Deterministic modelling of kinetics and radiobiology of radiation-cisplatin interaction in the treatment of head and neck cancers.

Abstract

One of the main objectives of combining radiation treatment and chemotherapy is to obtain a therapeutic gain by an improved tumour control with less or no enhancement of normal tissue toxicity. The optimal schedule for the combined treatment of cisplatin-radiation is still under investigation. Neither the optimal time interval, nor the most adequate sequence of administration of cisplatin and radiation are known. The results of the trials are also inconclusive. Some trials showed a supra-additive effect from the administration of cisplatin before radiotherapy, others, on contrary, from the injection of drug after radiotherapy. The present work encompasses the major challenges brought by the combined modality treatment: cisplatin-radiotherapy. The major goal of this work was to investigate the optimal treatment sequencing between cisplatin and radiotherapy and also the optimal schedule for head and neck carcinomas. Therefore, a computer-based tumour model with literature-given biological parameters has been developed which has allowed the simulation of treatment with radiation and chemotherapy. Radiotherapy has been simulated on the virtual tumour and the effects of radiotherapy on tumour regression and regrowth have been analyzed. Also, the mechanisms of cisplatin's action on tumour have been implemented, and the phenomena of drug resistance and tumour repopulation during chemotherapy studied. Finally, the combined modality treatment has been simulated, and the effect of drug-radiation interaction on tumour behaviour evaluated. The current investigation has shown that cisplatin administered immediately before radiation gives similar tumour control to the post-radiation sequencing of the drug. Furthermore, the killing effect of the combined modality treatment on tumour increases with the increase in cell recruitment. The individual cell kill produced by cisplatin and radiation leads to an additive-only tumour response when the treatments are given concurrently, and for a synergistic effect cisplatin must potentiate the effect of radiation. The final conclusion, by which cisplatin administered on a daily basis leads to a better tumour control than cisplatin administered weekly, is in accordance with the latest trial results on head and neck cancers. Therefore, treatment regimens that correlate better with the pharmacokinetics and the radiobiological properties of the therapeutic agents result in better outcomes.