Precision in Practice: Robotic Surgery and Laparoscopic HIPEC for Ovarian Cancer

Podcast Transcript

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 directing the Taussig Early Cancer Therapeutics program and co-directing the Cleveland Clinic sarcoma program. Today, I'm very happy to be joined by Dr. Joel Cardenas, a Gynecologic Oncologist at Cleveland Clinic Weston in Florida. He's here today to talk to us about robotic cytoreductive surgery with laparoscopic HIPEC for patients with ovarian cancer. So, welcome.

Joel Cardenas Goicoechea, MD, MBA: Thank you, Dr. Shepard.

Dale Shepard, MD, PhD: Tell us a little bit about what you do down at Cleveland Clinic in Weston.

Joel Cardenas Goicoechea, MD, MBA: Yeah. My role at Cleveland Clinic Florida in Weston is to provide gynecologic oncology care to our patients. I am a board certified gynecologic oncologist. I perform robotic and open surgery for ovarian cancer and endometrial cancer, and also surgery for cervical, vaginal, and vulvar cancer. The area of my interest is surgical innovations to improve oncologic outcomes and quality of life of my patients.

Dale Shepard, MD, PhD: Excellent. Well, we're going to be primarily focused on robotic assisted surgeries' use of laparoscopic administration of HIPEC. But maybe just to start, give us a really broad overview of how ovarian cancer is typically treated.

Joel Cardenas Goicoechea, MD, MBA: The current treatment options that are available for ovarian cancer, specifically for stage three or four, includes the combination of surgery and chemotherapy followed by maintenance therapy with target therapy such as PARP inhibitors, and also immunotherapy for selected cases. The surgical option have been evolving over time. The standard of care is open surgery via laparotomy, which entails a large midline vertical skin incision that extends from the pubic bone to the xiphoid process. The rationale of that approach is that ovarian cancer spreads all over the pelvis and also in the abdomen. In order to remove all the disease, it's important to have adequate access to those areas such as the diaphragm, the stomach, the liver, the spleen, the sacral-mentum bowel, and also to have access to the pelvis to perform a hysterectomy, remove the uterus, tubes and ovaries and the lymph nodes. The goal is to remove a hundred percent of the disease, which we call complete cytoreductive surgery or R0.

This traditional approach has been described in 1934 by Joseph Meigs at Massachusetts General Hospital. The traditional approach has changed over time with the introduction of minimally invasive surgery via laparoscopy and robotic, like my case. In 1989, the first laparoscopic hysterectomy was performed in Pennsylvania, and in September 2005, the FDA cleared the robotic platform for gynecologic surgery. Since then, there has been significant changes in the surgical approach for ovarian cancer. I personally prefer robotic surgery. It's a technology that I have been using since 2006. So today, in select cases, the state-of-the-art surgical approach is robotic surgery, and of course there are other clinical scenario that has changed. For example, the surgical manager of early stage ovarian cancer is also minimally invasive surgery. In selected cases of recurrent ovarian cancer, robotic laparoscopy has a role. For newly diagnosed advanced stage ovarian cancer, when surgery is performed at from, the standard of care is open surgery.

Dale Shepard, MD, PhD: We've had a couple of episodes where we've talked about robotic surgery, but just if people have not heard those, give us an idea. What does that mean when you say robot assisted surgeries?

Joel Cardenas Goicoechea, MD, MBA: So, the robotic is a technique, is an instrument, that allows the surgeons to perform the same procedure like open, which means removing the organs. But instead of making a big incision, we make smaller incisions, which measures about eight millimeters. Through those small incisions, we introduced tiny, minute instruments that are highly precise. Robotic surgery is an instrument that allows the surgeons to perform a procedure. The robotic itself does nothing. It's the surgeon who performed the actual surgery.

Dale Shepard, MD, PhD: And so in this case, we're talking about robotic surgery in combination with this procedure called HIPEC. What is HIPEC?

Joel Cardenas Goicoechea, MD, MBA: HIPEC, or hot chemotherapy, most patient knows as hot chemotherapy, it's done for hyperthermic intraperitoneal chemotherapy, which basically it's a procedure, it's a technique that we use after the radical cytoreductive surgery is performed, where we introduce into the abdomen and the pelvis at chemotherapy drugs, in this case cisplatin, at the high temperature, usually 41 to 43 Celsius degrees. And we perfuse the entire abdomen and pelvis for about 90 minutes. The science behind this approach is, one, with elevating the temperature of the body, we enhance the capability of the drug to better affect in the DNA repair of the cancer cells. It also induces apoptosis. It has effect in the angiogenesis of the tumor. So it's a procedure, it's a technique, that is performed at the end of the surgery.

Dale Shepard, MD, PhD: And give us a little bit of a perspective. You had talked about the evolution of surgery from open to laparoscopic robot-assisted. Tell us a little bit about the incorporation of the chemotherapy part.

Joel Cardenas Goicoechea, MD, MBA: This is a great question. So historically, the way how we treat was surgery followed by intravenous chemotherapy. Many years ago, we couldn't figure out the best way to treat those patients who did have recurrent disease. 70 to 80% of patients with that approach has recurrent disease and still they have recurrent disease. So one thought was since the tumor returns in the abdomen pelvis, how about giving the chemo actually where it recurs, which is in the abdomen pelvis? As a result of that, there was a lot of clinical trials. One of the most famous is GOG172, where we put a port in the abdomen and pelvis, and patient were receiving chemotherapy intravenously through the IV but also into the abdomen. And that was one of the first initiatives.

But that approach didn't have a lot of uptake in the community for both physicians and patients. It's very inconvenient, even though it did show a significant improvement in overall survival. So the HIPEC or hot chemotherapy comes along and it have a better uptake because it's a procedure that is done one time at the end of the surgery, and that does not require any other follow-up for this particular procedure.

Dale Shepard, MD, PhD: And I guess for people who aren't necessarily familiar with treating ovarian cancer, when you say the disease recurs in the abdomen, it is literally in the abdomen, not in organs in the abdomen.

Joel Cardenas Goicoechea, MD, MBA: It could be both. Unfortunately, 70 to 80% of patients who have recurrent disease is in the surface of the abdomen, pelvis. Sometimes it may present involving other organs such as the liver or the spleen or the lymph nodes. It can affect any other areas.

Dale Shepard, MD, PhD: But this does allow you to essentially, for lack of a better way to put it, bathe the tumor in chemo?

Joel Cardenas Goicoechea, MD, MBA: That is correct.

Dale Shepard, MD, PhD: And so, in this particular case, you recently had developed this system with minimally invasive, robotic-assisted surgery and then really minimal the laparoscopic HIPEC. And tell us a little bit about what led to that. Everything was very, very minimally invasive. Tell us a little bit about the outcomes from that.

Joel Cardenas Goicoechea, MD, MBA: This was extrapolated for every patient that we see these days, who meets all the criteria, but the decision-making process selecting the combination of robotic surgery and laparoscopic HIPEC was based on the patients' performance. Patients should be able to tolerate two or four hours of Trendelenburg positions. Patients should have a positive response to three cycles of neoadjuvant chemotherapy based on the CAT scan, tumor marker, physical exam and patient symptoms. The CAT scan should show resolution of ascites or pleural effusions. The CA125 should be normalized. And one thing that's important, and that's what I did in this case, is to perform a diagnostic laparoscopy at the very beginning of the case when I introduce a five-millimeter camera, look around the abdomen pelvis. And at that time, if I think based on my experience and expertise the tumor can be resected a hundred percent with small incisions robotically, then I will perform this approach. Otherwise, I should perform open surgery. The HIPEC in this case was performed also laparoscopically because all the disease was resected a hundred percent, and the ports that were used for robotic surgery were also used for the HIPEC.

Dale Shepard, MD, PhD: When we think about criteria, who would be a good candidate? Tell me about size of a tumor that might make a person either a candidate or not a candidate.

Joel Cardenas Goicoechea, MD, MBA: The whole idea of doing minimally invasive surgery is to try to remove tumor disease organs using a natural orifice, in this case the vagina. So if we remove an organ that can be removed easily through the vagina, that's a candidate. To put some numbers, for example, up to a 10-centimeter ovarian mass, that will be one of the criteria to perform robotic surgery. In a patient who has a 20-centimeter mass, probably that's not a good candidate. So it all depends the size of the disease, the tumor that can be removed using a natural orifice. For this ovarian cancer, it's using the vagina.

Dale Shepard, MD, PhD: And when you had mentioned response to neoadjuvant chemo, when you say response, does this mean documented shrinkage of tumor or do you really want pretty minimal tumor burden when you go into do that surgery?

Joel Cardenas Goicoechea, MD, MBA: Both. The whole idea of using neoadjuvant chemotherapy and later surgery is to minimize morbidity, but obtaining a hundred percent of tumor resection. The ultimate goal is to reset a hundred percent of the disease, and 70% of patients respond very well to carboplatin and paclitaxin. Did I answer your question?

Dale Shepard, MD, PhD: Yeah. When you think about response to chemo, sometimes that means you haven't developed new sites of disease. Sometimes that means you've got 30% reduction. I guess I was just trying to define what you meant by having a favorable response to chemo.

Joel Cardenas Goicoechea, MD, MBA: The criteria that I use comes from the clinical trials that were done in Europe. If the patient has at least a stable disease or even better a positive response, which resolution of a sinus pleural effusions, normalization of the CA125, those are good candidates to perform internal cytoreductive surgery. For those patients who actually do no response to carboplatin and paclitaxin, surgery may not be the best option for them, and we see this in about 15% of cases.

Dale Shepard, MD, PhD: And so, the chemotherapy that's being used, this is cisplatin. Is there work being done with other chemotherapies, novel therapies, as part of that HIPEC to try to get more complete either combination therapies, more complete killing of residual tumor?

Joel Cardenas Goicoechea, MD, MBA: That's a great question. So just to give a little bit of background, the HIPEC has been used I think more in colorectal literature.

Dale Shepard, MD, PhD: Or like appendiceal cancers and things like that?

Joel Cardenas Goicoechea, MD, MBA: Appendiceal cancer. Right. And they use different drugs. For what we use, and is consistent with the national guidelines, is to use cisplatin. And this is based in a multi-center randomized phase three trial from the Netherlands that was published in 2018 in the New England Journal. The trial did use cisplatin, 100 milligrams per meter square. Just to give you the trial, the trial compare surgery plus HIPEC versus surgery alone in patients with stage III epithelial ovarian cancer. This study, that's what we use, demonstrated a significant cancer survival. After a median follow-up of almost five years, the median overall survival was 33.9 months in the group that received surgery alone versus 45.7 months in the group that received surgery plus HIPEC with cisplatin. Clinically and statistically significant. And adverse events, grade three and four were similar to both groups. I'm aware of other drugs that we'd use, but I think for us in gynecology, it is consensus to use cisplatin.

Dale Shepard, MD, PhD: Makes sense. You told us at the beginning you had a couple of things of interest. One was new surgical techniques and the other was making sure that patients had a good quality of life. If we think about this procedure doing robot-assisted laparoscopic surgery, really using those same ports to do HIPEC, what's the difference between this procedure and a more traditional open procedure in terms of patient outcomes from the standpoint of hospital stay, recovery time, things like that?

Joel Cardenas Goicoechea, MD, MBA: That's a great question. So combining the two techniques, robotic and laparoscopic HIPEC, is just amazing and adherence to the procedure because it did improve parity outcomes, quality of life, and survivals. And this is very relevant in patients with advanced ovarian cancer and who are elderly. Remember, the median age of ovarian cancer is in the 60, and many patients rightfully demands both quality of life and improved survival. This is a state-of-the-art approach that provide both. The robotic surgical approach, when we compare to the standard opening surgery, it's associated with lower risk of complications, lower blood loss, lower surgical pain, smaller incisions, shorter hospital stay. My patient went home in three days. The average hospital stay when we do this combined procedure is one to two days versus four to six days in the literature when this procedure is being opened. Faster recovery to enjoy life, back to work, and to start chemotherapy.

Dale Shepard, MD, PhD: So tell me a little bit about the survival benefits associated with HIPEC.

Joel Cardenas Goicoechea, MD, MBA: Right, so the use of HIPEC at the time of internalized cytoreductive surgery improved significantly the survival. After a median follow-up of almost five years, the median overall survival was 33.9 months in the group that received surgery alone versus 45.7 months in the group that received surgery plus HIPEC. This means that almost one year of survival improving in our patients. Not exactly the same as GOG172 that improve overall survival in 16 months, but this approach takes one procedure that's done at the time of cytoreductive surgery, which has tremendous implications in the survival of our patients and especially in the elderly populations. The rate of complication from surgery is something significant, but I haven't seen those complications. Published data suggests that the rate of severe complication in the first 30 days from surgery is quite high, nine to 40% of patients.

Common complications include fistula abscess, infection, surgical wound dehiscence, bioperforation, ileus, but we don't see this anymore. Probably those data that has been published are related at a very early stage of this intervention. Another benefit in our case is that the surgical estate. In our patient who did have robotic surgery plus laparoscopic HIPEC went home in three days after surgery. For open procedure, the hospital stage ranges from eight to 24 days. So I think if we can validate this case with the LUNGS trial or the MIRRORS trial, this should become the standard of care. Minimally invasive surgery after new agent chemotherapy plus HIPEC.

Dale Shepard, MD, PhD: Makes sense. As a surgeon, you guys are always thinking of new ways to make things better. What's going to make this procedure better from where we are right now?

Joel Cardenas Goicoechea, MD, MBA: That's a great question. I will respond in two ways. One is for the surgical approach and the other is the HIPEC. From the surgical approach, what are we doing? It's based on multi-institutional studies here in United States and Europe, but there's no randomized trial that did prove this is the right approach for everybody. We are doing this for many different reasons. One of the reasons is patient age, performance status, the patient willingness to fight this with surgery. But the next step is to enroll patients in clinical trials. Here at Cleveland Clinic Florida in Weston, we're bringing the LUNGS trials to our institution. We are going to offer this trial as soon as it's available. We pass already the feasibility part of the trial. Now our research team is working on the logistics. The LUNGS trials is an international phase two trial designed for patient with advanced ovarian cancer who did receive new agent chemotherapy and have a positive response.

The study has two arms, and they are randomized to one arm, minimally invasive surgery, laparoscopic or robotic, or open surgery. The objective of this trial is to examine whether minimally invasive surgery is not inferior to laparotomy in term of disease-free survival. There's another study in UK which is similar, but using robotic surgery alone. I think that's what's coming up now. We have to validate that what are we doing actually produces or improve quality of life and survival. The HIPEC after new agent chemotherapy, for me, it's very well established. It's part of the NCC guidelines based on phase two randomized clinical trial. But I see a part of our society of gynecology and oncology are still hesitating to embrace and perform in all the patients who meets the criteria. So this data needs to be validated in every single standard, so patients and physician may feel more comfortable doing this approach.

The other innovative approach that I can see in the horizon is the use of fluorescence light to identify cancer cells. The FDA approved an imaging drug that attracts cancer cells and allows the surgeons to precisely identify which are cancer cells and which are not during surgery.

Dale Shepard, MD, PhD: Well, you have taken really what was a morbid, for lack of a better way to put it, procedure, have come up with some creative ways to improve patients' outcomes with this. As you said, we're trying to validate this, but you're doing some important work and we appreciate you giving some good insight today.

Joel Cardenas Goicoechea, MD, MBA: Thank you so much.

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