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Optimization of Dose Schedules for Chemotherapy of Early Colon Cancer Determined by High-Performance Computer Simulations.

ABSTRACT: Cancer chemotherapy dose schedules are conventionally applied intermittently, with dose duration of the order of hours, intervals between doses of days or weeks, and cycles repeated for weeks. The large number of possible combinations of values of duration, interval, and lethality has been an impediment to empirically determine the optimal set of treatment conditions. The purpose of this project was to determine the set of parameters for duration, interval, and lethality that would be most effective for treating early colon cancer. An agent-based computer model that simulated cell proliferation kinetics in normal human colon crypts was calibrated with measurements of human biopsy specimens. Mutant cells were simulated as proliferating and forming an adenoma, or dying if treated with cytotoxic chemotherapy. Using a high-performance computer, a total of 28?800 different parameter sets of duration, interval, and lethality were simulated. The effect of each parameter set on the stability of colon crypts, the time to cure a crypt of mutant cells, and the accumulated dose was determined. Of the 28?800 parameter sets, 434 parameter sets were effective in curing the crypts of mutant cells before they could form an adenoma and allowed the crypt normal cell dynamics to recover to pretreatment levels. A group of 14 similar parameter sets produced a minimal time to cure mutant cells. A different group of nine similar parameter sets produced the least accumulated dose. These parameter sets may be considered as candidate dose schedules to guide clinical trials for early colon cancer.

SUBMITTER: Cockrell C

PROVIDER: S-EPMC6330731 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Optimization of Dose Schedules for Chemotherapy of Early Colon Cancer Determined by High-Performance Computer Simulations.

Cockrell Chase C Axelrod David E DE

Cancer informatics 20190110

Cancer chemotherapy dose schedules are conventionally applied intermittently, with dose duration of the order of hours, intervals between doses of days or weeks, and cycles repeated for weeks. The large number of possible combinations of values of duration, interval, and lethality has been an impediment to empirically determine the optimal set of treatment conditions. The purpose of this project was to determine the set of parameters for duration, interval, and lethality that would be most effec ...[more]

PMID: 30675100

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Project description:BackgroundThe benefit of chemotherapy in colon cancer patients is well documented but depends largely on whether patients complete the planned treatment regimen. We evaluated predictors of early discontinuation (EDChemo) and dose reduction of chemotherapy, especially the role of adverse treatment effects, in stage III patients who received adjuvant chemotherapy.MethodsStage III colon cancer patients who were diagnosed in 2003-2014 and recruited into a population-based study in Germany and received FOLFOX [5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin], capecitabine monotherapy (CapMono), or 5-FU/LV were included. We assessed determinants of EDChemo and dose reduction using multivariable logistic regression. Also, we estimated proportions of EDChemo and dose reduction that are attributable to adverse effects using attributable fractions.ResultsEDChemo and dose reduction rates were 52% and 17% for FOLFOX, 28% and 9% for CapMono, and 45% and 6% for 5-FU/LV, respectively. Predictors of EDChemo were low-grade tumor and treatment in a medium-volume hospital (for FOLFOX), obesity (for CapMono), and increasing age, T4 stage, and treatment in a medium-volume hospital (for 5-FU/LV). Adverse effects were particularly strongly associated with EDChemo and contributed to about 63%, 51%, and 32% of EDChemo of FOLFOX, CapMono, and 5-FU/LV, respectively. Of the various adverse effects, gastrointestinal events showed the strongest associations with EDChemo and accounted for about 7%, 26%, and 20% of EDChemo of FOLFOX, CapMono, and 5-FU/LV, respectively. Adverse effects were, moreover, a strong determinant of dose reduction and accounted for about 82% of all cases.ConclusionsEDChemo is common in stage III colon cancer patients receiving chemotherapy and more than half of the cases of EDChemo and dose reduction are due to adverse treatment effects. Further research should address the potential for reducing EDChemo and dose reduction rates by close monitoring of patients for early signs and enhanced management of adverse effects, especially gastrointestinal events.

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Optimization of Dose Schedules for Chemotherapy of Early Colon Cancer Determined by High-Performance Computer Simulations.

Publications

Optimization of Dose Schedules for Chemotherapy of Early Colon Cancer Determined by High-Performance Computer Simulations.

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