The Medical Innovators Interview with Dr Lana Bijelic
Combat’s Guy Cooper in conversation with Dr Lana Bijelic, chief of the Peritoneal Surface Malignancy Unit at the Hospital Sant Joan Despí Moisès Broggi Hospital, Barcelona. In this wide-ranging interview, we cover the infamous PRODIGE 7 study and how HIPEC has since moved on – not least with the success of the HIPECT4 trials for colon cancer.
Dr Bijelic is a surgical oncologist and a specialist in peritoneal carcinomatosis. She received her medical degree from the University of Zagreb, Croatia, in 1998 and conducted her general surgery residency at the Medstar Washington Hospital Center, Washington DC. She was given the John M Keshishian Award for Surgical Excellence in 2003 and 2004 and is board-certified by the American Board of Surgery. Between 2006 and 2007, she was awarded a fellowship in surgical oncology and peritoneal surface malignancy and completed her training under the mentorship of Paul Sugarbaker MD. After four and a half years as medical director, surgical oncology, at Inova Fairfax Hospital/Inova Schar Cancer Institute, she joined the Moisès Broggi team in 2019. Dr Bijelic has published extensively and lectured internationally. She is currently developing minimally invasive techniques for the treatment of peritoneal metastases.
This is the only time I’ve ever walked into a department specifically called a Peritoneal Surface Malignancy Unit. That sort of answers my question, but tell me a little bit about what you’re working on now.
As a surgical oncologist with a very strong and specific interest in peritoneal surface malignancy, I am very lucky to be able to work in a unit that is so specialised and highly dedicated to the management of these patients.
That’s really what we do. We are a high-volume unit dedicated to treatment, surgical treatment, but really the multidisciplinary treatment of patients who have peritoneal metastases from a number of different diseases, different primary tumours. In our case, this is a mix of colon cancer, ovarian cancer, appendiceal cancer, mesothelioma and sometimes other rare cancers that can also produce peritoneal metastases. Our work is mostly clinical, but we also have a strong interest in research, so we try to combine those two activities.
You probably do more peritoneal surface treatment – and certainly more HIPEC treatments – in your centre than in the whole of the UK. I don’t know if that’s a good statistic or a bad statistic, but it’s certainly an interesting one.
I think it’s a little bit of reality. We have known for a while that when you look at all the tumours that can produce them, peritoneal metastases as a whole are not all that rare. But they have been a big challenge in terms of treatment for many, many years, and really with no solutions for many years.
So when the door opened for surgical treatment combined with systemic treatment, a whole new field opened up in surgical oncology, which is probably the greatest change we have seen in the last 30 years for these patients.
The UK is perhaps organised a little bit differently. It is true that it has fewer centres but they are dedicated to specific diseases. We have a slightly different scenario in at my unit in that we have the opportunity to treat peritoneal metastasis regardless of the tumour of origin. So I guess that is what differentiates our unit a little bit from those in the UK.
When I trained a hundred years ago, in the little bit of surgical oncology I did, most of the patients you would see – even those with relatively low PCIs [Pathological Peritoneal Cancer Index] – would never have reached the surgeon. If they did somehow, we would open and look and close immediately. So there’s real progress here, certainly in terms of the work being done. The UK and some of the rest of Northern Europe are becoming outliers now that they haven’t adopted these new and innovative procedures. Where did you get into this? What’s your training and your background? Is anybody born wanting to be a specialist in peritoneal surface malignancies?
I’m not sure anybody’s born to be one, but perhaps the newer, younger generations will find their love for this field early on in their training because they’ll be able to see it.
I had, I think, a very lucky path in the sense that I did my surgical training in the USA, in Washington DC. It happened to be in the hospital where the father of and the greatest innovator in the peritoneal surface malignancy field, Paul Sugarbaker, was working. He had his team and his unit there.
So I came in contact with this work as a senior resident. It was a very special experience and a moment of great change for me. I saw something that I had never seen before, that was so impactful in its result, in how different it was from the rest of the surgery or even the surgical oncology that I was exposed to, that it made a lasting impact. It became something that I wanted to pursue. I was very lucky to have this contact with a person who is a very, very special figure in this field.
I continued on with the fellowship with Dr Sugarbaker, and then I stayed on as part of the team for quite a number of years. From there, I moved to start a new program in the USA, not far from Washington DC, where I stayed for about five years. Then the call came from Europe, which is kind of my hometown. I’m originally from Croatia. Going back to Europe at some point in my life was definitely also in the cards, I guess and a secret wish. So I think I was lucky again. I was able to practise what I love to do and, on top of that, in a very advanced, high-volume, already established unit in Barcelona. That’s where I am today.
It must have been wonderful to have the opportunity to learn side by side with Dr Paul Sugarbaker, the surgeon who invented the procedure and probably went through some of the pathway of it originally being seen to be at the lunatic end of innovation and then being accepted as the gold standard procedure. What are you seeing in your general practice in the centre in Barcelona? Is it mostly ovarian, colon, stomach, or do you see a little bit of everything?
We do have a mix of patients with different profiles, different tumours. But as far as frequency goes, I think something that is relatively special and unique about this unit is that we treat a high proportion of patients with colon cancer.
On the one hand, that’s not surprising because colon cancer is the most frequent of all these different kinds of cancers that can cause peritoneal metastases.
Even though only about 15% of colon cancer patients will have this manifestation of disease globally, the total number of patients diagnosed with colon cancer is far higher than, for example, appendix or gastric cancer. So that translates to a large number of patients that may need this kind of intervention.
That is one explanation of why we see so many patients with colon cancer. The other one is the fact that you need a very close collaboration and communication between surgeons and medical oncologists for colon cancer to be recognised as a situation where this kind of surgery can be of help.
That has been something that’s been built here over the years, slowly. But it’s reached a very high and mutually beneficial level of collaboration, where the medical oncologists do their best and do their part with systemic treatment, which is essential for colon cancer. We are able to then select the right patients and offer them surgery, and also to great benefit. So I think it’s something that’s quite unique about our unit and we are really enjoying having reached this phase.
Talk to me a little bit about patient choice within that. You mentioned patient choice. I had the – let’s go with pleasure – of being in the room in France when the PRODIGE 7 trial was announced. From my vague recollection, it said that HIPEC doesn’t work, especially not in colon cancer, and we shouldn’t be doing it. But I was in a room with 10 other people who were all making a living from selling machines that helped with this treatment. We considered throwing them all in the Seine. How have things developed, post-PRODIGE 7? Did it influence your patients’ choices?
Well, I think anytime we advance in the scientific knowledge that has to change our approach to some extent. Of course, we learn from every study, whether it’s a clinical trial like the PRODIGE 7, which was really the first big, randomized clinical trial for surgical treatment of PSM for colon cancer. It’s the first and the only one of this profile, so it cannot answer all the questions we have about this at the same time. It certainly has advanced our knowledge and it has informed what we do. But it hasn’t closed the door of course, as it shouldn’t, in terms of eliminating, like you said, HIPEC.
So, just to summarize very briefly, PRODIGE 7 was a trial that basically evaluated the impact of complete surgery, cytoreductive surgery on peritoneal metastases of colon cancer with or without HIPEC, to see how much HIPEC could add.
Of course, HIPEC is not one thing. HIPEC is really a technique that can be used with different chemotherapy drugs for different durations at different temperatures.
It has many factors, many variables that can be played with and all of them probably do have an effect.
So, it shows one HIPEC treatment, which was a short treatment of 30 minutes with Oxaliplatin. It turns out that this particular HIPEC for colon cancer patients does not seem to add much more to what surgery can do. That being said, the surgery itself was very impactful. So, at the least we learned that and we confirmed that.
Then, we started to really focus on the details of this HIPEC. And it turns out that perhaps studying it in more detail, it shouldn’t even surprise us so much that this particular HIPEC was not as effective as we wanted it to be. But that doesn’t lead us to the immediate conclusion that different types of HIPECs also don’t work in colon cancer.
So, that’s really where we are right now. We are at the phase of, yes, perhaps selecting some patients with colon cancer for surgery only. But then the majority of patients we do add HIPEC, we do add a different HIPEC, that contains different drugs for different duration and trying to learn from that.
So even though building a new prospective clinical trial with a different kind of HIPEC is going to take time… Actually, there is one currently ongoing in Spain, and we are participating in it. For those patients who are not willing to join the trial and or don’t meet the criteria to enter the trial, we are collecting data and analysing it to see if we get some signal of whether a different kind of HIPEC can be beneficial and in what way.
We do a similar hyperthermia technique with urology surgeons in your centre and in many others across Spain and the world because they face the same problem of a potentially incomplete surgical resection of the tumour in a difficult cellular state, that they feel they should add chemotherapy treatments to. To heat it is a very natural option, but they only use one drug. In urology, you have primary treatment with one drug and then you have a radical surgery to remove everything. It’s excellent to see more debate in the surgical oncology world about what drugs should be used. Now, I’m from an orthopaedics background, so I can’t discuss pharmacology in any way without bleeding from my ears, due to the intellectual rigour required. But as the medical oncologists mix up their different magic potions, we hope we will find the right one. Let’s look at the other side of patient choice. Depending upon the degree of spread and the Peritoneal Carcinomatosis Index, what do you do? What techniques do you have available in this innovative unit?
Yes. That’s an aspect we have evolved a tremendous amount in terms of understanding the prognostic factors that really dictate outcomes of peritoneal metastasis and whether surgical treatment is appropriate and can give us satisfactory results.
But it’s not one size fits all. It’s very dependent on the biology of the tumour, certainly by tumour origin. So it’s not the same as PCI, which is a measure of tumour volume in the peritoneum that we would consider acceptable for surgery. It’s very different for pseudomyxoma, for example, which is a low-grade appendiceal tumor compared to a colon cancer compared to a gastric cancer. So that is very, very variable and it’s not the only factor we take into consideration.
The main message that I think we still sometimes struggle to get across is that you really need an expert in this field to determine all those factors and decide whether this kind of treatment could be offered or not.
I feel that sometimes those decisions are perhaps taken without consulting with an expert centre, which is a loss, because I’m quite sure there’s a number of patients that are not evaluated at the right time by the right people, to really make sure that everything we have nowadays at our disposal is offered to them.
This is speaking mostly about CRS and HIPEC, which is the main surgical treatment and also the one which is generally applied to patients, with the intention to eliminate or cure the disease or at least achieve long-term control.
Apart from cytoreductive surgery and HIPEC, what other tools are emerging?
PIPAC has slightly different goals and different patients are selected for it, but it’s an evolving field, both on the surgical side and certainly in terms of understanding all the complex biology of peritoneal metastases. There’s a whole field of immunotherapy that has opened up on the systemic treatment side that we haven’t quite translated on the local, regional side yet because there’s so much we need to understand about the immune environment of the peritoneum to be able to apply it.
Where are we with the PD-1, PD-L1s, that immuno-pharmaceutical side? Somebody very clever must have invented a Blitzerbumab that is going to be the wonder drug for peritoneal spread…
I think we are still in the early phase, but there’s definitely a lot of interest and activity. There’s still so much unknown about what makes the peritoneal environment different to the rest of the body from the immune standpoint. Some studies suggest it’s actually quite different. So there may be aspects of the peritoneal response to metastasis that are really unfavourable, in terms of the natural ability of the immune system to fight metastasis. There’s a lot more to learn. A peritoneal-specific drug would certainly be an incredible advancement. I don’t know of one existing yet, but it would be a line of innovation we’d all want to pursue.
That’s for the heavier end of the disease load. What should we be doing in the earlier stages? We have a trial ongoing in Italy, where every patient who has a colectomy where there is positive cytology in the peritoneal fluid gets an additional cytoreductive treatment, whether it’s HIPEC or PIPAC or something else. Is that where we’re going?
That is a very interesting question for two simple reasons. On one hand, we know that the more tumour burden that exists in the peritoneum, the worse our results are. So it seems logical to try and catch this process as early as possible, including treating patients who haven’t yet manifested it clearly but whom we know are high risk. That’s the logic of trying to put this treatment earlier in the process of how it evolves.
Second, there’s the difficulty for the patient when we have to treat already established peritoneal metastases with this really big traumatic surgery. If we could apply some aspect of the treatment earlier – for example, HIPEC, which is much less morbid compared to the surgical procedure – it would cause much less harm or less difficulty in recovering.
So, that’s the logic of why we would like to prevent as many peritoneal metastases as we would like to treat. The rationale is there. The question now is finding a high level of proof that that it works at an acceptable level of risk.
Very recently, the HIPECT4 trial has shown some positive results for colon cancer in terms of decreasing the chance of peritoneal metastases happening for patients who had a high risk of colon cancer, early stage but larger tumours and higher risk situation, in terms of preventing peritoneal metastases. So I think that’s still a very open area for research.
We know of cancers that have an even higher risk of developing peritoneal involvement, for example, gastric cancer. Prevention in gastric cancer certainly would be very, very interesting because the risk of developing peritoneal metastases is high. Once they develop, they are really, really difficult to treat. Our results with CRS and HIPEC for gastric cancer are not nearly as good as they are for colon cancer, for example.
We have the same study ongoing with gastric – GOETH – and the CHECK study for colon. It’s very interesting to see whether early-stage intervention is doing too much or whether it’s doing the right thing. What are your particular areas of interest in research at the moment? What exciting things are you doing?
Well, we’re excited even when we make small advances. You can’t expect to advance in this field by giant leaps. We’re participating in an ongoing, multi-institutional clinical trial, GECOP-MMC, which I think is going to give us some important answers about colon cancer. Whereas HIPECT4 was really more tiered towards prevention, GECOP-MMC is similar to PRODIGE 7 in design, but it’s looking at a longer HIPEC – 90 minutes – and uses mitomycin C as the main drug, to see if we get a better level of peritoneal control.
Then we have a number of projects within our institution that span from preclinical to postoperative care. On the preclinical side, we have just started and applied for funding for a detailed molecular analysis of colon cancer peritoneal metastasis. This is in terms of understanding the key biological variables that define these metastasis and differentiate them from other types of metastasis – like, for example, liver metastasis of colon cancer, which is more common. And also between different patients, because we know the pattern of failure, for example, after treatment with CRS and HIPEC for colon cancer is quite interesting. There are patients who will develop peritoneal disease again and others that will not. They will have liver metastasis, for example, in the future. So they must have a different molecular profile that we need to understand better to know what additional treatment might be beneficial to them.
In terms of clinical trials, we’re very interested in optimising postoperative care and recovery after these big surgeries. We know that ERAS principles – ERAS stands for Enhanced Recovery After Surgery – have been applied to a number of different surgeries with great results and have become standard of care, starting with laparoscopic surgery, for example, and moving on to the more complex side of things.
CRS with HIPEC is on the other extreme in terms of surgical complexity, but we also know that there’s great variability. Not all cases of CRS with HIPEC are the same. So we’ve developed a specific, tiered ERAS pathway for these patients. It has three sub-pathways aimed at giving a different pace of recovery to patients based on the complexity of surgery.
We have been applying this for the last year and have analysed the results. We presented it at the congress of peritoneal metastasis, PSOGI in Venice in October 2023. [Implementation and impact of CRS-specific, 3-tiered enhanced recovery after surgery protocol in high volume PSM centre.] I think we have learned some interesting things that could help other units optimise management and treatment.
Let’s move that on then, because we spoke a little bit there about personalized treatment, whether through the molecular nature of the metastasis in surgery or chemotherapy and also through the ERAS process in recovery. Is that how it’s going? I’ll phrase the question more broadly. I’ll throw you the keys to the DeLorean from Back To The Future. You arrive in your centre in Barcelona three years from now. What are you doing? What are the surgeons there doing? Are there actually any surgeons in there? What does it look like in the next generation?
Yeah. Wow. That’s a very, very hard question. Thirty years is a long time. But in fighting cancer, I’m afraid that we have a big enemy there, so we don’t advance as quickly as we would like to.
I think we will still have surgeons. We are not going to be able to eliminate cancer. Surgery still is a very, very powerful tool in fighting cancer, even metastatic cancer. So that’s one big lesson we have learned over the years. Certainly, the evolution of CRS and HIPEC has been a big factor in understanding that.
The idea is, getting to be as smart as cancer is, in terms of understanding all the different subtypes. I think the future will be perhaps not naming the cancer based on the organ where it started, which is what we mainly still do and how we treat it, but really giving it a name or a profile that’s going to be less linked to the organ and much more linked to its molecular and genetic make-up. I think that’s going to be a major innovation that is already happening, certainly in medical oncology – in surgery less, but it’s starting to impact us. The story of immune therapy is I think also more at its beginning. It’s going to be a big evolution.
The surgeon will more and more be integrated into this multidisciplinary team that works together and where each component of it really is like a puzzle, perfectly integrated with the other aspects. It’s not so sequential, perhaps. It’s going to be a lot more combined treatments before surgery, after surgery, than perhaps surgery again. We’re learning so much about how to make treatments less morbid for the patients, but also able to be given in a way that turns this disease into a more manageable, more chronic condition.
Yeah. Yeah. No, it’s good to hear as a former surgeon, there are still jobs out there for those of us with cold steel in our hands. It’s known in any surgical oncology, but perhaps even more so in peritoneal surface disease, that the closer you can get to T zero in the traditional fashion, that by far the better. Whether we have new and exciting chemotherapies administrations, immunologies, voodoo or whatever else we come up with, there’s still a role for the good and accurate surgeon. I’m glad to hear that.
Absolutely.
We’ve covered quite a broad range, from the very start of the disease to the end of the disease. We’re working on a number of early intervention projects through Combat Medical. We have an intraluminal system to look at because if you’re removing a tumour from the lumen, are you removing it 100% or would it benefit from perhaps some loco-regional treatment? Then in the gynae space and the ovarian cancer space, we’re doing multiple treatments. We’re also working with your friend and mentor, Dr Sugarbaker on NIPEC. In our urology world, where surgeons give 10, 15 treatments, do you think there’s an advantage in doing more in surgical oncology from the chemotherapy point of view, or are we just busying ourselves and should we take more of a watchful waiting approach?
Well, I think in terms of chemotherapy, repeating treatments has always been an integral part of how chemotherapy is used. So, I think the HIPEC being used only as a one-off is the exception.
Part of it is the difficulties we had in terms of being able to deliver something like HIPEC. We associated it only with the moment of surgery. But from all the other standpoints, certainly repeated treatments would be a more logical way of applying chemotherapy, local, regional, just the same as systemic.
So, the smarter we get about how to apply multiple treatments in an acceptable way, I think that’s going to be the key for moving HIPEC from one treatment to multiple treatments. That logical way of thinking should increase the efficacy of HIPEC. So, I think it’s a very intriguing idea.
We certainly know from other studies of normothermic chemotherapy that repeated intraperitoneal treatments work. We know that from multiple randomised trials in ovarian cancer. So that’s an interesting aspect that we should study more, for sure.
Well, hopefully we’re moving in the right direction to help with that. So, a couple of last questions then. I won the lottery in Spain last year and I’ve got a billion Euros of research grant to give away to my favourite centre in Catalonia. What are you going to spend it on? New machines, research into biomarkers, innovative trials that compare 15 different chemotherapy regimes?
That’s a very intriguing and difficult question. Well, since it’s such a great amount of money, I would have to come up with several ideas, not just one.
Oh, no, that’s cheating…
Certainly, I think we still have quite a bit more of work to do to understand the biology of the disease, to be able to come up with treatments that are more targeted, more personalized and that treat peritoneal metastases specifically.
We’re still applying basically the same drugs that we have developed for systemic use, locally, but perhaps that’s not the ideal way. Perhaps we really have to look at what is different about peritoneal metastases from other types of metastases and try to develop something more specific.
I think the lack of the billion dollars, like you said, it’s a big factor because we don’t have very good funding for this area of research, for peritoneal metastases and certainly not for innovations in surgical treatments. So, that has been a disadvantage that we are trying to solve by being humble and keep working small, but with passion. But there is a need to study peritoneal metastases specifically and not just metastatic cancer as a whole.
Dr Bijelic, thank you very much for your time today. It really is a pleasure to speak to somebody who’s working at the… well, bleeding edge of innovation in treatment – surgical treatment as well as medical treatment – of this misunderstood and probably historically undertreated but very important group of patients.
Thank you. It’s been a great pleasure.
