Optimal radiotherapy for prostate cancer: predictions for conventional external beam, IMRT, and brachytherapy from radiobiologic models.

PURPOSE: To determine, on the basis of radiobiological models, optimal modalities of radiotherapy for localized prostate cancer, and to provide a rational basis for therapeutic decisions. METHODS AND MATERIALS: An algorithm based on extensions to the linear-quadratic (LQ) cell survival model is constructed for fractionated and protracted irradiation. These radiobiological models include prostate tumor cell line-derived LQ parameters, clonogen repopulation, repair of sublethal damage, hypoxia, and radioisotope decay. In addition, dose inhomogeneities for both IMRT and brachytherapy (125I and 103Pd) from patient-derived Dose Volume Histograms (DVH), as well as dose escalation, are incorporated. Three risk groups are defined in terms of sets of biologic parameters tailored to correspond to clinical risk groups as follows: Favorable-iPSA <10 and bGS < or =6 and stage T2; Intermediate-one parameter increased; and Unfavorable-two or more parameters increased. Tumor control probabilities (TCP) are predicted for conventional external beam radiotherapy (EBRT, including 3D-CRT), intensity modulated radiotherapy (IMRT), and permanent brachytherapy.
RESULTS: Brachytherapy is less susceptible to variations in alpha/beta than EBRT and more susceptible to variations in clonogen potential doubling time (Tp). Our models predict TCP consistent with the bNED results from recent dose escalation trials and long-term outcomes from brachytherapy. TCP from IMRT are systematically superior to those from conventional fractionated RT, and suggests its possible use in dose escalation without additional dose to surrounding normal tissues. For potentially rapidly dividing tumors (Tp < 30 days) 103Pd yields superior cell kill compared with 125I, but for very slowly proliferating tumors the converse is suggested. Brachytherapy predicts equivalent or superior TCP to dose escalated EBRT. For unfavorable risk tumors, combined 45 Gy EBRT+brachytherapy boost predicts superior TCP than with either modality alone.
CONCLUSIONS: The radiobiological models presented suggest a rational basis for choosing among several radiotherapeutic modalities based on biologic risk factors. In addition, they suggest that IMRT may potentially be superior to 3D-CRT in allowing dose escalation without increased morbidity, and that brachytherapy, as monotherapy or as boost, may achieve superior tumor control compared with dose escalation 3D-CRT. The latter conclusion is supported by clinical data.