Varying Cancer Drug Doses to Balance Tumor Control and Resistance Evolution

The effectiveness of any cancer therapy depends on its dose and its treatment schedule. A potential third dimension of regimen design is whether intentional fluctuations in administered dose might improve treatment outcomes. In this issue, West and colleagues demonstrate that dose fluctuations can alter both tumor drug response and the evolution of drug resistance, in ways related to the shapes of dose-response functions. In mouse xenograft models of ALK-fusion non-small cell lung cancer treated with the ALK inhibitor alectinib, steady dosing produced the best immediate tumor response, but fluctuations in dose were better at delaying the evolution of drug resistance. Treatment schedules that switched between even and uneven dosing navigated this tradeoff, achieving comparable tumor control with steady dosing while better preserving drug sensitivity. By showing how dose-response measurements can guide when doses should remain steady or fluctuate, this work expands how cancer treatment schedules might be optimized. See related article by West et al., p. 4434.