Scheduling Chemotherapy: Catch 22 between Cell Kill and Resistance Evolution

Abstract

Dose response curves show that prolonged drug exposure at a low concentration may kill more cells than short exposures at higher drug concentrations, particularly for cell cycle phase specific drugs. Applying drugs at low concentrations for prolonged periods, however, allows cells with partial resistance to evolve higher levels of resistance through stepwise processes such as gene amplification. Models are developed for cell cycle specific (CS) and cell cycle nonspecific (CNS) drugs to identify the schedule of drug application that balances this tradeoff.The models predict that a CS drug may be applied most effectively by splitting the cumulative dose into many (>40) fractions applied by long-term chemotherapy, while CNS drugs may be better applied in fewer than 10 fractions applied over a shorter term. The model suggests that administering each fraction by continuous infusion may be more effective than giving the drug as a bolus, whether the drug is CS or CNS. In addition, tumors with a low growth fraction or slow rate of cell division are predicted to be controlled more easily with CNS drugs, while those with a high proliferative fraction or fast cell division rate may respond better to CS drugs.

Modeling Multi-drug Chemotherapy: Tailoring Treatment to Individuals

“…In most models, drug e!ects occur instantaneously, and all drugs applied in a given regimen are either CS (Hokanson et al, 1986;Birkhead et al, 1987;Gardner, 2000b) or nCS (Coldman & Goldie, 1987;Harnevo & Agur, 1991;Murray, 1995;Panetta, 1997;Gardner, 2000b), but do not consider combinations of drugs of di!erent kinetic types in the same regimen. Most models are limited to at most two drugs in any regimen.…”

The dynamics of drug resistance: A mathematical perspective

“…Most models consider tumors as composed of two groups, sensitive or resistant. But there are models in which partial resistance and its relationship to the concentration of the drug is being addressed (Gardner, 2000; Swierniak et al, 2009). …”

“…Several models predict that continuous infusion (in particular of cell cycle phase specific drugs) is more effective than short pulses (Gardner, 2002a; Gardner, 2000; Murray, 1990; Panetta, 1997; Shochat et al, 1999; Swan, 1990; Swan and Vincent, 1977). This is because continuous infusion prevents tumor re-growth between treatments, and exposes more cells to the drug when they are in the sensitive phase of the cell cycle.…”

Cell Cycle Phase-Specific CHemotherapy: Computation Methods for Guiding Treatment

“…34,42,45,[61][62][63][64] This occurs since continuous infusion: a. exposes more cells to the drug when they are in the sensitive phase of the cell cycle, thus overcoming kinetic resistance, and b. prevents tumor re-growth between bolus treatments.…”

“…Apply the drug too slowly by continuous infusion and drug resistance will evolve. Gardner 61 modeled this tradeoff, predicting that fewer, higher dose-rate, short-term infusions for cell cycle nonspecific drugs or many, lower dose-rate, long-term infusions for cell cycle specific drugs may result in the greatest chance of cure. The particular duration of infusion of a given drug in a given patient depends on the total dose used, the drug cell cycle phase specificity, and the patient's tumor cell kinetics (i.e., proliferative fraction and the vulnerable phase fraction such as S-phase fraction at the start of treatment).…”