Could Lower-Dose ImmunoTx Provide More Equitable Global Access?

David J. Kerr, CBE, MD, DSc


July 27, 2022

This transcript has been edited for clarity.

I'm David Kerr, professor of cancer medicine at University of Oxford.

I've talked many times before about how, as medical oncologists, dose and schedule are the aspects of treatment that we can control the most. Of course, we're interested in germline genetics and tumor biology, but these are things that we can't control. They are inherited, and while we can adapt our treatment to them, we cannot control them. Dose, though, is something that we hold within our own hands.

This is a topic that we've discussed recently in our clinic. The world's drug and supply chains have been disrupted hugely by world events — pandemics and wars, I'm sad to say — and we were running short of folinic acid. We use folinic acid in combination with 5-fluorouracil because there is compelling molecular evidence to show that folinic acid enhances the cytotoxicity of 5-fluorouracil. The molecular mechanism is well worked out: ternary stabilization of the complex of F-dUMP with its target enzyme, thymidylate synthase.

A dear friend of mine, Aimery de Gramont, introduced the de Gramont regime, in which relatively high-dose folinic acid has been used for decades. But there is compelling evidence — some of our own and some from the German groups and elsewhere — suggesting that we don't need high-dose folinic acid. There are randomized trials comparing high dose with low dose, given in bolus, given with infusion of 5-FU. It makes no difference.

But the difference in dose is 10-fold. And therefore, it was easy for me as a clinical pharmacologist to say to my colleagues in Oxford, in this time of straitened circumstances and drug [shortages], let's just give the lower dose of drug, and without any disservice to our patients whatsoever.

There's a nice article in Annals of Oncology by Ian Tannock, MD, PhD, and colleagues in which they've written very compellingly about how we can make immunotherapy drugs more widely available in low- and middle-income countries. They've done a fantastic retrospective review of the phase 1 trials, including the dose scheduling and pharmacokinetics of immune checkpoint inhibitors.

And what they're saying is that the dose that we use in the West is far too high. They provide good evidence to suggest that we could give lower doses less frequently. In fact, if we use their dose modifications, which are all rational and based on a strong underpinning of clinical pharmacology, we could use the same dose regime that we use to treat one patient in the West to treat 20 patients in lower-income countries.

Have a look at the article, which is thoughtful, thought-provoking, and shows how dose is something that we need to understand better. I moan a lot to our junior staff about how although they know everything about next-generation sequencing, they know nothing whatsoever about clinical pharmacology. The pillar upon which much of therapeutic medicine is based seems not to be taught in modern medical schools, or to the next generation of clever, young oncologists.

This is a thought-provoking article from Dr Tannock and colleagues, with practical measures that could be taken. The immune checkpoint inhibitors are on the WHO list of necessary anti-cancer drugs, but they're way beyond the reach of most individuals in most low- and middle-income countries. And here's a practical, evidence-based solution as to how we could deliver those drugs more equitably and fairly around the world.

Have a look — I'd be very interested in your comments. For the time being, Medscapers, ahoy. 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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