Dosage strategies for delaying resistance emergence in heterogeneous tumors

[Hazelgreen]

This difficult to read 2021 paper (febs.onlinelibrary.wiley.co... makes a very important observation. Based on mathematical modelling, it suggests that one reason why all cancer treatments ultimately fail may be due to the tendency for oncologists to treat cancer with the maximum tolerated dosages (MTDs) of cancer medications.

Based on earlier papers written by the authors and others, this paper suggests that all tumours contain two main types of cells: sensitive cells and resistant cells. MTDs of cancer medications may quickly kill more of the sensitive cells with the result that the proportion of resistant cells increases and ultimately results in the cancer medication ceasing to be effective.

I was interested in this paper as I am currently taking ribociclib on a 5 days on & 2 days off schedule. My oncologist thought it was possible that this schedule might contribute to early resistance, compared to the MTD schedule of 3 weeks on, 1 week off. According to the authors of this paper, this is unlikely to be the case. I am now wondering what the best schedule would be.

[Ursula_I]

Gosh. Thank you for this.

Lucy

[Dragonfly2]

YES! YES!YES! I’m a huge proponent of the 5/2 schedule (for IBrance) and am convinced that this is the way Oncs should consider prescribing it. Other trials have shown that it’s effective to prevent neutropenia, the source of debilitating fatigue but also, it keeps a moderate amount of drugs in the body with one all important short breaks. Thank you for posting.🙏

[TammyCross]

Interesting. Also argues in favor of starting with the lowest dose instead of maximum tolerated, and going up if necessary.

But 3 weeks on, 1 week off is 21 days on and 7 days off. The schedule you chose is basically 20 days on, 8 days off in a month. From that perspective, it doesn't seem that different. The frequency of days off must matter more than the number of days off in a month, right?

[Hazelgreen in reply to TammyCross]

It is hard to do the math for the breakdown of the CDK4/6 inhibitors in the body, but I think what happens is that the maximum CDK4/6 in the body is less on the 5 & 2 days schedule, but it also never goes to zero as it does on the 3 & 1 week schedule.