Meet The Professors: Pancreatic Cancer Edition, 2016 - Video 19Association between UGT1A1 genotype and irinotecan toxicity
3:18 minutes.
TRANSCRIPTION:
DR LOVE: Tony, a question we had gotten emailed in to us from an oncologist is about assessing patient’s homozygosity for UGT1A28 allele — which I didn’t even know what it is — for prediction of toxicity for irinotecan. What is it, and do you use it? DR BEKAII-SAAB: So it’s essentially SN-38, the byproduct of irinotecan, gets ”glucuronidated” through UGT1A1. That’s the way it gets cleared through the system. So if you lack, essentially, UGT1A1, homozygous lack of the gene, then you get much higher toxicities from irinotecan. DR LOVE: How often do you see it? DR BEKAII-SAAB: It’s uncommon. DR LOVE: Do you screen for it? DR BEKAII-SAAB: I do not screen for it, the same way I do not screen for it for irinotecan. I do not screen for it for nanoliposomal irinotecan. I think it has been postulated to be linked to the diarrhea and mucositis and others. The reality is, it’s actually mostly linked to neutropenia, which — DR LOVE: What fraction of patients have it? DR BEKAII-SAAB: It’s actually — homozygous? Less than 3%, probably. DR LOVE: And what’s the implication in terms of toxicity? Neutropenia? DR BEKAII-SAAB: Neutropenia, for the most. It actually hasn’t been strongly associated with diarrhea. Neutropenia is something that in actual practice you can check for a blood test. And if there is neutropenia, then you just adjust the dose. And, in fact, the original studies that looked at the value of testing for UGT1A1 with FOLFIRI suggests, essentially, that patients end up having transient neutropenia and, with dose adjustments, then patients will do fine. So I think it’s an unnecessary test. The only link, true link, between UGT1A1 and good prediction of toxicity with irinotecan is when you use the every 3-week regimen of irinotecan and you use a dose of 350 mg/m2, which is highly toxic. And that’s the only time I actually would check for UGT1A1, and I never actually use this regimen. But if I would, that’s the only time I would use it. And if a patient is homozygous, I knock down the dose by 25%. But with the biweekly regimen, there’s no evidence that it actually helps with much in terms of prediction. Just go with your clinical sense. DR BROOKS: On the same line, though, what about when you have a person who has or has suspected Gilbert syndrome and they have an elevated indirect bilirubin? How do you handle that? DR BEKAII-SAAB: Gilbert syndrome, because bilirubin gets “glucuronidated” as well, so the same mechanism of excreting bilirubin is the same mechanism you actually get rid of SN-38. And so Gilbert syndrome is essentially the poor man’s test for UGT1A1. And the same principle applies. If you’re going to use the biweekly regimen, you just be careful. Just check the labs at the weekly basis, just the first cycle. Make sure that the patient is “flying” okay, and they should be fine. I mean, you check the labs. You know what to do with them. But you’re not actually endangering patients, because you keep a close eye on them. And you don’t need to go through these expensive tests, frankly. |