Evaluation of current clinical target volume definitions for glioblastoma using cell-based dosimetry stochastic methods

Determination of an optimal clinical target volume (CTV) is complex and remains uncertain. The aim of this study was to develop a glioblastoma multiforme (GBM) model to be used for evaluation of current CTV practices for external radiotherapy.The GBM model was structured as follows: (1) a Geant4 cellular model was developed to calculate the absorbed dose in individual cells represented by cubic voxels of 20 μm sides. The system was irradiated with opposing 6 MV X-ray beams. The beams encompassed planning target volumes corresponding to 2.0- and 2.5-cm CTV margins; (2) microscopic extension probability (MEP) models were developed using MATLAB(®) 2012a (MathWorks(®), Natick, MA), based on clinical studies reporting on GBM clonogenic spread; (3) the cellular dose distribution was convolved with the MEP models to evaluate cellular survival fractions (SFs) for both CTV margins.A CTV margin of 2.5 cm, compared to a 2.0-cm CTV margin, resulted in a reduced total SF from 12.9% ± 0.9% to 3.6% ± 0.2%, 5.5% ± 0.4% to 1.2% ± 0.1% and 11.1% ± 0.7% to 3.0% ± 0.2% for circular, elliptical and irregular MEP distributions, respectively.A Monte Carlo model was developed to quantitatively evaluate the impact of GBM CTV margins on total and penumbral SF. The results suggest that the reduction in total SF ranges from 3.5 to 5, when the CTV is extended by 0.5 cm.The model provides a quantitative tool for evaluation of different CTV margins in terms of cell kill efficacy. Cellular platform of the tool allows future incorporation of cellular properties of GBM.L. Moghaddasi, E. Bezak and W. Harriss-Phillip

Hypoxia in head and neck cancer in theory and practice: a PET-based imaging approach

Hypoxia plays an important role in tumour recurrence among head and neck cancer patients. The identification and quantification of hypoxic regions are therefore an essential aspect of disease management. Several predictive assays for tumour oxygenation status have been developed in the past with varying degrees of success. To date, functional imaging techniques employing positron emission tomography (PET) have been shown to be an important tool for both pretreatment assessment and tumour response evaluation during therapy. Hypoxia-specific PET markers have been implemented in several clinics to quantify hypoxic tumour subvolumes for dose painting and personalized treatment planning and delivery. Several new radiotracers are under investigation. PET-derived functional parameters and tracer pharmacokinetics serve as valuable input data for computational models aiming at simulating or interpreting PET acquired data, for the purposes of input into treatment planning or radio/chemotherapy response prediction programs. The present paper aims to cover the current status of hypoxia imaging in head and neck cancer together with the justification for the need and the role of computer models based on PET parameters in understanding patient-specific tumour behaviour.Loredana G. Marcu, Wendy M. Harriss-Phillips and Sanda M. Fili

Calculation of the positron distribution from (15)O nuclei formed in nuclear reactions in human tissue during proton therapy

Copyright © Institute of Physics and IOP Publishing Limited 2008.To measure and verify the dose distribution within a patient during proton therapy, indirect methods must be used. One such method is to use positron emission tomography (PET), which takes advantage of the nuclear reactions that take place between protons and nuclei in the tissue. The dominant nuclear reaction in human muscle tissue involves oxygen nuclei and produces radioactive oxygen-15. Oxygen-15 decays through positron emission, and it is these positrons that go on to annihilate that produce the signal used in the PET technique. Finding the distribution of annihilation points, however, is not analogous to finding the proton dose distribution. The oxygen-15 and positrons travel finite distances within the tissue, blurring the detected PET distribution from the desired proton distribution. Through Monte Carlo modelling, an analysis of the differences between the positron, oxygen-15 and proton distributions has been made. The program SRIM 2003 was used to find the correlation between the three distributions within simulated muscle tissue. Results show that the distal edge of the proton Bragg peak correlates with the detectable positron distribution, which is a section of the dose distribution of interest due to the steep dose gradient and position of adjacent critical structures.W Tuckwell and E Beza

Monte Carlo radiotherapy simulations of accelerated repopulation and reoxygenation for hypoxic head and neck cancer

Published Online: January 28, 2014Objective: A temporal Monte Carlo tumour growth and radiotherapy effect model (HYP-RT) simulating hypoxia in head and neck cancer has been developed and used to analyse parameters influencing cell kill during conventionally fractionated radiotherapy. The model was designed to simulate individual cell division up to 108 cells, while incorporating radiobiological effects, including accelerated repopulation and reoxygenation during treatment. Method: Reoxygenation of hypoxic tumours has been modelled using randomised increments of oxygen to tumour cells after each treatment fraction. The process of accelerated repopulation has been modelled by increasing the symmetrical stem cell division probability. Both phenomena were onset immediately or after a number of weeks of simulated treatment. Results: The extra dose required to control (total cell kill) hypoxic vs oxic tumours was 15–25% (8–20 Gy for 5×2 Gy per week) depending on the timing of accelerated repopulation onset. Reoxygenation of hypoxic tumours resulted in resensitisation and reduction in total dose required by approximately 10%, depending on the time of onset. When modelled simultaneously, accelerated repopulation and reoxygenation affected cell kill in hypoxic tumours in a similar manner to when the phenomena were modelled individually; however, the degree was altered, with non-additive results. Simulation results were in good agreement with standard linear quadratic theory; however, differed for more complex comparisons where hypoxia, reoxygenation as well as accelerated repopulation effects were considered. Conclusion: Simulations have quantitatively confirmed the need for patient individualisation in radiotherapy for hypoxic head and neck tumours, and have shown the benefits of modelling complex and dynamic processes using Monte Carlo methods.W M Harriss-Phillips, E Bezak, and E K Yeo

The HYP-RT Hypoxic Tumour Radiotherapy Algorithm and Accelerated Repopulation Dose per Fraction Study

The HYP-RT model simulates hypoxic tumour growth for head and neck cancer as well as radiotherapy and the effects of accelerated repopulation and reoxygenation. This report outlines algorithm design, parameterisation and the impact of accelerated repopulation on the increase in dose/fraction needed to control the extra cell propagation during accelerated repopulation. Cell kill probabilities are based on Linear Quadratic theory, with oxygenation levels and proliferative capacity influencing cell death. Hypoxia is modelled through oxygen level allocation based on pO2 histograms. Accelerated repopulation is modelled by increasing the stem cell symmetrical division probability, while the process of reoxygenation utilises randomised pO2 increments to the cell population after each treatment fraction. Propagation of 108 tumour cells requires 5–30 minutes. Controlling the extra cell growth induced by accelerated repopulation requires a dose/fraction increase of 0.5–1.0 Gy, in agreement with published reports. The average reoxygenation pO2 increment of 3 mmHg per fraction results in full tumour reoxygenation after shrinkage to approximately 1 mm. HYP-RT is a computationally efficient model simulating tumour growth and radiotherapy, incorporating accelerated repopulation and reoxygenation. It may be used to explore cell kill outcomes during radiotherapy while varying key radiobiological and tumour specific parameters, such as the degree of hypoxia

Measurement of reoxygenation during fractionated radiotherapy in head and neck squamous cell carcinoma xenografts

Hypoxic tissues lack adequate oxygenation and it has been long established that tumours commonly exhibit hypoxia and that hypoxia is a factor contributing towards resistance to radiotherapy. To develop computer models and make predictions about the affects of tumour hypoxia on treatment outcome, quantitative tumour oxygenation and reoxygenation data from in vivo systems is required. The aim of this study was to investigate the timing and degree of reoxygenation during radiotherapy in a human head and neck squamous cell carcinoma xenograft mouse model (FaDu). Mice were immobilised using a novel restraining system and exposed unanaesthetised in 3 or 5 Gy fractions, up to a maximum of 40 Gy. Partial pressures of oxygen (pO2) measurements were recorded at six time points throughout the 2 week course of radiotherapy, using a fibre optic system. Tumours receiving 0-30 Gy did not exhibit an increase in pO2. However, the mean pO2 after 2 weeks of accelerated fractionated radiotherapy (40 Gy) was significantly increased (P<0.01) compared to the mean pO2 of tumours not receiving the full schedule (0-30 Gy). These results lead to the conclusion of an average reoxygenation onset time of 2 weeks in this group of xenografts. A relatively large range of pO2 values measured at each dose point in the study indicate a large inter-tumour variation in oxygenation among the tumours. Data from this experimental work will be used to define the range of reoxygenation onset times implemented in a Monte Carlo computer model, simulating hypoxic head and neck cancer growth and radiotherapy.Wendy Harriss, E. Bezak, E. Yeoh and M. Herman

Altered fractionation outcomes for hypoxic head and neck cancer using the HYP-RT Monte Carlo model

Objective: Altered fractionation radiotherapy is simulated on a set of virtual tumours to assess the total doses required for tumour control compared with clinical head and neck data and the doses required to control hypoxic vs well-oxygenated tumours with different radiobiological properties. Methods: The HYP-RT model is utilised to explore the impact of tumour oxygenation and the onset times of accelerated repopulation (AR) and reoxygenation (ROx) during radiotherapy. A biological effective dose analysis is used to rank the schedules based on their relative normal tissue toxicities. Results: Altering the onset times of AR and ROx has a large impact on the doses required to achieve tumour control. Immediate onset of ROx and 2-week onset time of AR produce results closely predicting average human outcomes in terms of the total prescription doses in clinical trials. Modifying oxygen enhancement ratio curves based on dose/fraction significantly reduces the dose (5–10 Gy) required for tumour control for hyperfractionated schedules. HYP-RT predicts 10×1.1 Gy per week to be most beneficial, whereas the conventional schedule is predicted as beneficial for early toxicity but has average–poor late toxicity. Conclusion: HYP-RT predicts that altered radiotherapy schedules increase the therapeutic ratio and may be used to make predictions about the prescription doses required to achieve tumour control for tumours with different oxygenation levels and treatment responses. Advances in knowledge: Oxic and hypoxic tumours have large differences in total radiation dose requirements, affected by AR and ROx onset times by up to 15–25 Gy for the same fractionation schedule.W M Harriss-Phillips, E Bezak, and E K Yeo