Title:

Modelling the effect of geometric uncertainties, clonogen distribution and IMRT interplay effect on tumour control probability

Geometric uncertainties are inevitable in radiotherapy. These uncertainties in tumour position are classified as systematic (Ε) and random (δ) errors. To account for these uncertainties, a margin is added to the clinical target volume (CTV) to create the planning target volume (PTV). The size of the PTV is critical for obtaining an optimal treatment plan. Dosebased (i.e., physical) margin recipes as a function of systematic and random errors based on coverage probability of a certain level of dose (90% or 95% of the prescription dose) have been published and widely used. However, with a TCPbased margin it is possible to consider fractionation and the radiobiological characteristics, especially the doseresponse slope (50) of the tumour. Studies have shown that the density of the clonogens decrease from the boundary of the gross tumour volume (GTV). In such a scenario, dose that is lower than in the GTV should be sufficient to eradicate these clonogens. Thus a smaller PTV margin with a gradual dose fall off can be used if the clonogen density in the GTVCTV region is found to be lower than in GTV. Studies have reported tiny tumour islets outside the CTV region. These tiny tumour islets can be eradicated in some cases by the incidental dose outside the PTV due to the nature of the photon beam irradiation, but if they are not in the beam path the treatment outcome is compromised. In this thesis, a Monte Carlo approach is used to simulate the effect of geometric uncertainties, number of fractions and doseresponse slope (gamma50) using the 'enhanced Marsden' TCP model on the treatment outcome. Systematic and random errors were drawn from a pseudorandom number generator. The dose variations caused by tumour displacements due to geometric uncertainties in the CTV are accumulated each fraction on a voxelbyvoxel basis. Required margins for ≤ 1% mean population TCP (TCPpop) for fourfield (4F) brick and a highly conformal spherical dose distribution for varying number of fractions, different γ50 and different combinations of Ε and δ are investigated. It is found that TCPbased margins are considerably smaller than dosebased recipes in most cases except for tumours with a steep doseresponse slope (high γ50) and a small number of fractions for both 4F and spherical dose distributions. For smaller geometric uncertainties (Ε = δ = 1 mm) margins can be close to zero for the 4F technique due to high incidental dose outside the PTV. It is evident from the analyses that margins depend on the number of fractions, γ50, the degree of dose conformality in addition to Ε and δ. Ideally margins should be anisotropic and individualized, taking into account γ50, number of fractions, and the dose distribution, as well as estimates of Ε and γ. No single 'recipe' can adequately account for all these variables. Using an exponential clonogen distribution in the GTVCTV region, possible PTV margin reduction is demonstrated. Moreover, the effect of extraCTV tumour islets is studied using a prostate IMRT plan. The islets were randomly distributed around the CTV with in a radius of 3 cm to represent different patients. The doses were rescaled up to 102 Gy to obtain the doseresponse curve (DRC). Interestingly, the obtained DRC showed a biphasic response where 100% TCP could not be achieved just by escalating the dose. Another potential problem encountered in intensitymodulated radiotherapy (IMRT) is the problems caused by the 'interplay' effect between the respirationinduced tumour motion and the multileaf collimator (MLC) leaves movement during treatment. Several dosimetric studies in the literature have shown that 'interplay' effects blur the dose distribution by producing 'hot' and 'cold' dose inside the tumour. Most of these studies were done in a phantom with ion chambers or films, which provide only 1D or 2D dose information. If 3D dose information is available, a TCP based analysis would provide a direct estimate of interplay on the clinical outcome. In this thesis, an inhouse developed dose model enabled us to calculate the 3D timeresolved dose contribution to each voxel in the target volume considering the change in segment shapes and position of the target volume. Using the model, delivered dose is accumulated in a voxelbyvoxel basis inclusive of tumour motion over the course of treatment. The effect of interplay on dose and TCP is studied for conventionally and hypofractionated treatments using DICOM datasets. Moreover, the effect of dose rate on interplay is also studied for singlefraction treatments. Simulations were repeated several times to obtain mean population TCP (TCPpop) for each plan. The average variation observed in mean dose to the target volumes were 0.76 ± 0.36% for the 20 fraction treatment and 0.26 ± 0.68%, 1.05 ± 0.98% for the 3 and singlefraction treatments respectively. For the 20fraction treatment, the drop in TCPpop was 1.05 ± 0.39%, whereas for the 3 and single fraction treatments it was 2.8 ± 1.68% and 4.0 ± 2.84% respectively. By reducing the dose rate from 600 to 300 MU/min for the singlefraction treatments, the drop in TCPpop was reduced by ~ 1:5%. In summary, the effect of interplay on treatment outcome is negligible for conventionally fractionated treatments, whereas a considerable drop in TCP is observed for the 3 and singlefraction treatments. Where no motion management techniques such as tracking or gating are available for hypofractionated treatments, reduced dose rate could be used to reduce the interplay effect.
