Interview with Oriol Parés and Bill Heald
Surgery is still the most frequent treatment option for rectal cancer worldwide. But for almost ten years now, a small group of people from the Champalimaud Foundation, lead by Bill Heald, currently the Chairman of the Foundation’s Colorectal Programme, and Oriol Parés, a 46 year-old Catalan radiation oncologist “wiz-kid” working at the Foundation's Radiotherapy Department, has been implementing a new, non-invasive approach, called Watch & Wait (W&W), which was pioneered by Brazilian doctor Angelita Habr-Gama and at first much criticised. She showed that, for certain rectal cancer patients who, before surgery, had received radiochemotherapy, surgery might be avoided if they were first submitted to a stringent Vigilance protocol, dubbed W&W, in order to see how the tumour reacted to these pre-operative treatments.
Bill Heald is an eminent British surgeon who, in 1982, invented a new form of rectal cancer surgery, “total mesorectal excision” or TME, which has become the gold-standard surgical treatment for rectal cancer worldwide because it encompasses the whole cancer completely and preserves important tissues and structures around the tumour, even in the most difficult cases (Bill Heald has demonstrated his TME operation in more than 60 countries). But he is also an extremely open-minded doctor, who is always looking to improve his patients’ quality of life – even if, in the end, it means foregoing surgery.
When Oriol Parés arrived at the Champalimaud Foundation, in 2012, he already knew about the W&W method, which involves radiotherapy, though he had never practiced it himself.
Then Bill Heald arrived at the Foundation the following year, and it didn't take long before the two met, put their heads together and started thinking about, so to speak, “fusing” TME with new, much more accurate radiotherapy regimens, to be able to offer W&W to more and more rectal patients before deciding if surgery was still needed.
Now, in 2022, their efforts seem to have really paid off: “Oriol’s work is beginning to suggest to us that almost half of all patients arriving with a cancer of the rectum might be cured without ever getting to the surgeon” says Bill Heald.
We seem to have come a long way in terms of rectal cancer management, don’t you think?
BH - Yes. If you go back a hundred years, it was then probably the most cruel of all the common malignancies in terms of local failure – the failure of the tumour to be cured within the pelvis by the surgeon. The cancer was very, very common, and it was cruel, dragged out over the years, with pain and all kinds of unpleasant symptoms. The terror that humans have felt for a hundred years or more, beside that of dying of the tumour, has been that the surgeon will give them a bag on the abdomen, that the tumour will be so low down that they have to lose their anal canal and with it their ability to control their lives in the sense of being continent of feces.
Why did this change when Total Mesorectal Excision entered the scene?
BH - Let me explain: the mesorectum is like an envelope around the rectum, and if the tumour is within that envelope, then probably surgery alone has a good chance of curing the cancer. This is due to the way the body is put together, which creates a shape, an envelope, for what is intrinsically the rectum, with its own blood supply and lymphatic drainage, and the venous drainage, so the cancer spreads within that envelope. So if the tumor has not crossed the mesorectum fascia, and if you’re able to perfectly resect the mesorectum, it means you have taken the rectal tumour out completely.
Nonetheless, Total Mesorectal Excision is still a very challenging operation to do perfectly. At the beginning, many, if not most of the local failures were in fact imperfections in the operations that were being done. As the operations got more accurate, the number of failures went down.
Where did the idea of the Watch & Wait protocol come from?
OP - It all started with the wise observation by a few surgeons, a couple of decades ago, that there were a number of patients that would go to surgery after radiotherapy and then the specimens collected would come back negative for viable tumour [that is, no detectable tumour at all]. This is well-known; it’s reported in the medical literature, and it’s estimated that 10 to 15% of the patients will be in this situation. Then a very important surgeon and very close friend of Bill’s, Angelita Habr-Gama, from Brazil (https://fchampalimaud.org/news/watch-wait, https://fchampalimaud.org/news/watch-wait-protocol ), started thinking about the actual need for surgery amongst these patients, and she raised the possibility that, before deciding to operate a patient, it was necessary to understand what was going on in those tumours. So, instead of immediately sending to surgery the patients who achieved a very good clinical response through radiochemotherapy only (disappearance of the tumour), she would observe them to see what happened. She was highly criticised by the community, which is saying it mildly. She was a woman in a world of men, she was from Latin America, so she was probably considered to be crazy.
Did skeptic surgeons also believe that the cancer would advance too rapidly and surgery couldn’t wait?
BH - Exactly. It’s all understandable, but it’s foolish, because the point about colorectal cancer is that it is, on the whole, a relatively slow-growing tumour – and we now know that waiting after the radiotherapy treatment and judging carefully what is the best next move is much more clever for the patient than rushing.
But why did some of the rectal cancer patients have to undergo radiochemotherapy prior to surgery in the first place?
OP - Because these patients most likely presented with local nasty features and more advanced tumour stages. The role of radiotherapy has classically been to downstage, downsize the tumours to reduce the risk of the surgeon leaving disease behind, which would assuredly lead to a catastrophic end of the life of the patient.
Today, at the Champalimaud Foundation, what percentage of patients go into the Watch & Wait Programme after waiting 10 to 12 weeks?
OP - Most of the results that have been published report that between 20 and 30% of the patients get into the Watch & Wait Programme. And in this niche of patients that end up being treated by radiotherapy, or radiotherapy plus chemotherapy previously to W&W, there are mostly those who initially present with high risk features and worse expected oncological outcomes and unfavourable prognosis.
But at the Champalimaud Foundation, the numbers appear to be better: we implemented some particular specifications for the radiotherapy such as the treatment delivery technique, the quality of the imaging used in the whole treatment process and the biological delivered dose of radiotherapy. Nowadays, we can say, after almost ten years of introducing patients to the Watch & Wait Programme, that there is a 50% chance for these patients to get into the Programme after radiochemotherapy.
BH - Amongst our patients with rectal cancer submitted to Radiotherapy plus Chemotherapy, up to a half may have cancers that would disappear completely with potentially no further treatment needed.
Do all the patients who enter it remain in the Watch & Wait Programme?
OP - No. We know there is a pretty stable percentage of patients who get into the Watch & Wait Programme will experience, mainly during the first year, the risk of tumour regrowth. And those patients will undergo surgery. But anyway, the 50% figure constitutes an excellent rate of complete clinical responses compared to the published rates from other centres, and we believe that it is due to the particular specifications of the radiotherapy that we deliver.
Only one year after the beginning of the clinical activity at the Foundation in 2013, we started a Watch & Wait Programme for patients with rectal cancer previously submitted to radiotherapy. We implemented a very dedicated and strict surveillance protocol that involved a multidisciplinary team with radiologists, surgeons, gastroenterologists, pathologists and medical and radiation oncologists.
We were the pioneers of Watch & Wait in Portugal, and probably also in the Iberian Peninsula, because as far as I know nobody else was doing it in Spain. We’ve proved that at the end of the radiotherapy treatment, we are not putting the patients at risk by waiting several weeks, but that we are actually gaining time. Basically, our philosophy is to allow radiotherapy to consolidate its effect. So we wait some 10 to 12 weeks to assess the response to the radiotherapy.
But not everyone is equal in their response to radiotherapy…
OP - It is a fact that the response to radiotherapy is very heterogeneous across patients with rectal cancer, but we have quite robust tools to detect those with complete clinical response. These may potentially coincide with the complete responses that surgeons have been observing on those specimens from surgically removed tumours which do not show any sign of cancer after radiotherapy. Those tumours that are highly sensitive to radiotherapy. And then, you can also observe the exact opposite: tumours that do not respond well to radiotherapy. But before irradiating, we don't know what is going to happen, we will only know approximately 10 to 12 weeks after the end of the irradiation treatment. And at that point, we will decide who is eligible to go into the Watch & Wait Programme (in an attempt to preserve the rectum) and who must go to surgery because their response to the radiotherapy was not good enough (complete).
Do the watching and the waiting ever end?
OP - Yes. After five years of a patient being in the Watch & Wait Protocol without tumour regrowth, we can assume that the risk of tumour regrowth for this patient becomes equivalent to the risk of having rectal cancer in the general population, so the patient can leave the Watch & Wait Programme and continue doing regular screening.
Bill Heald, do you think that the number of rectal patients who are offered radiotherapy followed by the Watch & Wait Protocol substantially increase in the near future?
BH - Yes, because Oriol is coming up with such remarkable results with radiotherapy. At the moment, we give radiotherapy to rectal cancer patients which we think have rather a local threat of recurring, and whose tumours need to be downsized or downstaged or both before the surgeon has a go at them. We have been selecting, as Oriol has said, those cancers that have gone through the mesorectal envelope somewhere, and therefore need to be downstaged to draw the tumour back into the envelope, so the surgeon can cure the patient. But now that we have such exciting outcomes with radiotherapy maybe surgery won’t be needed at all with many of these patients.
What is coming out of all this – and what I think is Colorectal Cancer Month’s big news –, is that, with the good results Oriol's been obtaining with radiotherapy, here at the Champalimaud Foundation, he is venturing to say that, provided we make it good enough, we may consider, in the future, giving our radiotherapy treatment to most low rectal cancer patients (those whose tumour is very close to the anus) and then assess the results to see if the patient can enter the Watch & Wait Programme to maybe avoid surgery altogether. If that is the case, that’s going to change the whole approach to rectal cancer around the world.
The truth is that, at the moment, others continue to just give old-fashioned radiotherapy, not particularly refined, and the impact is perhaps slightly limited compared with what we’re achieving here. And that’s what I would like us to get to, really. The refinement of the radiotherapy technique at the Champalimaud Foundation is actually delivering more complete disappearance of the cancer before the surgeon gets there. And that is something really exciting.
Do some of the patients you offer radiotherapy have metastasized disease?
OP - When patients present with limited metastatic disease, with a low burden of systemic spread, we always consider treating the primary tumour with curative intent. If the primary tumour meets the criteria for radiotherapy, threatening the surgical plane, for example, or presents with high risk features for local relapse, regardless of the metastatic disease we will observe the clinical response to radiotherapy and when a complete clinical response is achieved, organ preservation (W&W) might also be considered. We have several cases like that.
And then, how do you deal with the metastases?
OP - The metastases can be managed in several ways. If it’s limited metastatic disease in the liver or in the lung – these are the two most common places where the rectal cancer disease likes to migrate, they both can be operated, and they both can also be focally targeted with ablative radiotherapy in case surgery is not possible or not indicated; and if we have a spread disease, then the indication is chemotherapy. So when you have limited metastatic disease for rectal cancer, there is still a good chance that you can cure the patient. There are also other techniques (microwaves, radiofrequency) to focally ablate a metastatic lesion from the colorectal cancer.
BH - Death from the primary tumour has become rare. A lot of people will die from colorectal cancer, but they will die from the metastasis that we have failed to cure with liver surgery, not from the primary tumour in the pelvis.
How exactly is the radiotherapy protocol designed?
OP - Actually, we have two protocols, with two different doses of radiotherapy, the long- and the short-course. Classically, for the long-course, we deliver around 50 Gray (Gy) over 25 treatment days (the gray, or Gy, is the unit of measurement of the absorption of radiation), while in the short course delivers a total of 25 Gy (over five consecutive days). It’s a lesser dose, but radiobiologically, delivering 45 Gy over 25 consecutive days (long course) is assumed to be equivalent to delivering 25 Gy over five consecutive days (short course). Typically, the long-course is delivered concomitantly with a chemotherapy agent in tablets, whereas the short-course is delivered without chemotherapy.
Since the 1990’s, there have been three trials to randomly compare both protocols, and none of them has shown any differences, either in local control, or oncological outcomes (in terms of survival), or toxicity. It has never been proven that short course is inferior to long course. Even though the dose received in short course is smaller, it's assumed that its biological effect is equivalent to that of long course.
In the Champalimaud Foundation, we make it a little bit more complex. Besides our techniques being different, besides our particular specifications for radiotherapy and the way we deliver this radiation, we also have the means to safely increase the delivered dose, and potentially obtain higher biological effect. This is called “simultaneous integrated boost” (SIB) and it's delivered to the visible tumour and, if they exist, to involved lymph nodes.
Why are some patients doing long-course radiotherapy while others are doing short-course?
OP - This is based on a risk assessment. I would summarise it like this: if your local disease is presenting features of systemic risk – you are not metastatic, but you have, for example, extramural venous invasion –, we want to rapidly cope with both your local and your systemic risk. So we don’t have two months to deliver a long course of radiotherapy and to be only focused on your pelvis, we also have to cope rapidly with the systemic risk. In those cases, we will offer short-course radiotherapy and then we will go for systemic chemotherapy because of the risk of metastatic disease.
By the way, I am a strong supporter of another protocol, which is a protocol of short-course radiotherapy followed by consolidation chemotherapy during the waiting period. Instead of waiting some three months without doing anything, we would intensify, we would consolidate the radiotherapy treatment, afterwards, with chemotherapy.
Are you already doing this?
OP - This is still at the research stage. But the idea comes from a very important protocol that was recently published following a multicentric study, called the RAPIDO Trial. The RAPIDO trial was not designed to assess the patients’ eligibility for entering the Watch & Wait Programme; it was designed to assess other outcomes, but the published results were so good that they lead us to think that this protocol could also be easily implemented for patients who would not be operated afterwards, but put in a Watch & Wait Programme. Bill and I are strong supporters of this strategy.
BH - I would like to add that one of the most exciting things that came out of the RAPIDO trial, as Oriol’s mentioned, is that nobody was offered Watch & Wait if they were in that trial. They were testing something else. But one of the ways of measuring the effectiveness of the radiotherapy done is, of course, to look at the specimen that you have taken out surgically. And what was so exciting was that there were almost twice as many complete disappearances of the cancer in the specimens in the RAPIDO trial of patients given the short-course radiotherapy, which lasts one week, than in those with six weeks of radiotherapy. Imagine six weeks of five-day radiotherapy; it’s a big deal, in terms of people’s daily obligations, compared to having the whole thing over in one week. Many doctors seem to think that many weeks of a person’s life don’t really matter that much, but they actually do, and if you get twice as many complete responses by doing it all in one week, then that is a strong pointer towards shortening the amount of time that people have to go to the hospital to receive radiotherapy. It’s surprising how slow it has been to be taken up across Europe, particularly. And in the United States, even more so. They’re hanging on to long-course much too long in my opinion. That is not kind to the patients.
If a patient is treated with short-course radiotherapy for one reason or another, does he or she also have a chance to enter the Watch & Wait Programme?
OP - Of course, we also have short-course radiotherapy patients in the Watch & Wait Programme as well. So the idea, I would say, is that if you ever come to the Champalimaud Foundation and the multidisciplinary team is proposing you for radiotherapy, you will always have the chance to be assessed and the chance to avoid surgery regardless of your radiotherapy treatment protocol.
And if the short course results in a complete clinical response, you will also offer those patients the Watch & Wait Programme?
OP - Yes. A big yes. The management of these patients is very different in the Champalimaud Foundation compared to other places. For every single patient that we irradiate nowadays, regardless of whether it is by long course or short course, we will always assess their clinical response, and then if the clinical response is complete, we will always offer the patient the possibility to get into Watch & Wait. At the moment we have around 120 patients in the Watch & Wait Programme.
Who is doing more short-course radiotherapy at the moment?
OP - The Karolinska Institute has been extendedly using short course radiotherapy and sending the eligible patients for organ preservation [W&W]. We have also been doing that, but in a more limited way, and we have been using preferably long course chemoradiotherapy to short-course –, but we will get there at some point. We have the data.
So why do you still prefer long-course at the Foundation?
OP - Because the decisions are taken by a multidisciplinary board, and the multidisciplinary board argues that most of the data in Watch & Wait comes from long course chemoradiotherapy and there still isn’t enough mature data for Watch & Wait and short course. But anyway, my personal opinion is that we are a research institute and it is our job to bring the evidence for the short course to maturity as well. And we are doing it.
The choice of short course is more a patient-based discussion in a multidisciplinary team. For example, if we have a young patient with a lot of ugly features, like a very high risk of becoming metastatic, we don’t want to waste time on long course chemoradiotherapy and waiting. We want to tackle both problems – the primary tumour and the risk of systemic disease. To this patient, we will then offer short-course and rapidly full chemotherapy and then, depending on the response, the patient will be operated or will enter the Watch & Wait.
BH - Can I throw in the simple business of taking advice from an old doctor? You mustn’t get the idea that we give short-course preferably to people who could not stand long-course, in particular because they are frail. A highly intelligent patient came to us from Great Britain, but he was from Sweden and took advice from the people he respected most, in Stockholm. He was only 50, perfectly fit, and he said he wanted short-course. If you ask me, that’s what I would say too. Indeed, it’s what I would always say to a patient he should have; I am convinced by that RAPIDO data we mentioned. Twice as many complete responses, that’s a very big measure of the effectiveness of short versus long-course.
Let me now ask you about the particular radiotherapy techniques that have allowed you to get better results than anyone else at avoiding surgery after Watch & Wait.
OP - First, I have to say that the Champalimaud Foundation made a strong investment in technology at the beginning, especially in radiotherapy, and that that gave us access to the most advanced radiotherapy techniques. In the last three decades, most rectal cancer – most pelvis malignancies, actually – were treated with 2D or 3D so-called “conformal” radiotherapy techniques, which irradiated the whole of the pelvis and most of the organs in the pelvis. At the end of 2010, new radiotherapy techniques were developed, called “intensity-modulated radiotherapy” techniques. This means being able to modulate the intensity of your beam of photons, thus adapting it in a dynamic way to the shape of the tumour or of the organ that you want to irradiate. Nowadays, we are no longer irradiating the pelvis as if it were a box, but sculpting the dose in the shape of each patient’s mesorectum. We implemented these intensity-modulated techniques, called VMAT (Volumetric Modulated Arc Therapies), which we systematically use in the Foundation.
We also use MRI and dynamic PET/CT for planning the radiotherapy treatment individually for each patient, in order to accurately define the tumour and its relations to the rest of the pelvic organs (traditionally, only a basic planning CT scan has been used for this purpose). Being capable of this refinement when planning the treatment, we have increased the RT dose to the tumour – and to the lymph nodes, when necessary, with the aim of increasing the biologic effect.
And we also implemented on-board image-guided procedures, which means that everyday, before delivering the dose of radiation, we acquire imaging (a low-dose CT scan in order to fuse it with the planned image based on PET/CT and MRI), to observe the position of the tumour and adapt the irradiation to it.
Would you say that this is the equivalent of Bill Heald’s Total Mesorectal Excision, but done with radiation instead of surgery?
OP - Precisely. By the way, in the beginning, Professor Heald, Inês Santiago – a highly skilled radiologist in pelvis and rectal MRI – and myself (modestly learning from both of them), went through several sessions of discussion and came up with the idea of doing, not a TME [Total Mesorectal Excision, Bill’s life work], but a TMI (Total Mesorectal Irradiation). This was also Bill’s idea. He asked: “why don’t we stop irradiating the whole of the pelvis and stick our radiation field only in the inside of the mesorectum”?
We published a position paper with the idea and we have been delivering our treatments in accordance. We also defined the extended TMI to be implemented when the disease is present outside of the mesorectum.
This is what we have been doing over the years – defining different fields of radiotherapy. And the reason for doing that was exclusively to decrease the toxicity of radiotherapy. Radiotherapy is very badly seen across the medical profession, and the only reason for that is that the old radiotherapy techniques were causing a lot of damage. They were curing tumours, it’s true, but they were also toxic. And the combination with chemotherapy is even more toxic.
But surgery is not side-effect free either and, when in combination with radiotherapy, we get into the potentially worst side-effect combination: the so-called toxic-mix. That's why we have been working on offering the best possible treatment strategy, which brings the highest chance of tumor curability, balanced with the minimum acute toxicities and long term side effects. We have also seriously invested in quality of life for patients with rectal cancer.
Bill Heald, one last message?
BH - If there’s one message for Colorectal Cancer Month in 2022 it is that we cure the patient. Remember, rectal and colon cancer are the commonest malignancies for us actually to cure, so people live until they’re run over by a bus or die of old age. Cured, not just controlled, is more common in bowel cancer than in any of the others (apart from breast cancer, which is not an internal organ cancer). We can cure more people from bowel cancer than from all of the other internal malignancies added together.
By Ana Gerschenfeld, Health & Science Writer of the Champalimaud Foundation.