Modeling multi-drug chemotherapy: tailoring treatment to individuals.
BACKGROUND
Predicting and tailoring optimal cancer treatments presents a major challenge.


METHODS
A computational model (kinetically tailored treatment, or KITT model) is developed to predict drug combinations, doses, and schedules likely to be effective in reducing tumor size and prolonging patient life. Treatment strategies may be tailored to individuals based on tumor cell kinetics. The model incorporates intra-tumor heterogeneity and evolution of drug resistance, apoptotic rates, and cell division rates. Tumor growth may follow an exponential or a Gompertzian trajectory. Drug pharmacodynamic and pharmacokinetic models are used. Toxicity is modeled in several ways.


RESULTS
A key prediction of KITT is that including cytostatic drugs like tamoxifen and herceptin during treatment with cytotoxic drugs substantially increases the probability of cure and prolongs patient life. Results also suggest that altering drug scheduling may be more effective but not more toxic than dose escalation. CAF chemotherapy (cyclophosphamide, adriamycin, and 5-fluorouracil) is predicted to be more effective than CMF (cyclophosphamide, methotrexate, and 5-fluorouracil). KITT also suggests that tumors with a high proliferative index (PI) may respond better to drug combinations incorporating two cell-cycle phase-specific drugs than do tumors with a low PI. Tumors with a low PI, in contrast, are predicted to respond better to regimens involving two cell-cycle phase-non-specific drugs than do tumors with a high PI. These predictions are borne out by clinical trial results published in the literature, which are discussed. Simulated predictions of the model match well with results from a clinical trial by Silvestrini et al. (2000. Int. J. Cancer 87, 405). The results of simulating the growth of 26896 tumors are used to construct a decision tree for prognosis to identify the key tumor and treatment variables.


CONCLUSIONS
Additional tests of the model are needed in which physicians collect information on apoptotic and proliferative indices, cell-cycle times, and drug resistance from biopsies of each individual's tumor. Computational models may become important tools to help optimize and tailor cancer treatments.
Gardner
Shea N
SN
Lawrence Livermore National Laboratory, Biology and Biotechnology Research Program, L-452, Livermore, CA 94551-0452, U.S.A. gardner26@llnl.gov
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019295:Computational Biology; D003198:Computer Simulation; D003658:Decision Making, Computer-Assisted; D004334:Drug Administration Schedule; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010347:Patient Care Planning