Alan E. Nahum

Background: Mechanistic TCP (tumor control probability) models exist that account for possible re-sensitization of an initially hypoxic tumor during treatment. This phenomenon potentially explains the better outcome of a 28-day vs 14-day treatment schedule of HDR (high dose rate) brachytherapy of low- to intermediate-risk prostate cancer as recently reported. Methods: A TCP model accounting for tumor re-sensitization developed earlier is used to analyze the reported clinical data. In order to analyze clinical data using individual TCP model, TCP distributions are constructed assuming inter-individual spread in radio-sensitivity. Results: Population radio-sensitivity parameter values are found that result in TCP population values which are close to the reported ones. Using the estimated population parameters, two hypothetical regimens are investigated that are shorter than the ones used clinically. The impact of the re-sensitization rate on the calculated treatment outcome is also investigated as is the anti-hypothesis that there is no re-sensitization during treatment. Conclusions: The carried out investigation shows that the observed clinical data cannot be described without assuming an initially hypoxic state of the tumor followed by re-oxygenation and, hence, re-sensitization. This phenomenon explains the better outcome of the prolonged treatment schedule compared to shorter regimens based on the fact that prostate cancer is a slowly repopulating tumor.

A new transcranial focused ultrasound device has been developed that can induce hyperthermia in a large tissue volume. The purpose of this work is to investigate theoretically how glioblastoma multiforme (GBM) can be effectively treated by combining the fast hyperthermia generated by this focused ultrasound device with external beam radiotherapy. To investigate the effect of tumor growth, we have developed a mathematical description of GBM proliferation and diffusion in the context of reaction–diffusion theory. In addition, we have formulated equations describing the impact of radiotherapy and heat on GBM in the reaction–diffusion equation, including tumor regrowth by stem cells. This formulation has been used to predict the effectiveness of the combination treatment for a realistic focused ultrasound heating scenario. Our results show that patient survival could be significantly improved by this combined treatment modality. High priority should be given to experiments to validate the therapeutic benefit predicted by our model.

The impact of microscopic disease extension (MDE), extra-CTV tumour islets (TIs), incidental dose and dose conformity on tumour control probability (TCP) is analyzed using insilico simulations in this study. MDE in the region in between GTV and CTV is simulated inclusive of geometric uncertainties (GE) using spherical targets and spherical dose distribution. To study the effect of incidental dose on TIs and the effect of dose–response curve (DRC) on tumour control, islets were randomly distributed and TCP was calculated for various dose levels by rescaling the dose. Further, the impact of dose conformity on required PTV margins is also studied. The required PTV margins are ~2 mm lesser than assuming a uniform clonogen density if an exponential clonogen density fall off in the GTV–CTV is assumed. However, margins are almost equal if GE is higher in both cases. This shows that GE has a profound impact on margins. The effect of TIs showed a bi-phasic relation with increasing dose, indicating that patients with islets not in the beam paths do not benefit from dose escalation. Increasing dose conformity is also found to have considerable effect on TCP loss especially for larger GE. Further, smaller margins in IGRT should be used with caution where uncertainty in CTV definition is of concern.

Cavity theory is fundamental to understanding and predicting dosimeter response. Conventional cavity theories have been shown to be consistent with one another by deriving the electron (+positron) and photon fluence spectra with the FLURZnrc user-code (EGSnrc Monte-Carlo system) in large volumes under quasi-CPE for photon beams of 1 MeV and 10 MeV in three materials (water, aluminium and copper) and then using these fluence spectra to evaluate and then inter-compare the Bragg–Gray, Spencer–Attix and 'large photon' 'cavity integrals'. The behaviour of the 'Spencer–Attix dose' (aka restricted cema), D _S-A(▵), in a 1-MeV photon field in water has been investigated for a wide range of values of the cavity-size parameter ▵: D _S-A(▵) decreases far below the Monte-Carlo dose (D _MC) for ▵ greater than ≈ 30 keV due to secondary electrons with starting energies below ▵ not being 'counted'. We show that for a quasi-scatter-free geometry (D _S-A(▵)/D _MC) is closely equal to the proportion of energy transferred to Compton electrons with initial (kinetic) energies above ▵, derived from the Klein–Nishina (K–N) differential cross section. (D _S-A(▵)/D _MC) can be used to estimate the maximum size of a detector behaving as a Bragg–Gray cavity in a photon-irradiated medium as a function of photon-beam quality (under quasi CPE) e.g. a typical air-filled ion chamber is 'Bragg–Gray' at (monoenergetic) beam energies ≥260 keV. Finally, by varying the density of a silicon cavity (of 2.26 mm diameter and 2.0 mm thickness) in water, the response of different cavity 'sizes' was simulated; the Monte-Carlo-derived ratio D _w/D _Si for 6 MV and 15 MV photons varied from very close to the Spencer–Attix value at 'gas' densities, agreed well with Burlin cavity theory as ρ increased, and approached large photon behaviour for ρ ≈ 10 g cm⁻³. The estimate of ▵ for the Si cavity was improved by incorporating a Monte-Carlo-derived correction for electron 'detours'. Excellent agreement was obtained between the Burlin 'd' factor for the Si cavity and D _S-A(▵)/D _MC at different (detour-corrected) ▵, thereby suggesting a further application for the D _S-A(▵)/D _MC ratio.