FOxTROT Trial Sheds Light on Neoadjuvant Therapy for Colorectal Cancer

David J. Kerr, CBE, MD, DSc


March 16, 2023

This transcript has been edited for clarity.

I'm David Kerr, professor of cancer medicine from University of Oxford. I'd like to discuss a trial that's popped up recently in the Journal of Clinical Oncology: the FOxTROT trial. This is a trial of neoadjuvant chemotherapy vs conventional adjuvant chemotherapy in patients with colon cancer.

This was conducted in Birmingham, by a bunch of old friends of mine from 1000 years ago. The trial was started in 2008. We recruited around 1000 patients, with the trial finishing recruitment in 2015. There was a rather prolonged period of trial recruitment and quite a long period of follow-up between the trial finishing recruitment and being reported.

It was a 2:1 randomization in favor of the experimental arm in which patients were given 6 weeks of neoadjuvant chemotherapy — that's three cycles of FOLFOX, 48-hour infusion of 5-FU/oxaliplatin, followed by 18 weeks of FOLFOX. In the control arm, it would be 24 weeks of FOLFOX, 12 cycles, at intervals of 2 weeks.

I found the chemotherapy description a bit confusing because at one stage, they were considering 2:2 randomization in which some patients received panitumumab, and it looked as if some patients could get capecitabine and oxaliplatin. That would be two cycles of CAPOX, capecitabine/oxaliplatin, given in 3-weekly intervals and the remainder given subsequently.

The panitumumab didn't add anything. The key finding from this study was that the 2-year recurrence rates were around 17% in patients who received the 6 weeks of neoadjuvant chemotherapy compared with around 21.5% in patients who received conventional adjuvant chemotherapy.

Interestingly, there were some imbalances in the number of patients who had chemotherapy. This is because for patients who undergo radiologic staging of disease, I guess there will be under- and overstaging. There will be a degree of doubt — false-positives and false-negatives.

In those patients who undergo surgery and then receive full histopathologic review, of course, there'll be some patients who'll be found to have very early stage T3N0 disease. In that setting, it's quite possible that the clinician and patient would decide that chemotherapy wasn't in their best interest. There was a mismatch in the numbers, with fewer patients getting chemotherapy in the adjuvant arm.

The 2-year survival is a slightly unusual figure, to be honest. Usually, we look at 3-year disease-free survival, overall survival, and so on. With 1000 patients, the trial wasn't powered to look at overall survival, so we have this slightly unusual 2-year end point. Nevertheless, this is an interesting study, and I think we need to see more data.

With longer follow-up, surprisingly, we don't have more mature survival data given that the trial was initiated in 2008. There are other studies looking at similar questions, and therefore, there may be the possibility of meta-analysis — but it's still an interesting study.

In our practice, we were not rushing to engage giving neoadjuvant chemotherapy routinely — far from it. In those patients in whom the surgeons feel there is a question mark or a doubt as to whether they might be able to resect or not, we would aim to give 3 months of chemotherapy upfront before bringing those patients back to the multidisciplinary team for review, hoping that we would have converted borderline or marginally inoperable patients to a clinical situation where the surgeon felt comfortable with the possibility to resect.

One of the other things that always interests me is how to better select patients. There's no doubt that whether with neoadjuvant treatment or adjuvant treatment, there was some overtreatment of patients, where clinicians were giving too much chemotherapy for a relatively limited benefit. With the advent of circulating tumor DNA and better tissue-associated prognostic markers, we must become better at selecting patients that will benefit most from chemotherapy, whatever the timing of it.

That then introduces an interesting question about whether a biopsy in a neoadjuvant setting would be at all reflective of the primary tumor as a whole, which reflects the question of tumor heterogeneity. If we take a small bite or sample of the tumor at colonoscopy or whenever, how representative would that biopsy be of the wider tumor?

We know from our own and other work that colon tumors are significantly less heterogeneous, for example, than lung cancer. Therefore, with one, two, or three biopsies, it's possible that we would be able to sample sufficiently across the whole tumor to be comfortable with heterogeneity. As we apply more molecular biology and better patient selection, we need to look at how we take biopsies and the number of them to reflect the primary tumor in that early disease setting.

Have a look at the study and see what you think. Clearly, the world has moved on since 2008, and we've now shown that 3 months of chemotherapy by and large is as good as 6 months. We have better biological markers of prognosis to individualize the early treatment of colon cancer.

Have a look at the paper. I'm very interested in any comments or advice that you might have, and I'll be fascinated to hear how this will affect your own clinical practice.

Thanks for listening, as always. For the time being, Medscapers, over and out. Thank you.

David J. Kerr, CBE, MD, DSc, is a professor of cancer medicine at the University of Oxford. He is recognized internationally for his work in the research and treatment of colorectal cancer and has founded three university spin-out companies: COBRA Therapeutics, Celleron Therapeutics, and Oxford Cancer Biomarkers. In 2002, he was appointed Commander of the British Empire by Queen Elizabeth II.

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