HIPEC in Gynecologic Cancers
Robert DeBernardo, MD, Section Head of Gynecologic Oncology at Cleveland Clinic Ob/Gyn & Women’s Health Institute joins the Cancer Advances podcast to discuss hyperthermic intra-peritoneal chemotherapy (HIPEC), specifically in gynecologic cancers. Listen as Dr. DeBernardo discusses the procedure and use of HIPEC along with the type of patient and cancers that are ideal for HIPEC treatment.
HIPEC in Gynecologic Cancers
Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I in Sarcoma Programs. Today, I'm happy to be joined by Dr. Robert DeBernardo, Section Head of Gynecologic Oncology. Dr. DeBernardo established the OB/GYN and Women's Health Institute's HIPEC Program. He's here today to talk to us about the use of HIPEC for gynecologic cancers. So welcome, Rob. Maybe you could start off by telling us a little bit about your role here at Cleveland Clinic?
Robert DeBernardo, MD: Yeah. Sure. Thanks, Dale. It's so nice to be invited to chat about HIPEC, it's one of my passions. So I guess I've been with the Clinic about seven, eight years now. And I came from UH, I started a program there. So in terms of HIPEC, for those people who might not know the terminology, it's hyperthermic intra-peritoneal chemotherapy, and it's a technique that had been used in GI cancers, relatively rare GI cancers, with some success.
And since many of our most challenging gynecologic cancers are perineal surface malignancies, there are a number of us across the country and across the world that thought, "Hey, why not try to apply this same technique for our cancers?" And it was started slow, but we now have some really solid data in terms of efficacy in certain patients of ours with ovary cancer. So we can chat a little bit about that today, if you like.
Dale Shepard, MD, PhD: Perfect. So how does it work? So maybe just a walk us through, we think about intra-peritoneal chemo and we're talking about heated chemo, which I give a lot of chemo and I never heat it. So maybe a little bit about that aspect. How does this actually work? What's the procedure?
Robert DeBernardo, MD: Let me talk about the procedure first, and then we'll talk about some of the more interesting rationale of why it might be beneficial or what might be explaining the improvements that we're seeing. So HIPEC is really a technique that's performed in the operating room. So at the time of a surgical de-bulking of cancer, where you have peritoneal metastasis, we're trying to remove all the gross residual disease. And if there is disease left, it has to be very small volume, maybe one to two millimeters, but ideally no gross residual disease. So following those radical resections, the administration of typical chemotherapy agents and for ovary cancer, we'll use cisplatin typically.
Some folks are using carbo. Some people are using Taxol, but you can also give Adriamycin in either the abdominal cavity or the chest for that matter. So once the surgical de-bulking is gone, we put tubing in the abdomen, close the abdomen, and then essentially infuse these drugs in that peritoneal dialysis for 45, 90, 60 minutes. Here at the clinic, we use a 90-minute protocol. Once the infusion is over, we rinse the abdominal cavity empty, take the tubing out, and then whatever, if we've done a bowel resection, the bowel go back together and then essentially close. So it adds about a hour and a half to our surgical procedure, maybe a little bit more.
Now we typically, we're monitoring inflow and outflow temperatures and we're trying to achieve about 42 degrees centigrade. And so, we're typically going to look for the outflow for that. Does that answer your question Dale?
Dale Shepard, MD, PhD: Yeah, no. That's helpful. So, this primarily is being used in patients after a surgery, but tell us a little bit about other settings before surgery.
Robert DeBernardo, MD: The group of people we have the best data for are people with epithelial ovarian cancer. So the typical garden variety, high-grade ovary cancers. Most of these women are going to present with advanced stage disease, as many of you guys know. And typically, they're going to require both systemic chemotherapy and surgery. It's controversial a bit if that surgery starts first, or we give some induction chemotherapy, but regardless, there is very solid data from randomized controlled trials where people that get induction chemotherapy... So after three or four cycles of Taxol and Platinum, if you take them to the operating room, de-bulk the residual cancer, and then give them HIPEC.
It improves overall survival, and progression-free survival significantly with no increase in morbidity or mortality, which is really good. So, that's in terms of our newly-diagnosed ovary cancers, primarily how it's being used. For those, that subset of people that are not de-bulkable on presentation, either because of their age or because of the disease burden, if they have a good response, then they're great candidates.
There are some centers that are using it upfront. So somebody presents, they have a big ovary cancer. We de-bulk them, and giving them that. I'm not a fan of that for a number of reasons. Those people tend to be pretty compromised. And so getting them through a big de-bulking surgery with multi-visceral organ resections is challenging. We don't always even have pathology, except for a frozen section, when we're making these decisions. So I'm a little leery about that and the added time.
So you're taking a surgery that may be four or five hours, and then adding another hour and a half to it. So some centers have done it, but again, we don't have really solid data that it's beneficial in the upfront setting. The other area where I've used it, and it would be interesting to look is in consolidation. So for patients who have had surgery and chemotherapy typically intravenous for consolidation, so now they're done with their therapy. They're essentially cancer-free, putting a scope in, and then this procedure can be formed laparoscopically as well. And I have a handful of patients who've done extremely well. Clearly that's not data, but it is certainly something that potentially warrants further study.
Dale Shepard, MD, PhD: Are we doing studies here at the clinic with a HIPEC?
Robert DeBernardo, MD: We are, actually. We have a lot of interesting things going on. So we have a lab, and in the lab we have ovarian cancer cell lines that Platinum-resistant and Platinum-sensitive, which we're looking at. We also have developed an animal model, where we can mimic what we're doing a little bit more realistically than in cell culture. And we also have a trial, it's on hold right now, but we have a trial where these women who have had neoadjuvant chemo and are going for their interval cellular reduction and getting HIPEC, we have a really cool protocol. What we're doing is leaving a portion of omental tumor behind.
So we sample half of the omental tumor, right before we give HIPEC. And then we give HIPEC and that second half of the tumor comes out after HIPEC. So we have the same exact tumor, 90 minutes apart. We sort that by cell type. And then we do sequencing of all RNA changes and stuff. And what's really fascinating is we've I think done five or six patients so far, the shift in what's happening in these tumor cells and the microenvironment is fascinating. This is really, there's a lot of immunologic change that we're seeing that has not really been described.
So a lot of cool stuff going on, in terms of lab work and some basic science, because the interesting thing is we have solid clinical data for upfront patients like we talked about. Also for patients in the recurrent setting, if they're going back to the operating room, HIPEC improves progression-free and overall survival in randomized controlled trials. Which is hard to move the bar with ovary cancer. But we don't really know how this works, so that's what our lab is trying to sort out, some of the mechanisms through which this may be occurring. Is this driven by immunologic mechanisms only, or is this increased Platinum adduction? We don't really know. So a lot of really interesting things I think are going on.
Dale Shepard, MD, PhD: I'm going to ask what might be an obvious question that people might be wondering, why heated? So what's the advantage of that?
Robert DeBernardo, MD: So the thing about heat is fascinating, and this comes from Dr. Sugarbaker, who I think many of us consider the grandfather of this therapy. I think initially started to heat this because he was dealing with a lot of these low-grade mucinous tumors and pseudomyxomas and thought all the heat might help, like with Jello, kind of make it a little more liquified. But what happens when you look at this in the lab, heat will do a number of things, and we've shown in our data that it increases heat shock proteins. But that's probably not what's necessarily driving the response.
We do know that the penetration of Platinum into these tumors is significantly higher with the addition of heat. So somewhere on the order of five or 10-fold higher concentrations, just from the addition of heat. So heat itself may be... Well, is cytotoxic at a high enough level. It may impair the cancer cells' ability to repair the damage. And we know clearly that it's impacting the penetration of these tumors. So when you give a Platinum drug intravenously, you can see that effect in the center of the tumor, but not on the periphery. And so when you give these drugs intra-perineal, these Platinum drugs will actually penetrate through the peritoneal surface, then get absorbed systemically through the peritoneal cavity.
So you kind of are treating twice the tumor, because you can't penetrate as deeply with simply IV fluid. And the heat increases the amount of distance that they can penetrate as well as the number of Platinum adducts that we're seeing. So mechanistically, that's what's been proposed. What we've learned from our data is that there's also a immunologic response, which may be in play.
Dale Shepard, MD, PhD: Now in the GI arena, which is where I've encountered HIPEC more frequently, you always think about this being peritoneal disease. And if a patient has visceral disease, you may want to avoid this. So what does that look like with the tumors you treat? Can you do combination approaches? What if someone has a liver met, or a lung met? Is this something that's off the table, or how do you approach that?
Robert DeBernardo, MD: So it's very much on a case-by-case basis. Our data for ovary cancer is pretty well-established. Surgery where we can optimally cyto reduce somebody is beneficial to their long-term outcomes. So if they have an isolated liver met and it can be resected, and it leaves them with no gross residual disease or minimal gross residual disease, then it's probably beneficial.
Now, if they're 85 and have multiple medical problems, that's a different story. You always have to balance obviously the morbidity with what you're doing to get somebody optimal. So we don't typically explore people's chests. I mean, the folks at Sloan Kettering are doing that. If they have people they think have disease in the chest, they'll start with a VATS. And if they have disease, they'll try to de-bulk that. And if they're successful, then go into the abdomen. But those are to be honest, relatively rare patients. Most people that have significant burden of disease in the chest are rendered not optimally de-bulkable based on what's going on in their abdomen and pelvis as well.
So, but it's interesting you mentioned that, because the quality of surgery varies dramatically across the country. Certain centers are just much more aggressive and they have either the expertise in this G1 oncology program or have teams of surgeons that can render these people with no residual disease or minimal residual disease where other programs just don't have that expertise. So, the surgical effort is a big part of it.
Dale Shepard, MD, PhD: So you mentioned other programs. How common is this? So, as we talk to people who may be across the country, how common is it that they may have access to this kind of procedure?
Robert DeBernardo, MD: Not actually terribly common, which is unfortunate. Let me just back up for one second, because... What was it? It was in 2006, or maybe a little later than that. We did a huge randomized trial in ovary cancer where we randomly assigned women with ovary cancer to surgery followed IV chemotherapy versus intra-peritoneal chemotherapy without heat. And that was a tremendously impactful study where we shifted overall survival and progression-free survival by a year and a half.
And yet, very few programs started giving intra-peritoneal chemotherapy. And the rationale was, "Oh, it's too... a little bit more toxic and it's one study." And the fact is that it's complicated and difficult to give, because it would require a hospitalization with every cycle, and then coming back in a week later and things. It's the same thing with HIPEC. If an institution has a HIPEC program because they're using it for GI malignancies, it's relatively easy to spin that and start taking care of ovary cancer patients. But if not, it's a pretty big, heavy lift.
I mean, when I started my first program, it was challenging because there's a lot of just things you don't think about. Pumps and infusion and chemotherapy dosings and protocols, and the morbidity we don't really know about. So it's a pretty heavy lift to create a program de novo. So I will tell you, there are probably, my guess would be one in 20 programs in the country, if that, offer it. And that might be even generous. So you're going to find it at some big centers, but not all. I think we're certainly the largest program in Ohio, hands down, in terms of HIPEC and one of the largest in the country that offer it.
Dale Shepard, MD, PhD: It sounds like a therapy that certainly can provide good benefit to patients. We'll talk about toxicity in a second. And you talked about the patients that benefit, but if someone's listening, who's the patient that might be most benefited by a visit here to the Cleveland Clinic, to talk to you guys about incorporating this? So is there an ideal patient that you would say should come here?
Robert DeBernardo, MD: Of course. So there's two people that need to be considered. Anybody who has newly-diagnosed ovary cancer, who is getting chemotherapy upfront, that surgery that they're going to get after their third cycle typically is really important. And that's where HIPEC has been shown to significantly improve progression-free and overall survival. So if they're getting treated in say, Nevada, and they're getting their chemo there, and their surgery is planned for three months down the road, it would be worth them giving us a call. We could do a virtual visit, and then coming into town, having their surgery, having their HIPEC, and then they recover. And they're back on their normal chemotherapy at home, three weeks after surgery, four weeks after surgery.
Again, it doesn't increase the morbidity. It's a little bit longer in the OR, but the morbidity is the same as their surgery. So I will tell you, I think somebody like that would be an ideal candidate. You come in, or if it's not the Clinic, some center that's doing it, because it's certainly an added benefit.
The other people that potentially benefit from this would be somebody with recurrent disease. Now most often, when people with ovary recur, they're going to have an abdominal recurrence. And oftentimes it's multifocal with peritoneal carcinomatosis. Those are generally not the best candidates. There's a subset of those women though that have what I call oligometastatic disease. So maybe they have a splenic met and an omental tumor, or maybe a pelvic mass. And if it's surgically resectable, we've shown in again, randomized trials, that surgically resecting that and giving them HIPEC improves outcomes dramatically.
Not just progression-free survival, but overall survival. So certainly worth a look at. It's a little trickier, because I would tell you most people in the new adjuvant setting would benefit from HIPEC. That was the first group we talked about. In a recurrent setting, it's a little different. And then again, in that small subset of patients, patients with Platinum-resistant disease are probably our worst prognosis patients. So for those people that are listening, just to define a term, so we have patients with ovary cancer we always treat with Platinum. And we typically give them Platinum-based agents with recurrence after recurrence, until they become resistant to those drugs.
And at that point, we know that the clock is ticking because they have about six, eight, 12 months to live. In that setting, there are some patients that have surgically resectable disease with Platinum resistance. And then we know again from randomized data, that addition of HIPEC changes that curve and now puts them back on a Platinum-sensitive survival curve. So the biggest improvement we see is in Platinum-resistant patients, which ties back into the work that we're doing in the lab, where we can penetrate these tumors and get more Platinum drug in.
So whatever resistance mechanism they have, if it's pumping it out or whatever it is, or repairing the DNA damage, it's overwhelmed probably by the heat and the administration of peritoneal chemo, so that we're seeing improved outcomes. That rubric is a little bit more complicated, depends on obviously their disease status and how fit they are, but there's a number of patients that we really significantly helped with that approach.
Dale Shepard, MD, PhD: So Rob, you mentioned that second category of recurrent patients. Is there a dependence on whether they are Platinum-resistant or refractory in that group?
Robert DeBernardo, MD: So refractory would be really challenging. Obviously the refractory patients, patients who progress on primary chemo, they're really hard. And I have to tell you, I've been doing HIPEC for probably 12 years now. There may have been one patient that we did, because most of them are just too sick and their disease is too extensive that they're not likely to benefit from it. So the Platinum-resistant folks, there are a number that fit into that category where HIPEC will help. Although again, in the subset of Platinum-resistant patients, it's going to be the minority.
Dale Shepard, MD, PhD: But it's certainly worth noting, because often times when you have refractory patients, people start thinking about as aggressive a therapy as possible, so.
Robert DeBernardo, MD: Right. And so again, it's always worth looking at these folks because again, there's a lot of therapies that we can offer. I mean, a lot of excitement has been going on with PARP inhibition for our ovary cancer patients. But what's fascinating, and Peter, we're just about to publish a paper on our experience with PARPs.
I mean, all the literature out there and the drug companies are selling these as these are phenomenal drugs, but there's not yet one study that's shown its improved overall survival. Everything moves progression-free survival, even substantially. But when the data matures, we're not seeing improvement in overall survival. And that's probably driven by the fact that these are chemo drugs. They don't want to market them as chemo drugs, but they're chemo. And when you have your patient who recurs ultimately on a PARP, either their bone marrow can't handle further chemo or you're driving them to a Platinum-resistant state without using a Platinum.
So it's really interesting, because our data supports that point of view, that these folks after extended PARP use don't respond terribly well. So that's why in the world of cancer, progression-free survival is super important, but ultimately the measure is going to be overall survival in the end.
Dale Shepard, MD, PhD: Right. Now you mentioned PARP. Certainly there's lots of interest in immunotherapies. Has there been a move toward thinking about combining HIPEC with those things like PARP and immunotherapy?
Robert DeBernardo, MD: Oh, yeah. So what's interesting is with immunotherapy and ovary cancer, for all comers, response rates are probably 8%, which is pretty terrible. There's some interesting data looking at the combination of PARP and immunotherapy PARPs and VEGF inhibitors and immunotherapy. So there's all these interesting combinations we're looking at in studies right now to try to improve immunotherapy for this group of patients.
So yes, HIPEC in addition of those things I think are going to be interesting, but what's fascinating, what we've learned from our... It's very preliminary data that our immune response that we're seeing in our HIPEC patients is all B-cell driven, not T-cell driven. So it's an interesting story that's unfolding, because we have hundreds of thousands of points of data to look at in these folks. But the big picture thing is we may be driving an immune response that we're not typically expecting.
So the answer to that question is, yeah, there's a lot of interesting things. And most of the work has been done with Platinum. I give my patients with ovary cancer Taxol as well, and we don't know how that mechanism is happening. Again, we have data from our cohorts of ovary cancer patients that have gotten Taxane and a Platinum and cisplatin at their surgery, versus Platinum alone. And it looks like, and again, the data hasn't matured completely, but there's a pretty significant trend of those folks that get both Taxol and Platinum at HIPEC are doing better. So it's interesting because the randomized trial that was done just used cisplatin. There was no Taxol in that.
Dale Shepard, MD, PhD: Got you. Well, you've provided some great insight today on the use of HIPEC and novel ways to treat these patients. Do you have any additional comments?
Robert DeBernardo, MD: We're working pretty hard to try to educate GI oncologists and help them develop programs. We've assisted with growing programs across the country, you have the program started in Texas, another one in Montana, another one in California. So we're creating a consortium of all these folks and trying to support their growth.
I think it's a promising technique, but I'm afraid just like normal thermic intra-peritoneal chemotherapy, despite the benefit, it's going to be a heavy lift, because I really think that physicians are... They're just more comfortable writing a prescription for chemotherapy than they are to actually do something like this in the operating room. So we're going to continue to work hard and develop it, and as more data come out, especially data from the lab and understanding how it's working could impact significantly how we're giving this down the road.
Dale Shepard, MD, PhD: Well, thank you very much for being with us today.
Robert DeBernardo, MD: Oh, well thank you. It was a pleasure talking to you about this stuff.
Dale Shepard, MD, PhD: This concludes this episode of Cancer Advances. You will find additional podcast episodes on our website, ClevelandClinic.org/CancerAdvancesPodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget, you can access real-time updates from Cleveland Clinics' Cancer Center experts on our Consult QD website at ConsultQD.ClevelandClinic.org/cancer. Thank you for listening. Please join us again soon.