COMMENTARY

Colorectal Cancer Therapy Gets a Tune-up: ESMO 2017

David Kerr, CBE, MD, DSc, FRCP, FMedSci; Dirk Arnold, MD, PhD

Disclosures

October 02, 2017

David Kerr, CBE, MD, DSc, FRCP, FMedSci: Hello. I'm David Kerr, professor of cancer medicine from the University of Oxford. I would like to welcome you to Medscape Oncology Insights, coming to you from the very heart of the 2017 European Society for Medical Oncology (ESMO) Congress.

I'm absolutely delighted to be joined by my great friend and colleague, Prof Dirk Arnold, from the University of Hamburg. Today we would like to talk a little about the highlights around colorectal cancerology, a disease which Dirk and I have been studying for what feels like most of our lifetimes.

Dirk, you played an important role in putting the program together. ESMO is a fantastic meeting with 23,000 people. The quality of the meeting was of the very highest order. What caught your eye in terms of colorectal cancerology?

A Quiet Year for Colorectal Cancerology?

Dirk Arnold, MD, PhD: Thanks for the introduction and question. Colorectal cancer is clearly not the top focus here, although there have been some interesting reports presented. We see many new drugs entering the field for various cancer types. In colorectal cancer, it's the years of consolidation that we currently see.

Prof Kerr: You are, as always, being politically correct. Is there not much going on in colorectal cancerology?

Prof Arnold: No, I wouldn't say that. We do see many novelties on posters and on the poster level. We do see immunotherapy combinations, etc. But when it comes to randomized trials, answers are not ready to be reported.

Prof Kerr: Is anything majorly practice-changing?

Prof Arnold: No. What we currently have is some adjustment of the current standards. I would say that the standards are really at their top and we can now compare them to the incoming novelties and new drugs coming out of the field.

Prof Kerr: We are refining that which exists. There is a stronger international flavor because we are seeing presentations coming from our colleagues in Japan and elsewhere. What caught your eye? What would you like to tell us about?

Treatment Intensification for First-line Metastatic Colorectal Cancer

Prof Arnold: Today we had an interesting and very lively discussion on treatment intensification for first-line treatment of patients with metastatic colorectal cancer. Some countries like to see triple chemotherapy as the standard, as we do now in some parts of Italy, and others like this high-intensity treatment. A randomized trial from Germany[1] was the first using triple chemotherapy. The question was whether the addition of anti-EGF receptor antibody would benefit patients.

A bit more than 100 patients underwent randomization. The primary endpoint was response rate. Although the response rate was so high with triple chemotherapy, specifically more than 60%, the surprising thing was that it could add another 25%. We will say that now we have response rates of more than 86%. This means we can now have, at least with RAS wild-type patients, nearly every patient responding. That's interesting.

Prof Kerr: Here is the $64,000 question: Do you think that improvement in response rates will carry over into some substantial improvement in progression-free, or, more importantly, overall survival?

Prof Arnold: This is the open question which we still have to answer. I've seen that progression-free survival was not improved. These are highlights, but again we do need to see [results] in colorectal cancer. It's not only inducing response; it's also defining the whole strategy over the first-line treatment phase, then the second-line phase, third-line phase, etc. Therefore, we now see that we can increase treatment intensity. We can decrease tumor burden. The question is, what does it mean?

Prof Kerr: What is the cost to the patient? Not the dollar cost, but the cost in terms of toxicity, mortality, and so on—is it a big difference?

Prof Arnold: It's clearly relevant. With these regimens, toxicity becomes an issue. Patient selection is crucial. The right population needs to be defined of who would benefit from the relief of tumor burden, either being highly symptomatic or being a candidate for secondary resection, etc.

Prof Kerr: We are old and wise enough to be philosophical. We would always say, and I think you would agree, that cancer biology is king, patient selection is queen. One wonders whether, in selecting patients who are fit enough to withstand triple combination chemotherapy (with some bias that we do not understand), we might be selecting patients with a higher chance of responding.

The other thing is that we are part of a multidisciplinary team (MDT). Think how aggressively we manage metastatic disease now with surgery and radiofrequency ablation. The idea that we can get that degree of tumor responsiveness might play into the MDT and open up increased possibilities for ablation and surgery.

At some point, metastatic colorectal cancer became a chronic myeloid leukemia. We do unselective cytoreduction and then use weapons intelligently in the chronic phase.

Prof Arnold: High-intensity treatment regimens need to be used intelligently; they are not administered for a long time. You are just inducing response as we do with lymphoma or leukemia, etc. We then have to define the best maintenance strategy, which could be ablation, resection, or whatever. But it could also be the molecular targeted approach in selected patients. We use what we do in different trials. We use the immunotherapies or immunotherapy combinations or signal transduction inhibitors plus immunotherapy to maintain what has been achieved during the first 12 weeks of treatment.

Prof Kerr: I like that concept. I like the idea of a moderately intensive, pretty heavyweight chemotherapy to induce [response], with some further interventions if possible, and then seeing if we can step back a little. I'm terribly interested in metronomic chemotherapy—low-dose continuous and so on.

Prof Arnold: Even this could play a role here. At some point, metastatic colorectal cancer became a chronic myeloid leukemia. We do unselective cytoreduction and then use weapons intelligently in the chronic phase.

Prof Kerr: You heard it here first. This is good. Our Medscape viewers have had heard us philosophizing. I think we could crystallize that into some interestingly clever clinical trials.

Anything else? What is happening across the water? Any word from the wise men in the East? Anything interesting happening with our colleagues in Japan?

New Fluoropyrimidine Shows Benefit

Prof Arnold: We have seen here some evaluation of their home fluoropyrimidine in these combinations. They are achieving really great results across all molecular subtypes when substituting capecitabine with S-1.[2] A randomized trial showed very nice, very promising results. No idea whether this will be translatable 1:1 into the white population or our treatment landscape. Interesting result.

Prof Kerr: You draw an important point. They are interesting results but are they translatable? The more we understand genetics, the more we realize that we are the same. We know that we are genetically almost indistinct from mice. But there are some key differences in how Japanese, Chinese, Asian patients metabolize anti-cancer drugs. It does make a difference in terms of thinking how we translate those fascinating results into white populations.

Prof Arnold: I completely agree, David. I have the feeling that in colorectal cancer, we are genetically not that diverse; [we are] more or less one. By contrast, in gastric cancer disease, it's different. The gastrointestinal field with these east and west comparisons is very complex.

Duration of Adjuvant Therapy

Prof Kerr: That's fantastic. I would be really interested in your take on duration of treatment of adjuvant therapy. We had a presentation at ASCO [American Society of Clinical Oncology meeting] with the SCOT trial,[3] a fantastic collaborative effort. I'm just dead interested to see how you condense those new data on 3 versus 6 months into practical advice. I'm faced with a 60-year-old patient in the clinic with a T4, N1 tumor. What do I tell them? What do I do? Nothing is easy.

Prof Arnold: That is really a tough story. There will be an extra session here tomorrow and an update of this 3-versus-6-months trial in their plethora of [topics]. The general finding is that the differences are small. Whatever comes out as different, be it statistically significant or nonsignificant, be it within the range of expected or diverging by 0.1%, etc, the differences are small. We need the patient in our focus, on our mind. If we have an intermediate- or low-risk group for relapse in stage III disease, it's clearly justifiable to give them only 3 months of treatment.

Prof Kerr: Agreed. What do you do with him?

Prof Arnold: The complication in his situation is that he has T4 disease. T4 disease would, for me, mean that he is in an intermediate- to high-risk group for relapse. Therefore, I would keep him on 6 months' treatment. However, if this were T3 disease with only one or two lymph nodes and an adequate lymph node sampling, then I would say that this is a low-risk condition and I would suggest at least 3 months of treatment.

Prof Kerr: I find myself agreeing entirely. How did that happen? I know it's subgroup analyses, but I still think for those younger, fitter patients with longer life expectancy who are coming in with a greater burden of disease, I would still favor the 6 months. I would find ways to mitigate toxicity. I agree with you. It would be so interesting to see how our viewers interpret the results in their own practice and follow that through.

That is a discussion for another day on how we need real-world data as to what regimes are being used in the clinic and so on.

On behalf of our viewers, let me thank you for what has been a really interesting session. It's always enjoyable. Two friends chatting provocatively and so on. Thanks for coming along with the spirit.

Thanks to all of you for watching. We would be happy to take any points or comments that you might want to make. For the time being, Medscapers, over and out from ESMO. Thank you.

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