ONCAlert | Upfront Therapy for mRCC

Case 2: Primary Treatment Options

Targeted Oncology
Published Online:12:31 PM, Wed May 29, 2019


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Robert L. Coleman, MD: So this patient, Shannon, as you said, underwent a primary cytoreduction. It looks as if they got her resection down to very small, microscopic residual disease. Then the germline data became available, and she showed a BRCA1 mutation. So tell us what your thoughts are with primary therapy now. You’ve got a young, relatively healthy patient. She had a cytoreduction, obviously large-volume disease now down to no visible growths. What’s the best treatment for her?

Shannon N. Westin, MD: You just basically throw your dart at the board. You can do whatever you want, right? I think we’ve come full circle. We originally had paclitaxel-carboplatin intravenously every 3 weeks. And we’ve gone through a number of different modality assessments looking at dose-dense paclitaxel and dose-dense carboplatin, or intraperitoneal [IP], and then the addition of bevacizumab. This is why it should be like a 20-year fellowship instead of just 3 years.

But I think for somebody like this, who has minimal residual disease and is known to have a BRCA mutation, I’m going to already start thinking maintenance. That’s going to help inform what I’m going to do for their treatment. For a patient like this, I know that I’m going to go ahead and give olaparib down the line. And so I’ll look at how I’m going to give that in terms of modality. For the patient who I’ve essentially debulked, I would likely just give it every 3 weeks. That’s just based on the most recent data that we have. Despite all these different modalities that were utilized, essentially the progression-free survival [PFS] and overall survival [OS] were the same, or in the ones who are reported overall.

Robert L. Coleman, MD: What do you think about this dose-dense idea? It’s like the world shifted on us.

Susana M. Campos, MD, MPH: It did, and it shifted back, you know? It was just Q3-week scheduling [every 3 weeks], and that’s actually what we’re back to. But this case is interesting, because you know she’s a BRCA mutation carrier, and you know very well there are clinical trials that have now emanated and that she could be an eligible candidate for that. Not only would you present to her a PARP [poly (ADP ribose) polymerase] inhibitor, in this case, olaparib, because it’s actually approved, but you could ask whether or not immunotherapy has any role. You would probably shy away from giving her anything that wouldn’t guarantee her a PARP inhibitor.

Shannon N. Westin, MD: I think the majority of up-front trials now are guaranteed, right? So there’s the ATHENA trial. And as you mentioned, there are the FIRST and DUO-O trials. I think the BRCA-mutant population is going to be assured to get a PARP on those trials.

David O’Malley, MD: But I think we have so many up-front trials right now. Every single patient has to be discussed to go on a clinical trial. We have to do better. I was so happy to hear you say intraperitoneal chemotherapy.

Robert L. Coleman, MD: Oh, I was just going to ask you that. I didn’t even hear her say that.

David O’Malley, MD: We have retrospective subanalyses of our GOG [Gynecologic Oncology Group] data. Our friend Wendel Naumann, MD, just had a publication with regard to BRCA-positive patients and how much better they have done with intraperitoneal chemotherapy. Once again, my first choice is always going to be a clinical trial. None of the clinical trials are enrolling intraperitoneal chemotherapy, but if she was not interested and I knew she had a BRCA mutation, I would have a serious conversation about intraperitoneal chemotherapy in this patient.

Gregory Riedlinger, MD, PhD: The rationale is that’s platinum based and it would be targeting the...

Shannon N. Westin, MD: Yeah, there are retrospective data that demonstrated a pretty impressive progression-free and overall survival benefit in those BRCA-mutant…

Gregory Riedlinger, MD, PhD: Yeah, the BRCA1s that had staining. It was kind of, it wasn’t really...

David O’Malley, MD: But again, I think we’re starting to see some really interesting data. We need to do this more prospectively and we need to identify those patients.

Robert L. Coleman, MD: So let me take it down 1 more even further controversial topic. If you think that the intraperitoneal chemotherapy is actually causing all that damage in the BRCA patients, to make them have such long outcomes, what about HIPEC [hyperthermic intraperitoneal chemotherapy]?

David O’Malley, MD: Should it do more? I don’t know. We have 1 New England Journal of Medicine article on HIPEC in the neoadjuvant interval debulking setting. So at the time of interval debulking, they had HIPEC. Again, they showed us a progression-free survival improvement. We really need to look at it as an option. But I think the most important aspect to that paper is that you’re not going 6 or 8 weeks, maybe even 10 or 12 weeks, without chemotherapy. So you’re doing that chemotherapy between.

Susana M. Campos, MD, MPH: Absolutely. I think there is tremendous regrowth in that short period of them. We did a small stud, and then all these patients had to get CT [computed tomography] scans before they enrolled in a certain portion of the study. These were optimally debulked patients, and yet they had measurable disease. You could argue the point that this is just inflammation, what have you, postsurgical. But to your point, are we seeing reemergence of disease so soon, and that’s why HIPEC actually has gained the popularity or the interest that it has?

Shannon N. Westin, MD: You also wonder, though, is it HIPEC, or is it just IP after surgery? I think that’s another big…

Robert L. Coleman, MD: Yeah, we’ve mentioned this many times. The quality control here is we don’t really know that we’re actually heating the cancer. We know we’re putting hot stuff into the abdominal cavity, but how many tumor probes do we have that actually say that we’re actually heating the tissue?

Gregory Riedlinger, MD, PhD: And for the people who have done HIPEC, to have a trial in the New England Journal Medicine that has no difference in their toxicities, for those who have done HIPEC, there is a significant difference of toxicity.

Shannon N. Westin, MD: That gives me a lot of pause to see that.

Robert L. Coleman, MD: Yeah, and then it’s the old argument with the neoadjuvant versus primary surgery, right? They look at the absolute benefit—the 12-month PFS and the 30-month OS—and they go, “All our trials are better than that.” And this was the same thing. The numbers were not that impressive. It was that good. It’s just better than placebo or the nontreatment arm. So, OK, we got HIPEC on the table. Everybody can be happy.

David O’Malley, MD: So yes to intraperitoneal.

Robert L. Coleman, MD: The good news is, there are lots of trials ongoing now. Thank gosh they finally got this sorted out. So hopefully we’ll get some more information as that rolls out.

Transcript edited for clarity.


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Robert L. Coleman, MD: So this patient, Shannon, as you said, underwent a primary cytoreduction. It looks as if they got her resection down to very small, microscopic residual disease. Then the germline data became available, and she showed a BRCA1 mutation. So tell us what your thoughts are with primary therapy now. You’ve got a young, relatively healthy patient. She had a cytoreduction, obviously large-volume disease now down to no visible growths. What’s the best treatment for her?

Shannon N. Westin, MD: You just basically throw your dart at the board. You can do whatever you want, right? I think we’ve come full circle. We originally had paclitaxel-carboplatin intravenously every 3 weeks. And we’ve gone through a number of different modality assessments looking at dose-dense paclitaxel and dose-dense carboplatin, or intraperitoneal [IP], and then the addition of bevacizumab. This is why it should be like a 20-year fellowship instead of just 3 years.

But I think for somebody like this, who has minimal residual disease and is known to have a BRCA mutation, I’m going to already start thinking maintenance. That’s going to help inform what I’m going to do for their treatment. For a patient like this, I know that I’m going to go ahead and give olaparib down the line. And so I’ll look at how I’m going to give that in terms of modality. For the patient who I’ve essentially debulked, I would likely just give it every 3 weeks. That’s just based on the most recent data that we have. Despite all these different modalities that were utilized, essentially the progression-free survival [PFS] and overall survival [OS] were the same, or in the ones who are reported overall.

Robert L. Coleman, MD: What do you think about this dose-dense idea? It’s like the world shifted on us.

Susana M. Campos, MD, MPH: It did, and it shifted back, you know? It was just Q3-week scheduling [every 3 weeks], and that’s actually what we’re back to. But this case is interesting, because you know she’s a BRCA mutation carrier, and you know very well there are clinical trials that have now emanated and that she could be an eligible candidate for that. Not only would you present to her a PARP [poly (ADP ribose) polymerase] inhibitor, in this case, olaparib, because it’s actually approved, but you could ask whether or not immunotherapy has any role. You would probably shy away from giving her anything that wouldn’t guarantee her a PARP inhibitor.

Shannon N. Westin, MD: I think the majority of up-front trials now are guaranteed, right? So there’s the ATHENA trial. And as you mentioned, there are the FIRST and DUO-O trials. I think the BRCA-mutant population is going to be assured to get a PARP on those trials.

David O’Malley, MD: But I think we have so many up-front trials right now. Every single patient has to be discussed to go on a clinical trial. We have to do better. I was so happy to hear you say intraperitoneal chemotherapy.

Robert L. Coleman, MD: Oh, I was just going to ask you that. I didn’t even hear her say that.

David O’Malley, MD: We have retrospective subanalyses of our GOG [Gynecologic Oncology Group] data. Our friend Wendel Naumann, MD, just had a publication with regard to BRCA-positive patients and how much better they have done with intraperitoneal chemotherapy. Once again, my first choice is always going to be a clinical trial. None of the clinical trials are enrolling intraperitoneal chemotherapy, but if she was not interested and I knew she had a BRCA mutation, I would have a serious conversation about intraperitoneal chemotherapy in this patient.

Gregory Riedlinger, MD, PhD: The rationale is that’s platinum based and it would be targeting the...

Shannon N. Westin, MD: Yeah, there are retrospective data that demonstrated a pretty impressive progression-free and overall survival benefit in those BRCA-mutant…

Gregory Riedlinger, MD, PhD: Yeah, the BRCA1s that had staining. It was kind of, it wasn’t really...

David O’Malley, MD: But again, I think we’re starting to see some really interesting data. We need to do this more prospectively and we need to identify those patients.

Robert L. Coleman, MD: So let me take it down 1 more even further controversial topic. If you think that the intraperitoneal chemotherapy is actually causing all that damage in the BRCA patients, to make them have such long outcomes, what about HIPEC [hyperthermic intraperitoneal chemotherapy]?

David O’Malley, MD: Should it do more? I don’t know. We have 1 New England Journal of Medicine article on HIPEC in the neoadjuvant interval debulking setting. So at the time of interval debulking, they had HIPEC. Again, they showed us a progression-free survival improvement. We really need to look at it as an option. But I think the most important aspect to that paper is that you’re not going 6 or 8 weeks, maybe even 10 or 12 weeks, without chemotherapy. So you’re doing that chemotherapy between.

Susana M. Campos, MD, MPH: Absolutely. I think there is tremendous regrowth in that short period of them. We did a small stud, and then all these patients had to get CT [computed tomography] scans before they enrolled in a certain portion of the study. These were optimally debulked patients, and yet they had measurable disease. You could argue the point that this is just inflammation, what have you, postsurgical. But to your point, are we seeing reemergence of disease so soon, and that’s why HIPEC actually has gained the popularity or the interest that it has?

Shannon N. Westin, MD: You also wonder, though, is it HIPEC, or is it just IP after surgery? I think that’s another big…

Robert L. Coleman, MD: Yeah, we’ve mentioned this many times. The quality control here is we don’t really know that we’re actually heating the cancer. We know we’re putting hot stuff into the abdominal cavity, but how many tumor probes do we have that actually say that we’re actually heating the tissue?

Gregory Riedlinger, MD, PhD: And for the people who have done HIPEC, to have a trial in the New England Journal Medicine that has no difference in their toxicities, for those who have done HIPEC, there is a significant difference of toxicity.

Shannon N. Westin, MD: That gives me a lot of pause to see that.

Robert L. Coleman, MD: Yeah, and then it’s the old argument with the neoadjuvant versus primary surgery, right? They look at the absolute benefit—the 12-month PFS and the 30-month OS—and they go, “All our trials are better than that.” And this was the same thing. The numbers were not that impressive. It was that good. It’s just better than placebo or the nontreatment arm. So, OK, we got HIPEC on the table. Everybody can be happy.

David O’Malley, MD: So yes to intraperitoneal.

Robert L. Coleman, MD: The good news is, there are lots of trials ongoing now. Thank gosh they finally got this sorted out. So hopefully we’ll get some more information as that rolls out.

Transcript edited for clarity.
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