20 March 2024
In some patients, localised rectal tumours can be treated with chemoradiotherapy, without immediately (or ever) recurring to surgery. But what if undetectable residual cancer cells were to remain in the body and regrow a tumour? Those patients would then be operated right away, but would the fact of having delayed their surgery lead to a higher risk of developing distant metastases?
A strategy called Watch & Wait (W&W) has increasingly been used, including at the Champalimaud Foundation, to avoid surgery and its associated complications, in a selected group of patients whose tumours become undetectable after chemoradiotherapy. In terms of the local tumour control, it has been shown to be as safe to operate them later – if ever their tumour gives any sign of coming back – as to operate them immediately after chemoradiotherapy treatment. But up to now, there wasn’t enough data to study the systemic consequences of the surgical delay on these patients – that is, the potential metastisation of their cancer.
Now, a study by an international group of researchers, whose first author is Laura Fernández, colorectal surgeon at the Champalimaud Foundation’s Digestive Unit, has been presented at the annual symposium of American Society of Clinical Oncology-Gastroinstestinal Cancers, giving the first quantitative assessment of this risk.
In this interview, Laura Fernández talks about W&W and about the new results, which have been submitted for publication.
For patients with low rectal tumours (“low” tumours are those that are close to the sphincter, at the margin of the anus) the standard treatment is chemoradiotherapy followed by surgery.
Low rectal tumour surgery itself has serious complications. When we remove the rectum, this can lead to faecal incontinence, and severe consequences for urinary and sexual function. In addition, there are many patients whose tumour is either at the level of the sphincters or even invades the sphincters and then, the only surgical option implies a permanent colostomy, leaving them for life with a bag in the abdomen to collect their faeces. In any case, surgery will always greatly affect the quality of life of these patients.
Chemoradiotherapy before surgery has significantly changed the modern management of rectal cancer. The observation of tumour response has introduced new possibilities in the treatment algorithm. In fact, we know that for approximately 30-40% of patients who have surgery after chemoradiotherapy, when the removed rectum is analysed, there is not a single tumour cell left in it. The chemoradiotherapy leads to the complete disappearance of the tumour.
This is what motivated, 20 years ago, a Brazilian surgeon [Angelita Habr-Gama, co-author of the new study] to create the Watch & Wait programme, to try to identify these patients with complete tumour response to chemoradiotherapy in order to avoid surgery and all its associated complications.
And that’s what a number of cancer centres are doing today, and in particular the Champalimaud Foundation. After a patient received chemoradiotherapy for low rectal tumour, an evaluation – which consists of an endoscopy, a rectal examination and a rectal magnetic resonance (MRI) – is performed in order to identify tumour response. If there is no evidence of a residual tumour, the patient is considered a candidate for this program and enters a very strict surveillance protocol (W&W) with an excellent quality of life and maintaining acceptable oncological outcomes.
However, one of the risks of keeping the rectum in situ is that approximately 25-30% of those patients will develop a local tumour regrowth during the first three years, the majority of which can be successfully controlled by deferred surgery and appears to have no negative impact on local disease control.
Because there is no method to see the cells themselves non-invasively. And in about 25 to 30 percent of the patients that go into the Watch & Wait Protocol, at some point during the follow-up the tumour becomes evident again. This means that there were residual tumour cells, a few tiny ones, that could not be seen either by endoscopy or MRI, but in a year or more have become visible because they have started to grow again. In this case, we don't wait any longer; the patients undergo surgery.
So through W&W, you can control the tumours locally. But in you latest work, you have started considering another type of risk: that residual cancer cells might migrate to distant parts of the body, causing metastases. Why only now?
For many years the studies of W&W were very focused on the local aspect of the disease. We have to consider that the risk of metastasis in all patients followed by W&W is very low, it is approximately 10%. We described this in our previous work. This time, we particularly wanted to analyse the subgroup of patients with a local regrowth.
Considering that the total number of these patients is low, we needed large database to study them. Now we have a large database of WW patients and research can advance further. We have an international database with more than 2,000 patients from 27 countries who followed the WW Protocol. Of those, around 508 developed a local regrowth. That was the group we considered for our study, which we presented at the annual symposium of American Society of Clinical Oncology-Gastroinstestinal Cancers (ASCO-GI), in San Francisco, last January (and that was selected as one of the submitted abstracts with the most merit, the best academic impact).
The challenge here was to find a comparator group for these patients with local regrowth. Previous studies have attempted to investigate the oncological outcomes of patients with local regrowths. First, local regrowths were compared with Watch & Wait clinical responders who never developed a local regrowth. The results were strikingly different in terms of distant metastasis rates (local regrowths had a significantly higher risk).
However, these results are expected because we are comparing patients with residual tumour to patients with no residual tumour at all! In contrast, other studies have attempted to compare patients with local regrowths to incomplete responders treated with surgery, and haven’t found any significant differences.
We believe that such a comparison is “unfair”. While local regrowths necessarily have excellent initial responses, patients who undergo immediate surgery at restaging have varying degrees of response, including patients with minimal response, which is known to be one of the worse oncological outcomes.
For these reasons, we decided to perform a comparison of the risk of distant metastasis between local regrowths and patients with an excellent, but incomplete, response to chemoradiotherapy.
Considering that W&W local regrowths are incomplete responses (non-identified residual tumour cells) with an excellent initial response, they should ideally be compared with patients managed by immediate surgery after chemoradiotherapy and with an excellent pathological response: 10% residual cancer cells or less, based on the pathological evaluation of the resected rectum.
Our team decided to use a Spanish database where surgeons from hospitals in Spain introduce their surgical data: the Vikingo database, a national rectal cancer program established in Spain to standardise rectal cancer management. All the patients in this database underwent immediate radical surgery after chemoradiotherapy, regardless of the response. From this database, we selected only those patients with less than 10% of residual tumour cells (excellent responses!).
Because up to 10%, that corresponds to patients with near pathological complete response. It is the minimum percentage of residual tumour cells that we have from the pathological classification.
In summary, the only difference between these two groups, which both have residual cells, is that one group is operated immediately and the other only a year or two later (when the regrowth is identified). So we think this is the best comparator group that we can find to compare with W&W patients with local regrowth.
We found that the Watch & Wait group had a higher risk of distant metastasis (DM) than the group that underwent immediate surgery. In our paper, which we have now submitted for publication in the Journal of Clinical Oncology (a publication of ASCO), we conclude that the DM rate was significantly higher among W&W patients with local regrowths: 22.8% vs. 10.2% in the immediate surgery group with local regrowths. Therefore, we wrote, “leaving the primary undetectable tumour in situ until development of local regrowth may result in worse oncological outcomes” [in W&W patients].
This is a very important question. Here we have to explain that the risk we are talking about is very low considering the whole population of patients with rectal cancer. Around 40% of patients with rectal cancer may be candidates for the W&W protocol, and only 30% of those will have a local regrowth, – that is, 12% of all patients with rectal cancer. Then the 20-25% of those who will have distant metastases correspond to 3% of all patients with rectal cancer and chemoradiotherapy. This is the reason we need large series of patients to demonstrate any significant association. This is the first time that we're putting it in evidence.
The message here is that there is a subgroup of patients that may be a higher risk of distant metastases. Does it concern a small subgroup within the W&W programme? Yes. Is it important to know and recognise it? Of course it is. This information is also important for future studies in this area.
Probably not. Choices always imply risks. However, this information is crucial for patient counseling and for doctors. When WW is an option, we should be able to inform patients about all the benefits and the risk of their treatment options.
No. What we are saying is that we have to be cautious. The Watch & Wait Protocol is not for all patients with rectal cancer. We really need to select the right patients to go into the programme. There are endoscopic, radiological and clinical criteria to define which patients have a complete clinical response. The Watch & Wait Protocol is not going to disappear, it is a great option for a selected group of patients, but we need to select the right patients.
