Safe to Omit Bolus in 5-FU for Colorectal Cancer?

David J. Kerr, CBE, MD, DSc


October 04, 2021

This transcript has been edited for clarity.

Hello. I'm David Kerr, professor of cancer medicine from University of Oxford. Today I'd like to talk about a nice study that's been published in one of our own journals, JCO Global Oncology. It's an ASCO journal I help set up that's now being overseen by Editor-in-Chief Gilberto Lopes.

This is a study from a Brazilian group who were interested in making a nationwide survey of oncologists about what type of chemotherapy they use to treat adjuvant and advanced colorectal cancer. The question that they posed was whether we need bolus 5-FU. Let's step back a little.

Commonly, these days, we use a chemotherapy regimen called FOLFOX or FOLFIRI. It's a combination of oxaliplatin, irinotecan, with leucovorin and 5-FU, which is given as a bolus of 400 mg/m2 followed by a 46-hour infusion of 2.4 g/m2.

This was developed by a great friend of mine called Aimery de Gramont. I have a habit of calling it the de Gramont regimen. Of course, it seems out of fashion now to name chemotherapy regimens after individuals.

My brief brush with fame, the Kerr regimen, was when we developed an infusional regimen for hepatic arterial chemotherapy. It didn't work in randomized trials; therefore, my shot at immortality fell by the wayside.

In the Brazilian study, they undertook a survey. They asked junior and senior medical oncologists in Brazil whether they always include the bolus or do they omit it? They found that, for patients with advanced disease, only 40% of Brazilian oncologists would add bolus 5-FU. In the adjuvant setting, 60% would add bolus 5-FU.

Interestingly, there was a difference between junior and senior medical oncologists, particularly in the advanced setting. The more senior medical oncologists would be quite happy to omit the bolus 5-FU compared with the younger colleagues.

The addition of bolus 5-FU is more associated with hematologic toxicity. Therefore, one might argue, I think, logically that in a low-income setting, if omitting the bolus 5-FU could be done without having a major negative impact on efficacy, it would be a reasonable thing to do. It would improve tolerability, keeping patients out of hospital.

Indeed, there is a growing literature suggesting that the bolus can be omitted without there being a major effect on progression-free and overall survival. It's a small, nonrandomized study, but nevertheless quite supportive.

I used to be Rhodes Professor of Medicine, Cancer and Clinical Pharmacology, when I first came to Oxford. I love pharmacokinetics and drug modeling. The reason that we give a bolus when we're giving a prolonged infusion of a drug is to get to steady state more quickly.

Usually, it takes a drug five drug half-lives to get to steady state. However, 5-FU only has a half-life of around 10 minutes, so you get to steady state quickly. Therefore, giving the bolus up front doesn't really add very much when we're considering a 46-hour infusion.

Therefore, I think it would be entirely reasonable to omit the bolus. For the leucovorin component, often we use a dose of 200 mg/m2. I think that could be given at a tenth of that dose. There are some randomized studies comparing high- and low-dose folinic acid. It doesn't make a difference in efficacy, nor would one predict [a difference in] the molecular pharmacology of 5-FU.

It was a nice study. The split between old and young, experienced and relatively inexperienced, about whether they omit the drug was very interesting.

And this is an important message for my colleagues who are delivering infusional 5-FU with oxaliplatin or irinotecan in a low-resource setting: It is perfectly reasonable to omit the bolus 5-FU to improve safety. And it is very reasonable just to give low-dose folinic acid rather than the normal high dose. It's an important lesson to be learned.

Thanks very much for listening, as always. I'd be really interested in any of your comments. If there are any nascent clinical pharmacologists out there or if anyone disagrees violently, let's discuss it. For the time being, shipmates, over and out. Thanks for listening, as always. Bye-bye.

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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