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“We’re studying how using HIPEC for T4 colon cancer reduces the possibility for future carcinomatosis. We’ve performed intermediate analysis and that analysis has been promising”

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The Medical Innovators Interview #4 Dr Alvaro Arjona
February 2022

Minimally invasive surgery vs open surgery, refining the laparoscopic approach for peritoneal carcinomatosis, AI and a key trial for HIPEC® in T4 colon cancer. Combat Medical’s Guy Cooper is discussing all these topics and more in this month’s Medical Innovators Series interview with Dr Alvaro Arjona, consultant surgeon in surgical oncology at the Reina Sofia hospital in Córdoba, in Spain.
Our Medical Innovators Series investigates developments in the medical and clinical worlds with the people right at the cutting edge. If you’re a fellow medical innovator who would like to be featured, please get in touch – we’d love to speak with you.

What does the average working day look like in your practice, Alvaro?

We do approximately two or three HIPEC cytoreductions per week. Today, for example, I have outpatient clinics for revisions during the morning, this evening I will have pancreas transplantation, and tomorrow we’ll have cytoreduction surgery with HIPEC. We’re very busy in our unit.

Good to hear they’re keeping you out of trouble! What’s your background? Are you a gynaecologist by training or a general surgeon by training? And how does the crossover work there between the two?

Between gynaecologists and surgeons? I think that’s a difficult question to answer because it’s different between countries due to the differences in education or specialties.
In Spain, gynaecology is a huge and complete speciality with many branches, including hysteroscopy, fertilisation, obstetrics etc. It’s only four years of specialty training and you have to involve all these different branches and gain all the skills needed to operate – I think it’s not enough for surgery.
Surgical oncology is also very difficult to define as a specialty, because if you treat any cancer, you will be in surgical oncology. But when doctors say “surgical oncology”, they are usually referring to a surgeon who eliminates very complex oncology disease.
Surgical oncologists have to be like stem cells – able to remove anything that it is involved, including the pancreas, liver and stomach, and being prepared to do complex surgery in the abdominal cavity, because we don’t know where the disease will be in peritoneal carcinomatosis.

In countries less HIPEC is done, it’s often the gynaecologists who are driving it. The UK is a great example, because they see a lot of later-ovarian patients and they want a surgical or a more radical surgical solution for those that have metastasised up into the abdominal cavity. But then the general surgeons who have the specialty and the training in colon, stomach, liver, pancreas, gallbladder, omentectomy, whatever else, wherever else it ends up, are rightly defensive of their cavity. Usually, the departments can find a way to work together, though. What’s the split with the patients that you see – are they of ovarian primary or abdominal primary?

I think we see around 50% each. We do both the primary ovarian and recurrent ovarian.

The position in Spain and in the UK is very different. How many centres are doing HIPEC in Spain?

We’ve got 37 or 38 HIPEC centres here in Spain included in GECOP [Grupo Español de Cirugia Oncológica Peritoneal – the Spanish Peritoneal Oncological Surgery Group], but I think there are also some private centres performing HIPEC.

What does the average working day look like in your practice, Alvaro?

We do approximately two or three HIPEC cytoreductions per week. Today, for example, I have outpatient clinics for revisions during the morning, this evening I will have pancreas transplantation, and tomorrow we’ll have cytoreduction surgery with HIPEC. We’re very busy in our unit.

Do you know the number in the UK?

I think it’s four centres.

Well, even four is an optimistic number. We’d go with two.

Manchester and Basingstoke?

Yes. Why do you think there are that many centres in Spain, plus 60 in Italy and 70 in Germany, yet only two in the UK?

I think the reason is politics. I believe that in the UK the political case is to centralise complex pathology. In Spain, centralisation is not an option – all centres here can do any surgery and any procedure. I think that in the middle we would find the solution – not too much centralisation and not too much freedom.

Medical oncologists still hold a very strong position in the UK and the evidence supports this in many ways. Patients with disseminated intra-abdominal disease are not all referred to Basingstoke or Manchester. They’re generally treated by the medical oncologists, with their clever use of chemotherapies, rather than what we’re doing with surgery and HIPEC.

Really? I think that could be a mistake, because surgery has shown a better survival benefit over any chemo.

The situation is changing in the UK and the Northern European inertia and reticence about change is slowly shifting. We may be able to increase the number of centres to eight over the next year or so, probably led by the gynaecologists. HIPEC is seen as pretty innovative in the UK. When did you start doing HIPEC in your centre?

We started in 1996.

[Whistles] OK, this isn’t an innovation for you – it’s something that has been done for over 25 years. So, while the UK is slowly catching up, what’s the next innovation you’ll be looking at in your department?

We’re going for the minimally invasive approach for peritoneal carcinomatosis.

I’m an orthopaedic surgeon by training, and orthopods like to think we pioneered minimally invasive procedures in many cases in arthroscopy, but there are still lots of people who think making a big incision is the right way to go. With HIPEC, a peritoneal clearance for abdominal carcinomatosis is a maximally invasive procedure. How are you converting this to a minimally invasive procedure?

We have a lot of cases, and all our patients receive neo-adjuvant chemo. When we were operating, we realised that in some patients there wasn’t too much disease; there were very few nodules and very little peritoneal disease. So we thought, “Why do we have to do a big incision for this limited disease?”
We started to perform a laparoscopic approach for these patients, and gradually we increased the complexity of the procedure and tried pelvic peritonectomy, which hadn’t previously been performed laparoscopically. We’ve published the technical data and the results obtained were very good, and our patients are happy with the procedure because they are at home after three or four days in a good condition.

And it’s wonderful stuff. I’ve seen you operate in Córdoba and do hysterectomy and salpingo-oophorectomy and remove not so-isolated-abdominal metastasis of the peritoneum as well, all through little holes, then take the sections out through the vagina, so the patient is left with three or four small holes.

Yes, all the pieces are being extracted through the vagina – it’s fantastic for the patient.

What do you think the limits of this are? What sort of patients, how high a PCI [peritoneal cancer index], are you now treating laparoscopically?

We try to break the limits every day. It’s subjective, because each time we operate we’re performing the laparoscopic approach better, we’re perfecting the technique and reducing the operation time. So, for now, the limit is a low PCI – less than 10 – but I think we can go further in future cases.

And it’s wonderful stuff. I’ve seen you operate in Córdoba and do hysterectomy and salpingo-oophorectomy and remove not so-isolated-abdominal metastasis of the peritoneum as well, all through little holes, then take the sections out through the vagina, so the patient is left with three or four small holes.

Yes, all the pieces are being extracted through the vagina – it’s fantastic for the patient.

What do you think the limits of this are? What sort of patients, how high a PCI [peritoneal cancer index], are you now treating laparoscopically?

We try to break the limits every day. It’s subjective, because each time we operate we’re performing the laparoscopic approach better, we’re perfecting the technique and reducing the operation time. So, for now, the limit is a low PCI – less than 10 – but I think we can go further in future cases.

What do you have now, and what do you need next, to do more laparoscopically and minimally invasively?

Right now, we have a very good team, so it’s all going well, and the HIPEC is good with the laparoscopic approach. But we do have some issues with the laparoscopic approach.
For example, we need more mobilisation and visualisation around the patient, because if the peritoneal carcinomatosis has spread throughout the cavity, that needs more than one operating point of view to deal with the different places the disease has spread to. And that means we need more than one screen and all the instruments and then it means a logistic challenge, but we are getting there.
We’ll also need to use the new imaging technologies like fluorescence, linked with specific antibodies that go to the peritoneal nodules – that will be the future.

We spoke with one of your colleagues in London a couple of interviews ago, Dr Wei Shen Tan at UCL, and his opinion was the same – so much of your procedure is based upon what the eye can see, and the haptic sensation of your gloves. It’s crying out for some form of antibody-specific immunofluorescence to be developed. Your friends in urology have begun this path with the blue-light system, whereby the carcinoma in situ can be viewed with an immunofluorescent drug and device that makes it a different colour.

Yes, all the pieces are being extracted through the vagina – it’s fantastic for the patient.

And it’s wonderful stuff. I’ve seen you operate in Córdoba and do hysterectomy and salpingo-oophorectomy and remove not so-isolated-abdominal metastasis of the peritoneum as well, all through little holes, then take the sections out through the vagina, so the patient is left with three or four small holes.

Yes – because if we can link to fluorescence, we could link the specific antibody for that patient’s tumour, and that would help us to identify if the nodules that we are seeing are active tumour or not. That would be a real advantage for us.

Yes, I agree. OK, let’s stretch that a little bit further, then. If I give you a billion euros of investment today, what will you develop?

We’d develop the specific fluorescence marker of tumour activity for our laparoscopic surgery. That would be fantastic for enabling us to preserve structures that are not infiltrated by tumour – there are occasions when you think they are infiltrated, but afterwards the pathology says there is no tumour.
Another project would be to develop highly specific optical devices, like flexible endoscopes, to get to all the hidden places in the cavity. That would be a very good strategy for finding all the nodules. And another idea is a retractor similar to open retractors for use within the abdominal cavity, which would be very useful for managing the bowel loops.

Laparoscopic inter-abdominal retraction – I’m sketching it out now on a beermat and will ask our engineers! So now I’m giving you the keys to the DeLorean, and you jump in and go forward to the surgical oncology department theatre in 2050. What does it look like?

I think artificial intelligence will be helping us select the specific treatment for a patient according to the genetic profile of the tumour.
For technology in the surgical field, because we are using increasingly less invasive approaches for the patient, I think that microtechnology such as nanorobots will be the future for eliminating disease in the abdominal cavity without any surgical insult. It’ll be like in the futuristic movies where they don’t need to touch the patient to cure them!

So, our aim is not to make surgery obsolete, just to make surgeons obsolete?

[Laughs] Yeah. Maybe. It’s possible in the future, in 50 years, maybe the next generation, but my job will be OK!

What trials are you involved in today?

We are performing a very important trial for HIPEC in T4 colon cancer – studying how the use of HIPEC for advanced colon cancer reduces the possibility for future carcinomatosis. It’s a multi-centre trial in Spain which we are coordinating, and the recruitment is already finished.
We are also conducting two phase I trials, one using bromelain and acetylcysteine in Pseudomyxoma peritonei in order to dissolve the mucin into the abdominal cavity, and the other using a neutral plasma argon to eliminate the nodules in the abdominal cavity.

All of this is pretty innovative stuff. The last large trial of colon surgery HIPEC was the PRODIGE 7 trial in France, which said – and I’m paraphrasing slightly – it doesn’t work. Why do you expect your results to be different? Or do you expect your results to be different?

Well, I expect different results because we’ve performed intermediate analysis and that analysis has been promising. The drug that we are using is different – in PRODIGE 7 they used oxaliplatin-based HIPEC and we are using mitomycin C. The time for chemo exposure is also longer than PRODIGE 7 – they did 30 minutes and we’re doing 60 minutes. In PRODIGE 7 they used systemic chemo and we don’t. And our comparison group is very similar to our HIPEC arm, whereas theirs wasn’t. So there is no confusion factor in our trial, which I think is important – the only factor we are analysing is the use or not of HIPEC.

What about patient choice? A criticism often levelled at the French trial is that the patient population was highly selective and the PCIs were too high. Have you taken this into account?

Well, they chose patients with PCIs up to 25, so it’s difficult to make a serious conclusion. But I think the conclusion they obtained is that HIPEC with 30 minutes of oxaliplatin in these patients doesn’t work – it doesn’t mean that HIPEC doesn’t work.
With HIPEC, we have to analyse the different drugs with different doses and different indications. For example, they said HIPEC works in patients with a PCI of 11-15, but the number of trial patients with this PCI range was limited. However, it could be an option to perform another trial with patients all with PCIs of 11-15 – the overall conclusion might not be so negative with them.

We were all there in Paris when the results were announced. There must have been five companies with HIPEC devices downstairs and the results were announced upstairs. And we all felt like taking our machines and throwing them into the Seine. It’s good to see the heterogenicity of their groups and their choice of drug are now being looked at by big trials. When do you expect to publish from HIPEC T4?

We are doing the analysis right now and if the results are statistically significant, we’ll publish the interim analysis before we finish the follow-up. But if we want to finish all the patient follow-ups, we won’t be publishing before January 2024.

Thank you very much for your time and a fascinating conversation. Is there anything else you would like to add about the concept of surgical innovation?

I think surgeons have to love their surgery, they have to improve their technical skills, and they have to go forward with innovative ideas.

If you’d like to share your own ideas and opinions as a fellow medical innovator, please email Guy Cooper at
grc@combat-medical.com

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