Dose-limiting toxicity is the toxicity that appears first as dose rises and prevents further escalation. The maximum tolerated dose is the highest dose that keeps that toxicity at an acceptable grade. Because the tumor and the vulnerable normal tissue share the same damage-and-death pathway, the normal-tissue threshold is often reached at a dose the tumor could survive. The therapeutic index is therefore capped by the normal-tissue threshold, not by tumor sensitivity.
Strategies that raise the tolerated dose
- Granulocyte colony-stimulating factor shortens neutropenia and allows the next cycle to be delivered on schedule.
- Leucovorin bypasses the methotrexate block in normal cells, reducing mucosal and marrow toxicity.
- Amifostine scavenges reactive oxygen species in normal tissue, reducing radiation and some chemotherapy toxicity.
- Dexrazoxane chelates iron and reduces anthracycline cardiotoxicity.
Rescue and supportive care do not make the tumor more sensitive. They raise the dose ceiling from the normal-tissue side, which is the only way to widen the window when the tumor and the normal tissue share the same molecular target.