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Surgical Management of Advanced 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: Wednesday, Feb 01, 2017


Transcript:

Bradley J. Monk, MD:
Let’s transition a little bit to treatment. I wish we could talk more about prevention, but we don’t really understand how to prevent ovarian cancer other than identifying those at risk and doing risk-reducing surgery. There are others, like hysterectomy and birth control pills. I get it. The best way to prevent ovarian cancer is through genetic testing. Let’s transition to treatment.

Surgery is an important component. All of us are surgeons, but as gynecologic oncologists, we also all give chemotherapy. There has been a lot of discussion about when to do the operation. When the operation is done in the beginning, that’s called primary debulking. When it’s being sandwiched between the third and the fourth cycle of chemotherapy, it’s called neoadjuvant. Angeles, there has been a lot of discussion, and even a consensus statement, about neoadjuvant chemotherapy versus primary debulking. Tell us about that.

Angeles Alvarez Secord, MD: Well, it’s a very good and informative article. I encourage everybody to go and read it. One of the most important things about this article, I think, is that it provides the background and a review of the data in this area. There have been 4 randomized clinical trials now exploring neoadjuvant chemotherapy versus primary cytoreductive surgery. There’s actually another trial that’s ongoing, the TRUST trial, and that started in Europe. They’re trying to open it here in the States, which I hope we’ll be able to do. But what’s important with all the 4 trials that have been completed is they’ve all demonstrated that in these select patients, and I think they are high-risk patients, the morbidity with the primary debulking surgical approach, rather than a neoadjuvant approach, is higher.

And then, the other thing that 2 of the trials have demonstrated is that there’s no difference in overall survival outcomes between either approach. But these are very select patients whom I don’t think are represented across all the trials that we’ve done in the Gynecologic Oncology Group (GOG), for instance. These are probably patients that are at higher risk for having suboptimally debulked disease or harder-to-resect disease and probably more aggressive tumor biology.

Bradley J. Monk, MD: So, we have 2 options: start with an operation or start with chemotherapy. It’s the toughest decision we make. It’s great if we do an operation. We completely resect the tumor. We feel good about ourselves; we’ve made the right decision. We do an operation, we leave a lot of the tumor behind. We should have used neoadjuvant as you suggested. How do you figure it out? Who gets started with chemotherapy? Who gets started with surgery?

Thomas Herzog, MD: Well, I think there are some easy answers in that complex question. The first one is obviously a patient that has significant comorbidities who you’re not going to be able to get through the primary debulking very easily or it’s going to result in an SICU stay of many days that has its own set of sequalae. So, that’s an easy one; someone that you don’t think can withstand that. And then there are some patients who you can see on imaging or some people are now using a laparoscopic platform to assess whether they think they can get this patient down to optimal disease. Now, the new optimal is really trying to get these patients down to R0 with no gross residual disease. There are some scans and exams that you do that you just know there’s no way that’s going to happen. And in those cases, it makes some sense to go to the neoadjuvant.

I think the biggest problem with neoadjuvant is, for those who are not strong believers in it, looking at contemporary databases from centers that do aggressive cytoreduction. You look at their survivals and they’re 30% to 40%, maybe even higher than what we see with the 29 to 30 months that we see with the largest trials, like the EORTC and the CHORUS trial. So, that makes you think better than 29 to 30 months. Now, we’re going up to 40 months and higher. Are those fair comparisons or not? We don’t know. We’d love to see that construct within the framework of randomized trials, and certainly, that’s important. The other thing I’d say about the neoadjuvant that is really appealing is that you do increase your R0 rate. You increase your optimal debulking and your R0 rate while decreasing blood loss and mortality.

Bradley J. Monk, MD: But the survival is not the same.

Thomas Herzog, MD: The survival doesn’t stay the same, so why isn’t that R0 translating? Is it that we’re inducing resistance with so many cells being exposed to chemotherapy? Is it that we’re not giving enough?

Bradley J. Monk, MD: They have more tumors and they’re sicker?

Thomas Herzog, MD: Maybe we’re not giving enough cycles, though, after the surgery.

Robert L. Coleman, MD: Could be.

Angeles Alvarez Secord, MD: Sorry to jump in, but you said you’re comparing these different trials. It’s not just apples and oranges, it’s fruit salad. These patients are completely different. To do a comparison of a randomized GOG trial—where patients have surgery, they’ve done well, they have a strong enough performance status, they can go on trial—is completely different than taking a newly diagnosed patient and randomizing them to one of these studies. It’s not even the same. It’s not a fair comparison.

Robert L. Coleman, MD: But I do think that there’s a lot of ambiguity about who’s still the best candidate; we all have those. You see the CT scan exam; they’ve got a big pelvic disease, it’s not infrequent that they’re going to need a rectosigmoid resection. The diaphragms are hard to assess, and the hardest part to assess is really how much mesenteric involvement there is, which is really a “go, no-go” decision. There have been multiple different ways to try to assess that. We think, in our place, that the best way to assess that with the highest fidelity is with laparoscopy. But we’ve looked at CT scans and different algorithm CT scans, as other people have, and it’s very hard to find a set of parameters that have external validity, like what I can do at my shop versus what you can do at your shop. And I’ll take it one more step: when we look at our educated radiologists trying to reproduce the feasibility and no feasibility by laparoscopy, we can’t even reproduce it within our own center.

So, I think there’s a lot to be done here. I think maybe the ultimate answer is going to end up with this combination of knowing the molecular profile, as you mentioned, and assigning that with findings that we get from other noninvasive ways. And so, circulating tumor cells and such may be a way to come up with those kinds of profiles.

Thomas Herzog, MD: Well, we’re coming a long way. There’s a paper from your center that you combined with Memorial Sloan Kettering where you looked at 20 clinical parameters and 4 laboratory parameters, and you came up with 9 that were predictive. Then you came up with a scoring system that yet needs to be validated. But, nonetheless, it’s very interesting because we’re much further along than we were 5 to 10 years ago.

Bradley J. Monk, MD: But here’s the thing I hate to see. The gynecologic oncologist makes the decision, then makes an incision and says, “Oh, I had to try.” So, they get in there, they stir it all up, they remove half of the tumor, they lose a lot of blood and leave a lot of tumor behind. You say, “Why did you do that?” “Well, I made the wrong decision. I should have done neoadjuvant.” And I say, “What you should have done was stop, make an incision, do a little biopsy, close her up, and come back and fight another day.”

Angeles Alvarez Secord, MD: What Rob was alluding to was laparoscopy. The first look at laparoscopy, I’ll give Michael Fromowitz credit for it because he said that years ago. But I find that that has been really helpful. So, like Tom was saying, I use those clinical factors to help determine who I’ll even think is a candidate for that surgical assessment. And then, based on those clinical factors and their CT scan, we go to the OR, we do that small incision, and we make an assessment. And I have to tell you, one of the things that I think is the hardest to debulk to R0 is the patients who have miliary diffuse peritoneal disease.

Bradley J. Monk, MD: You can’t do it.

Angeles Alvarez Secord, MD: So, I’m going to say something that may be pretty crazy to you all, but if I can get somebody less than 1 cm, I’m going to go for it. I’m not going to not go for it if I can’t get them to R0. I think there is some value in trying to debulk as much of the disease as possible. I’m concerned that that R0 number was based on the EORTC trial that just showed that patients who were debulked to R0, that was the only thing that was statistically significant for prognosis in the clinical factors they evaluated. Maybe that’s old school, but I still think it’s worthwhile to do surgery.

Bradley J. Monk, MD: Let’s keep moving here. I think the bottom line is that when you’re trying to make this decision, surgery versus chemotherapy, first a gynecological oncologist has to get involved. That’s the take-home message, and we understand it’s a tough decision.

Thomas Herzog, MD: It has to be up front. That’s the key when that decision for the incision is made.

Bradley J. Monk, MD: Before the first dose of chemotherapy.

Robert L. Coleman, MD: And to emphasize that point, if you were to go in, make a mistake, take out not as much tumor as you had hoped that you could have obtained, going back and redoing the operation after an induction set of cycles is not the answer.

Kathleen N. Moore, MD: Right, we’ve shown that.

Robert L. Coleman, MD: We know that from randomized trials.

Bradley J. Monk, MD: As long as you’re trying the first time. That little mini laparotomy in omental biopsy is not trying.

Robert L. Coleman, MD: That’s not trying.

Bradley J. Monk, MD: But if you try a second operation, it’s not going to help.

Transcript Edited for Clarity
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Transcript:

Bradley J. Monk, MD:
Let’s transition a little bit to treatment. I wish we could talk more about prevention, but we don’t really understand how to prevent ovarian cancer other than identifying those at risk and doing risk-reducing surgery. There are others, like hysterectomy and birth control pills. I get it. The best way to prevent ovarian cancer is through genetic testing. Let’s transition to treatment.

Surgery is an important component. All of us are surgeons, but as gynecologic oncologists, we also all give chemotherapy. There has been a lot of discussion about when to do the operation. When the operation is done in the beginning, that’s called primary debulking. When it’s being sandwiched between the third and the fourth cycle of chemotherapy, it’s called neoadjuvant. Angeles, there has been a lot of discussion, and even a consensus statement, about neoadjuvant chemotherapy versus primary debulking. Tell us about that.

Angeles Alvarez Secord, MD: Well, it’s a very good and informative article. I encourage everybody to go and read it. One of the most important things about this article, I think, is that it provides the background and a review of the data in this area. There have been 4 randomized clinical trials now exploring neoadjuvant chemotherapy versus primary cytoreductive surgery. There’s actually another trial that’s ongoing, the TRUST trial, and that started in Europe. They’re trying to open it here in the States, which I hope we’ll be able to do. But what’s important with all the 4 trials that have been completed is they’ve all demonstrated that in these select patients, and I think they are high-risk patients, the morbidity with the primary debulking surgical approach, rather than a neoadjuvant approach, is higher.

And then, the other thing that 2 of the trials have demonstrated is that there’s no difference in overall survival outcomes between either approach. But these are very select patients whom I don’t think are represented across all the trials that we’ve done in the Gynecologic Oncology Group (GOG), for instance. These are probably patients that are at higher risk for having suboptimally debulked disease or harder-to-resect disease and probably more aggressive tumor biology.

Bradley J. Monk, MD: So, we have 2 options: start with an operation or start with chemotherapy. It’s the toughest decision we make. It’s great if we do an operation. We completely resect the tumor. We feel good about ourselves; we’ve made the right decision. We do an operation, we leave a lot of the tumor behind. We should have used neoadjuvant as you suggested. How do you figure it out? Who gets started with chemotherapy? Who gets started with surgery?

Thomas Herzog, MD: Well, I think there are some easy answers in that complex question. The first one is obviously a patient that has significant comorbidities who you’re not going to be able to get through the primary debulking very easily or it’s going to result in an SICU stay of many days that has its own set of sequalae. So, that’s an easy one; someone that you don’t think can withstand that. And then there are some patients who you can see on imaging or some people are now using a laparoscopic platform to assess whether they think they can get this patient down to optimal disease. Now, the new optimal is really trying to get these patients down to R0 with no gross residual disease. There are some scans and exams that you do that you just know there’s no way that’s going to happen. And in those cases, it makes some sense to go to the neoadjuvant.

I think the biggest problem with neoadjuvant is, for those who are not strong believers in it, looking at contemporary databases from centers that do aggressive cytoreduction. You look at their survivals and they’re 30% to 40%, maybe even higher than what we see with the 29 to 30 months that we see with the largest trials, like the EORTC and the CHORUS trial. So, that makes you think better than 29 to 30 months. Now, we’re going up to 40 months and higher. Are those fair comparisons or not? We don’t know. We’d love to see that construct within the framework of randomized trials, and certainly, that’s important. The other thing I’d say about the neoadjuvant that is really appealing is that you do increase your R0 rate. You increase your optimal debulking and your R0 rate while decreasing blood loss and mortality.

Bradley J. Monk, MD: But the survival is not the same.

Thomas Herzog, MD: The survival doesn’t stay the same, so why isn’t that R0 translating? Is it that we’re inducing resistance with so many cells being exposed to chemotherapy? Is it that we’re not giving enough?

Bradley J. Monk, MD: They have more tumors and they’re sicker?

Thomas Herzog, MD: Maybe we’re not giving enough cycles, though, after the surgery.

Robert L. Coleman, MD: Could be.

Angeles Alvarez Secord, MD: Sorry to jump in, but you said you’re comparing these different trials. It’s not just apples and oranges, it’s fruit salad. These patients are completely different. To do a comparison of a randomized GOG trial—where patients have surgery, they’ve done well, they have a strong enough performance status, they can go on trial—is completely different than taking a newly diagnosed patient and randomizing them to one of these studies. It’s not even the same. It’s not a fair comparison.

Robert L. Coleman, MD: But I do think that there’s a lot of ambiguity about who’s still the best candidate; we all have those. You see the CT scan exam; they’ve got a big pelvic disease, it’s not infrequent that they’re going to need a rectosigmoid resection. The diaphragms are hard to assess, and the hardest part to assess is really how much mesenteric involvement there is, which is really a “go, no-go” decision. There have been multiple different ways to try to assess that. We think, in our place, that the best way to assess that with the highest fidelity is with laparoscopy. But we’ve looked at CT scans and different algorithm CT scans, as other people have, and it’s very hard to find a set of parameters that have external validity, like what I can do at my shop versus what you can do at your shop. And I’ll take it one more step: when we look at our educated radiologists trying to reproduce the feasibility and no feasibility by laparoscopy, we can’t even reproduce it within our own center.

So, I think there’s a lot to be done here. I think maybe the ultimate answer is going to end up with this combination of knowing the molecular profile, as you mentioned, and assigning that with findings that we get from other noninvasive ways. And so, circulating tumor cells and such may be a way to come up with those kinds of profiles.

Thomas Herzog, MD: Well, we’re coming a long way. There’s a paper from your center that you combined with Memorial Sloan Kettering where you looked at 20 clinical parameters and 4 laboratory parameters, and you came up with 9 that were predictive. Then you came up with a scoring system that yet needs to be validated. But, nonetheless, it’s very interesting because we’re much further along than we were 5 to 10 years ago.

Bradley J. Monk, MD: But here’s the thing I hate to see. The gynecologic oncologist makes the decision, then makes an incision and says, “Oh, I had to try.” So, they get in there, they stir it all up, they remove half of the tumor, they lose a lot of blood and leave a lot of tumor behind. You say, “Why did you do that?” “Well, I made the wrong decision. I should have done neoadjuvant.” And I say, “What you should have done was stop, make an incision, do a little biopsy, close her up, and come back and fight another day.”

Angeles Alvarez Secord, MD: What Rob was alluding to was laparoscopy. The first look at laparoscopy, I’ll give Michael Fromowitz credit for it because he said that years ago. But I find that that has been really helpful. So, like Tom was saying, I use those clinical factors to help determine who I’ll even think is a candidate for that surgical assessment. And then, based on those clinical factors and their CT scan, we go to the OR, we do that small incision, and we make an assessment. And I have to tell you, one of the things that I think is the hardest to debulk to R0 is the patients who have miliary diffuse peritoneal disease.

Bradley J. Monk, MD: You can’t do it.

Angeles Alvarez Secord, MD: So, I’m going to say something that may be pretty crazy to you all, but if I can get somebody less than 1 cm, I’m going to go for it. I’m not going to not go for it if I can’t get them to R0. I think there is some value in trying to debulk as much of the disease as possible. I’m concerned that that R0 number was based on the EORTC trial that just showed that patients who were debulked to R0, that was the only thing that was statistically significant for prognosis in the clinical factors they evaluated. Maybe that’s old school, but I still think it’s worthwhile to do surgery.

Bradley J. Monk, MD: Let’s keep moving here. I think the bottom line is that when you’re trying to make this decision, surgery versus chemotherapy, first a gynecological oncologist has to get involved. That’s the take-home message, and we understand it’s a tough decision.

Thomas Herzog, MD: It has to be up front. That’s the key when that decision for the incision is made.

Bradley J. Monk, MD: Before the first dose of chemotherapy.

Robert L. Coleman, MD: And to emphasize that point, if you were to go in, make a mistake, take out not as much tumor as you had hoped that you could have obtained, going back and redoing the operation after an induction set of cycles is not the answer.

Kathleen N. Moore, MD: Right, we’ve shown that.

Robert L. Coleman, MD: We know that from randomized trials.

Bradley J. Monk, MD: As long as you’re trying the first time. That little mini laparotomy in omental biopsy is not trying.

Robert L. Coleman, MD: That’s not trying.

Bradley J. Monk, MD: But if you try a second operation, it’s not going to help.

Transcript Edited for Clarity
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