Inclusion of molecular biotherapies with radical radiotherapy: modeling of combined modality treatment schedules.
OBJECTIVE
The use of molecular biology based therapies concurrently with radical radiotherapy is likely to offer potential benefits, but there is relatively little use of classical radiobiology in the rationale for such applications. The biological mechanisms that govern the outcomes of radiotherapy need to be completely understood before rational application and optimization of such adjuvant biotherapies with radiotherapy.


METHODS
Existing biomathematical models of radiotherapy can be used to explore the possible impact of biotherapies that modify tumor proliferation rates and/or radiosensitivity parameters during radiotherapy. Equations that show how to incorporate biotherapies with the linear-quadratic model of radiation cell kill are presented. Also considered are changes in tumor physiology, such as improved blood flow with enhanced delivery of biotherapy to the tumor cells and accelerated clonogen repopulation during radiotherapy. Monte Carlo random sampling methods are used to simulate these effects in heterogenous tumor populations with variation in radiosensitivities, clonogen numbers, and doubling times, as well as variations in repopulation onset rates and in vascular perfusion rates with time.


RESULTS
The time onset and duration of exposure of each type of biotherapy during radical radiotherapy can influence the predicted tumor cure probabilities in subtle ways. In general, the efficacy of biotherapies that radiosensitize will depend upon the number of radiotherapy fractions that are sensitized and the change in blood flow with time during radiotherapy. Biotherapies that control repopulation will depend not only on the duration of exposure but also, where accelerated repopulation occurs, on the time at which biotherapy is initiated during radiotherapy. From the ranges of radiobiological parameters and biotherapy efficacies assumed for exploratory examples, large changes of tumor control probability (TCP) are encountered in individual tumors from the application of cytostatic therapy. There are predictions of smaller increments in TCP in heterogenous tumor populations from the application of cytostatic and radiosensitizing biotherapies in combination.


CONCLUSIONS
The exercises show how the scheduling of biotherapies may critically influence tumor cure probabilities in subtle ways and give considerable insight into the interacting biological mechanisms that influence these changes. Future therapeutic developments should be guided by these principles.
Jones
B
B
Department of Oncology, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, UK. bleddyn.jones@ic.ac.uk
Dale
R G
RG
D002455:Cell Division; D003131:Combined Modality Therapy / Q000379:methods; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D008954:Models, Biological; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D016012:Poisson Distribution; D011836:Radiation Tolerance