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Randomised phase 3 study of S-1 versus capecitabine, with bevacizumab optional in both arms, in the first-line treatment of metastatic colorectal cancer (mCRC), the SALTO study of the Dutch Colorectal Cancer Group
Interview with Prof. Cornelis (Kees) Punt
Prof. Cornelis (Kees) Punt – Department of Medical Oncology, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands
- How is metastatic colorectal cancer (mCRC) usually treated?
- What did we learn from the results of the SALTO trial presented at ECCO17
- Will this change the treatment approach for patients with metastatic colorectal cancer?
- What do you think will happen next in terms of development of new treatments for patients with colorectal cancer?
Prof. Kees Punt, Chairman of Department of Medical Oncology of the Academic Medical Centre, Amsterdam, Netherlands shared his interest in patients with colorectal cancer. The treatment for metastatic colorectal cancer (mCRC) has two objectives, first is to downsize the metastases in order to allow secondary resections and combination chemotherapy with a targeted agent is initiated to achieve this. Second, is if there are permanently non-resectable metastases then the option is to start with mono-chemotherapy with targeted agents (such as mono-treatment with fluoropyrimidine and oral agent capecitabine is used). The SALTO study with the Dutch colorectal cancer group compared treatment with capecitabine with the other oral agent, S-1 or oral fluoropyrimidine. It was a randomised study and the use of bevacizumab was optional in both treatment arms. The primary endpoint was the incidence of hand-foot syndrome. The results showed significant decrease of the incidence of hand-foot syndrome and the efficacy of both drugs was similar. In a recently published study which evaluated 52 patients the switch from capecitabine to S-1 because of the hand-foot syndrome showed a decrease of symptoms and also a complete resolution of hand-foot syndrome in some of the patients. S-1 has certainly shown to improve the quality of life and it can also be used in combination with other cytotoxic agents. There are some promising agents which are in the phase I and II studies which can be considered in future in terms of development of new treatments for patients with colorectal cancer.
My name is Kees Punt, I am the Chairman of the Department of Medical Oncology of the Academic Medical Centre, Amsterdam in The Netherlands and my main interest is patients with colorectal cancer.
How is metastatic colorectal cancer (mCRC) usually treated?
To summarise treatments for metastatic colorectal cancer, I think if the objective is cure, so you want to have downsizing of metastases in order to allow secondary resections, you usually have combination chemotherapy with a targeted agent.
However, in patients with permanently non-resectable metastases you also have the option of starting with monochemotherapy with targeted agents and these are typically patients who are either in a very good condition so are eligible for subsequent treatments or patients who are elderly or frail who will not tolerate combination chemotherapy regimens and those patients we usually treat with mono treatment with fluoropyrimidine and for that purpose it is usually the oral agent, capecitabine that is used.
What did we learn from the results of the SALTO trial presented at ECCO17
Some patients are on capecitabine treatment for a long time, especially since we last year have shown in the CAIRO3 study that maintenance treatment with capecitabine and bevacizumab is better than observation so this will expose patients for a long time to this treatment and one of the most cumbersome toxicities of capecitabine is hand-foot syndrome. That may certainly in elderly patients compromise their quality of life.
The SALTO study compared treatment with capecitabine with the other oral agent, S-1 or Teysuno. It is also an oral fluoropyrimidine which was mainly developed in Asia and data on Asian patients showed that these patients have a significantly reduced incidence of the hand-foot syndrome, but of course Asian patients have a different metabolism compared to Western patients.
The data on efficacy were quite comparable in a lot of GI cancers, so we were pretty confident that the efficacy would also be the same in the Western patients but we were concerned of extrapolating these data on the toxicity so therefore we designed the SALTO study of the Dutch colorectal cancer group. We randomised patients with capecitabine versus the oral agents S-1. The use of bevacizumab was optional in both treatment arms and the primary endpoint was the incidence of hand-foot syndrome.
Our results showed that indeed there was a significant decrease of the incidence of hand-foot syndrome. The all-grade hand-foot syndrome was 73% for capecitabine and it was around 45% in patients treated with S-1 but more importantly the most severe hand-foot syndrome, the Grade 3 hand-foot syndrome, the incidence was 21% in capecitabine and only 4% in patients treated with S-1. These were the incidence which was scored by the physicians and we also had patient diaries or patient reported their own interpretation of this toxicity and this confirmed the results.
We also of course evaluated the progression-free survival and it was highly similar in both groups, so again confident that the efficacy of both drugs are the same.
The only toxicity which was more prominent in S-1 compared to capecitabine was anorexia but it was quite a low incidence and it was the only significant difference in favour of capecitabine and all other toxicities were quite comparable and low, so our conclusion is that S-1 is a very well tolerated oral fluoropyrimidine and is certainly a good alternative for patients who do not tolerate capecitabine because of hand-foot syndrome.
Will this change the treatment approach for patients with metastatic colorectal cancer?
I think that it’s a common problem and certainly patients who are on capecitabine and do not tolerate it, I think there is good reason to switch to S-1. We also recently published a paper on 52 patients who actually switched from capecitabine to S-1 for reasons of hand-foot syndrome and the majority of patients, 94% experienced a decrease of symptoms and even 56% a complete resolution of hand-foot syndrome so this strengthens the case for S-1 that it is a really better tolerated agent in terms of hand-foot syndrome.
What do you think will happen next in terms of development of new treatments for patients with colorectal cancer?
Of course there are always two objectives for cancer treatment. It’s to improve the quality of life and I think S-1 has certainly contributed to that and it may also be used I think in combination with other cytotoxic agents, known cytotoxic agents.
In terms of other treatments for patients with metastatic colorectal cancer, we know that metastatic colorectal cancer is rather a collection of different subgroups of patients who are molecular defined and who require specific treatments.
At this ECCO meeting there was not really a breakthrough on novel agents, but we know that for several subgroups there are very promising agents being developed in early Phase I, Phase II studies. For instance the checkpoint inhibitors in microsatellite instable metastatic colorectal cancer and also in the small subset of HER2 positive colorectal cancer there is also promising data of combined inhibition, dual inhibition of the HER2 receptor, so I think it will gradually improve and these are probably not treatments that really will cure patients but will add to the prolonged lifespan of patients with metastatic colorectal cancer.
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