatment and recurrence should be. It used to be platinum-resistant, platinum-sensitive. Now people don’t like to use that term any more. So, what are the factors that determine treatment of recurrent ovarian cancer?

Michael J. Birrer, MD, PhD: Well I think you’re reflecting the evolution of the field, whereas when patients recurred 15, 20 years ago, it unfortunately was a very short period of time, and we didn’t have these multiple agents, or multiple treatments. So, we’ve done much better on that. But it also reflects the fact that I don’t know if any of us really believe that for a recurrent ovarian cancer patient we can cure them. That’s the challenge. And so, we still need new agents and an effective way to approach them.

But once the patient recurs, I would say the other evolution has been that they can get treated so many times with different agents. And this whole concept of 6 months is the cutoff, it sort of faded because you could have a patient who has recurred at 7 months, technically platinum-sensitive, but has had 7 lines of treatment, and that’s going to be different than a patient who recurs 7 months after one line. So, it gets complex and I think some of the factors now are how much pretreatment have they had.

Bradley J. Monk, MD: Yes.

Michael J. Birrer, MD, PhD: I do think the time interval does [have] some relevance. The type of recurrence, is this miliary disease, ascites, or it is a solitary lesion? Those would, in my view, dictate what you might use and may even have a surgical approach to some of those patients.

Bradley J. Monk, MD: So, you said number of lines of therapy, time from last platinum. We already said molecular signatures [are] in the mix, and then there’s the type of recurrence, which includes, you didn’t mention it, but lingering toxicities from prior regimens.

Michael J. Birrer, MD, PhD: Sure.

Ursula A. Matulonis, MD: Sure, absolutely.
Bradley J. Monk, MD: You didn’t mention cell type. Does the cell type also factor into the treatment of recurrent ovarian cancer? What I mean, the rare cell types using this, low-grade and clear cell. Is the cell type important?

Ursula A. Matulonis, MD: I think it’s important to certainly recognize, absolutely. We’ve already alluded to this in terms of PARP [poly ADP ribose polymerase] inhibitor, although BRCA mutations can be found in all types of histologies, most commonly seen in high-grade serous, clear cell endometrioid. Much rarer in low-grade serous or mucinous tumors. However, for low-grade serous, these are very hormonally sensitive diseases. Like we’re sort of harkening back to our initial discussion about primary treatment. We should also mention that the paper by a group at [The University of Texas] MD Anderson [Cancer Center] using an aromatase inhibitor as maintenance therapy in patients with low-grade serous carcinoma, I’ve definitely incorporated that into my practice for patients who are newly diagnosed, high-risk patients.

But now we’re talking about recurrence. Certainly, aromatase inhibitors, there’s some indication that perhaps MEK inhibitors might be usable in low-grade serous cancers, although I think the [jury is still out] about that. For mucinous tumors, they are very difficult tumors to treat and certainly next-generation sequencing might find a KRAS mutation and there are KRAS directed clinical trials around them. So, I do think that the histology is really important, yes.

Bradley J. Monk, MD: So, let’s try to create some scenarios. The most common early recurrences are platinum sensitive; I’m sorry I used that term. The most common early recurrences happen more than 6 months after last treatment. Again, we’re talking earlier recurrences. And many people would treat them with a platinum doublet. We have FDA-approved platinum doublets, 2 of them: with bevacizumab [and] carboplatin/gemcitabine based on this trial called OCEANS, [and] carboplatin/paclitaxel based on GOG213 with bevacizumab. Again, we asked you what the chemotherapy backbone was in frontline; we kind of agreed carboplatin/paclitaxel. What’s the chemotherapy doublet backbone again in earlier lines of recurrence in second-line more than 6 months; what’s the platinum doublet?

Ursula A. Matulonis, MD: I think you’ve mentioned all of them.

Bradley J. Monk, MD: Which one would you use?

Ursula A. Matulonis, MD: Well, it really depends upon the clinical situation. And I still think that all those factors that we just talked about, the level of platinum sensitivity. That term still does come in to how we think about it because you wouldn’t want to give patients with primary platinum refractory cancers platinum again.

Bradley J. Monk, MD: Right.

Ursula A. Matulonis, MD: So that term has to come into play. The underlying BRCA status or other DNA repair gene abnormalities within the cancer. Toxicities that you want to avoid. That’s really important now because for patients with recurrent disease you do have all these choices. You’re tailoring your doublets or triplets to the patient, but then the patient really has to tell you if she has a wedding or she doesn’t want to lose her hair—you know, kid’s wedding coming up—or she has underlying neuropathy still from her original regimen; you’re not going to want to use paclitaxel.

Bradley J. Monk, MD: So at this meeting there was a randomized phase III to try to help inform this idea. I told you we had carboplatin/gemcitabine/bevacizumab; we had carboplatin/ paclitaxel/bevacizumab; and we had carboplatin/PLD [pegylated liposomal doxorubicin]. We didn’t have a phase III of carboplatin/PLD/bevacizumab, and by PDL I mean pegylated liposomal doxorubicin. So [he] and the Germans and other cooperative groups within the European Network of oncology trials, did a randomized phase III of carboplatin/PLD/bevacizumab; [and] carboplatin/gemcitabine and bevacizumab; and carboplatin/PLD was a little better. And then you talk about the convenience factor. Carboplatin, pegylated liposomal doxorubicin, at least the chemotherapy components every 4 weeks, and there’s no alopecia, and less neuropathy, more hand-foot syndrome. Is that really now kind of level 1 evidence that the platinum doublet bevacizumab triplet should be carboplatin/PLD/bevacizumab? Or it depends on all these other things?

Ursula A. Matulonis, MD: You’ve got choices, and you’ve got to engage the patient in this discussion, and you’ve got to also now think about what should we talk about, the BRCA status, the histology, her responsiveness to chemotherapy, her prior toxicities. But also her underlying medical problems; if she’s got underlying cardiac disease; [if] she has congestive heart failure. Maybe her LVEF [left ventricular ejection fraction] is 40%; you probably don’t want to use PLD because you have other options.

Michael J. Birrer, MD, PhD: You know when they designed that trial I was sort of a skeptic, saying you know we already know these are active, what’s the point of it? I actually think it’s a very important study.

Bradley J. Monk, MD: I do too.

Michael J. Birrer, MD, PhD: Because what it really did fill in, in my own practice, [is that] carboplatin/PLD is actually the favored one with patients.

Bradley J. Monk, MD: I’m trying to get her to say that.

Michael J. Birrer, MD, PhD: For all of the reasons.

Michael J. Birrer, MD, PhD: In fact, when I mentioned retreating with paclitaxel, they just run out of the room. But what was nice about that study, let me just finish this, [is] that because it involved bevacizumab, and because we didn’t really have that data together, we had to piece it together. I think that helps.

Ursula A. Matulonis, MD: Yes. I think that if you’re using bevacizumab and you’re going to use carboplatin/pegylated liposomal doxorubicin, it does complicate the issues around PARP inhibitor use in maintenance.

Transcript Edited for Clarity

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Transcript: 

Bradley J. Monk, MD: All right, well let’s transition to recurrent epithelial ovarian cancer. Although there are only about 24,000 cases, the death rate remains high. Fortunately, the survival rate though is relatively long, and I’ve tried to [give the] message that the prevalence is 10 times the incidence. So, if it’s somewhere around 24,000 per year, there’s more than 200,000 women fighting in the recurrent setting. And so, what happens is that they’re diagnosed in the advanced stage. Unfortunately, recurrences are common, and then they get treated over and over again. So, I want us to begin by outlining the factors that predict or inform what that treatment and recurrence should be. It used to be platinum-resistant, platinum-sensitive. Now people don’t like to use that term any more. So, what are the factors that determine treatment of recurrent ovarian cancer?

Michael J. Birrer, MD, PhD: Well I think you’re reflecting the evolution of the field, whereas when patients recurred 15, 20 years ago, it unfortunately was a very short period of time, and we didn’t have these multiple agents, or multiple treatments. So, we’ve done much better on that. But it also reflects the fact that I don’t know if any of us really believe that for a recurrent ovarian cancer patient we can cure them. That’s the challenge. And so, we still need new agents and an effective way to approach them.

But once the patient recurs, I would say the other evolution has been that they can get treated so many times with different agents. And this whole concept of 6 months is the cutoff, it sort of faded because you could have a patient who has recurred at 7 months, technically platinum-sensitive, but has had 7 lines of treatment, and that’s going to be different than a patient who recurs 7 months after one line. So, it gets complex and I think some of the factors now are how much pretreatment have they had.

Bradley J. Monk, MD: Yes.

Michael J. Birrer, MD, PhD: I do think the time interval does [have] some relevance. The type of recurrence, is this miliary disease, ascites, or it is a solitary lesion? Those would, in my view, dictate what you might use and may even have a surgical approach to some of those patients.

Bradley J. Monk, MD: So, you said number of lines of therapy, time from last platinum. We already said molecular signatures [are] in the mix, and then there’s the type of recurrence, which includes, you didn’t mention it, but lingering toxicities from prior regimens.

Michael J. Birrer, MD, PhD: Sure.

Ursula A. Matulonis, MD: Sure, absolutely.
Bradley J. Monk, MD: You didn’t mention cell type. Does the cell type also factor into the treatment of recurrent ovarian cancer? What I mean, the rare cell types using this, low-grade and clear cell. Is the cell type important?

Ursula A. Matulonis, MD: I think it’s important to certainly recognize, absolutely. We’ve already alluded to this in terms of PARP [poly ADP ribose polymerase] inhibitor, although BRCA mutations can be found in all types of histologies, most commonly seen in high-grade serous, clear cell endometrioid. Much rarer in low-grade serous or mucinous tumors. However, for low-grade serous, these are very hormonally sensitive diseases. Like we’re sort of harkening back to our initial discussion about primary treatment. We should also mention that the paper by a group at [The University of Texas] MD Anderson [Cancer Center] using an aromatase inhibitor as maintenance therapy in patients with low-grade serous carcinoma, I’ve definitely incorporated that into my practice for patients who are newly diagnosed, high-risk patients.

But now we’re talking about recurrence. Certainly, aromatase inhibitors, there’s some indication that perhaps MEK inhibitors might be usable in low-grade serous cancers, although I think the [jury is still out] about that. For mucinous tumors, they are very difficult tumors to treat and certainly next-generation sequencing might find a KRAS mutation and there are KRAS directed clinical trials around them. So, I do think that the histology is really important, yes.

Bradley J. Monk, MD: So, let’s try to create some scenarios. The most common early recurrences are platinum sensitive; I’m sorry I used that term. The most common early recurrences happen more than 6 months after last treatment. Again, we’re talking earlier recurrences. And many people would treat them with a platinum doublet. We have FDA-approved platinum doublets, 2 of them: with bevacizumab [and] carboplatin/gemcitabine based on this trial called OCEANS, [and] carboplatin/paclitaxel based on GOG213 with bevacizumab. Again, we asked you what the chemotherapy backbone was in frontline; we kind of agreed carboplatin/paclitaxel. What’s the chemotherapy doublet backbone again in earlier lines of recurrence in second-line more than 6 months; what’s the platinum doublet?

Ursula A. Matulonis, MD: I think you’ve mentioned all of them.

Bradley J. Monk, MD: Which one would you use?

Ursula A. Matulonis, MD: Well, it really depends upon the clinical situation. And I still think that all those factors that we just talked about, the level of platinum sensitivity. That term still does come in to how we think about it because you wouldn’t want to give patients with primary platinum refractory cancers platinum again.

Bradley J. Monk, MD: Right.

Ursula A. Matulonis, MD: So that term has to come into play. The underlying BRCA status or other DNA repair gene abnormalities within the cancer. Toxicities that you want to avoid. That’s really important now because for patients with recurrent disease you do have all these choices. You’re tailoring your doublets or triplets to the patient, but then the patient really has to tell you if she has a wedding or she doesn’t want to lose her hair—you know, kid’s wedding coming up—or she has underlying neuropathy still from her original regimen; you’re not going to want to use paclitaxel.

Bradley J. Monk, MD: So at this meeting there was a randomized phase III to try to help inform this idea. I told you we had carboplatin/gemcitabine/bevacizumab; we had carboplatin/ paclitaxel/bevacizumab; and we had carboplatin/PLD [pegylated liposomal doxorubicin]. We didn’t have a phase III of carboplatin/PLD/bevacizumab, and by PDL I mean pegylated liposomal doxorubicin. So [he] and the Germans and other cooperative groups within the European Network of oncology trials, did a randomized phase III of carboplatin/PLD/bevacizumab; [and] carboplatin/gemcitabine and bevacizumab; and carboplatin/PLD was a little better. And then you talk about the convenience factor. Carboplatin, pegylated liposomal doxorubicin, at least the chemotherapy components every 4 weeks, and there’s no alopecia, and less neuropathy, more hand-foot syndrome. Is that really now kind of level 1 evidence that the platinum doublet bevacizumab triplet should be carboplatin/PLD/bevacizumab? Or it depends on all these other things?

Ursula A. Matulonis, MD: You’ve got choices, and you’ve got to engage the patient in this discussion, and you’ve got to also now think about what should we talk about, the BRCA status, the histology, her responsiveness to chemotherapy, her prior toxicities. But also her underlying medical problems; if she’s got underlying cardiac disease; [if] she has congestive heart failure. Maybe her LVEF [left ventricular ejection fraction] is 40%; you probably don’t want to use PLD because you have other options.

Michael J. Birrer, MD, PhD: You know when they designed that trial I was sort of a skeptic, saying you know we already know these are active, what’s the point of it? I actually think it’s a very important study.

Bradley J. Monk, MD: I do too.

Michael J. Birrer, MD, PhD: Because what it really did fill in, in my own practice, [is that] carboplatin/PLD is actually the favored one with patients.

Bradley J. Monk, MD: I’m trying to get her to say that.

Michael J. Birrer, MD, PhD: For all of the reasons.

Michael J. Birrer, MD, PhD: In fact, when I mentioned retreating with paclitaxel, they just run out of the room. But what was nice about that study, let me just finish this, [is] that because it involved bevacizumab, and because we didn’t really have that data together, we had to piece it together. I think that helps.

Ursula A. Matulonis, MD: Yes. I think that if you’re using bevacizumab and you’re going to use carboplatin/pegylated liposomal doxorubicin, it does complicate the issues around PARP inhibitor use in maintenance.

Transcript Edited for Clarity
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