Thread by @VincentRK

More is not always better in cancer. Maximum tolerated dose doesn't make sense for many new treatments.

In a lot of the consults I do for second opinions, I'm not changing the recommended regimen. My advice centers on the appropriate dose.

Dosing in initial cancer trials are based on Western populations, and in patients with good performance status and organ function.

Extrapolating them to other settings can lead to severe toxicity.

Even in the tested population, Pharma companies worried about missing out on efficacy tend to push the dose up as high as possible. For some of these drugs studies subsequently show that a lower dose/schedule can be safer and more effective.

Sometimes you don't know you are causing harm with high doses until your run a trial testing high versus low dose. That's how we found that we were losing almost 10% of myeloma patients in the first of therapy to high doses of steroids. @TheLancetOncol

Sometimes we find out the hard way that we were giving too much drug & causing toxicity: when toxicity causes us to lower the dose midway through trials. That's how we found that bortezomib causes 3-4 times more severe neuropathy when given twice a week compared to once a week.

Sometimes doctors find out by trial and error that doses recommended in the West are too high for their populations. Eg. Lenalidomide dose in Asian countries.

Sometimes a trial unexpectedly shows that you get almost all the benefit in the first few months with a drug, and giving it month after month for many years may provide no real benefit and may be unnecessary. Eg., Daratumumab in the CASSIOPEIA trial.

Sometimes you think combining two effective drugs increases efficacy, only to find later that it may cause harm. As we saw recently with melflufen and pomalidomide.