Influence of cachexia on chemotherapy toxicity
Dr Michael Sawyer – University of Alberta, Canada
You’re at the NCRI meeting in Liverpool talking about cachexia.
That’s an interesting step for a clinical pharmacologist.
Well, what I’m here to talk about is the role of cachexia and low lean body mass in chemotherapy toxicity. This is work that we started at the University of Alberta and it relates to how chemotherapy drugs are dosed. Drugs have classically been dosed by body surface area or, in the case of the modern drugs, the tyrosine kinase inhibitors, we dose them as a standard dose. So what that means is a seventy year old grandmother would get the same dose of sorafenib for liver cancer that if Shaquille O’Neal, who plays for the NBA, who is 6’6”, and if he got liver cancer they would both get the same dose. What we have shown is that the toxicities related to chemotherapy relate to the amount of lean body mass that a person has.
And that’s a conventional measurement of lean body mass or is it a bit more sophisticated than some callipers?
It is much more sophisticated than callipers and height and weight. We use CT scans and we use the X-Ray density of the tissues to calculate out the lean body mass. So this is work based in normal patients…
What’s a normal patient?
In normal people without cancer. It was done at the University of Columbia and what they showed using MRIs and CAT scans was that the CT scan slice at the lumbar third vertebra correlated with the amount of lean body mass and fat in a human being. What my collaborator and colleague showed was that it was also true in cancer patients. Then together we have looked at 5FU, capecitabine, sorafenib, epirubicin and found that the toxicities of those chemotherapy drugs are related to the amount of lean body mass that a person has.
In which direction?
That the more drug per lean body mass, the more likely a person is to have toxicity. The drug that we first looked at was 5FU and 5FU is one of the oldest drugs in medical oncology.
It’s about my age actually, 67 years old.
Actually, yes, it’s about right. It was in the 1950s. What has been known in medical oncology for years and decades is that women are more likely to get toxicities than men and nobody has actually satisfactorily explained that. What we showed is we took the absolute amount of 5FU that each person received and divided it by the amount of lean soft tissue, lean body mass. What we then discovered is that by body surface area everybody got 425mg/m2; by lean body mass it varied almost twofold from 16 to 30. What we found is that women were much more likely to get a higher dose of 5FU per lean soft tissue than men. In fact, eleven out of ten women got…
Ten out of eleven.
I shouldn’t say… eleven women received 20mg/kg of 5FU, ten of the eleven women had dose limiting toxicity. In contrast only two men got that high and one developed dose limiting toxicity. That was in a study of about seventy patients.
Now the drugs you mentioned are a range from an anti-metabolite like 5FU to anthracycline to a kinase inhibitor. Is it OK across the board? All of them come up with this sort of picture?
They all seem to follow the same pattern and that was very interesting to us and very key. So once we did 5FU we actually had done a similar study, a pharmacogenetic study of capecitabine and we also had CAT scans of those patients. They were all women and what we found was broadly the same thing, that the women with breast cancer, with metastatic breast cancer, who were treated with capecitabine, the women with the lower lean body mass that got the same standard dose as the women with normal lean body mass had almost twice the toxicity that the women with normal lean body mass had.
I’m very tempted, of course, to ask whether you’ve got correlations with anti-tumour response or not? I guess it’s going to be too early.
Yes, it is too early for that although the interesting thing is we noted that the patients who were cachexic, who had low lean body mass were also less likely to respond to treatment. We did a larger article, larger study, that was published in Lancet Oncology where we looked at GI and lung cancer patients and found that there was about a ten month difference between the patients who didn’t have low lean body mass, which we call sarcopenia, and the patients who didn’t.
In favour of whom?
The patients who did not have the low lean body mass lived ten months longer than the patients who were sarcopenic.
I just want to get that completely clear for me, double negatives – did not have a low body mass. So people who have a low body mass do worse?
That’s the bottom line.
And they also have more toxicities.
Thank you very much indeed, that’s very enlightening. It’s taken fifty years to work that one out and congratulations.