“MTD” is misleading

Dose-finding trials of chemotherapy agents look for the MTD: maximum tolerated dose. The idea is to give patients as much chemotherapy as they can tolerate, hoping to do maximum damage to tumors without doing too much damage to patients.

But "maximum tolerated dose" implies a degree of personalization that rarely exists in clinical trials. Phase I chemotherapy trials don't try to find the maximum dose that any particular patient can tolerate. They try to find a dose that is toxic to a certain percentage of the trial participants, say 30%. (This rate may seem high, but it's typical. It's not far from the toxicity rate implicit in the so-called 3+3 rule or from the explicit rate given in many CRM ("continual reassessment method") designs.)

It's tempting to think of "30% toxicity rate" as meaning that each patient experiences a 30% toxic reaction. But that's not what it means. It means that each patient has a 30% chance of a toxicity, however toxicity is defined in a particular trial. If toxicity were defined as kidney failure, for example, then 30% toxicity rate means that each patient has a 30% probability of kidney failure, not that they should expect a 30% reduction in kidney function.

Related posts:

• Stopping trials of ineffective drugs earlier
• Probability of long runs
• Personalized medicine
• Dose-finding: why start at the lowest dose?
• How to pick simulation scenarios