Radiobiological end-points for the theoretical evaluation of the effectiveness of carbon ions and photons in treating tumours with dynamic hypoxia

Tumours are characterised by unorganised vasculature, which often results in hypoxic regions. Hypoxia is a common cause for photon radiotherapy (RT) treatment failure, as hypoxic cells require up to 2-3 times higher doses compared to well-oxygenated cells for the same effect in terms of cell kill. The increase in dose that would be required to treat the tumours of cancer patients is limited by the radiation sensitivity of surrounding normal tissues. Using carbon ions instead of photons, the radiation dose can be conformed to the tumour to a much higher degree, resulting in an improved sparing of normal tissues. In addition, carbon ions have a much higher radiobiological effectiveness near the end of their range, which is positioned in the tumour. Also, the radiation modes of action leading to cell death when carbon ions interact with living tissues, are less sensitive to the oxygen status compared with the action modes of photons. The focus of this thesis lies in the development of models for the computation of the cell surviving fraction and tumour control probability (TCP) in hypoxic tumours after photon and carbon ion RT. The impact of fractionation was evaluated with regard to possible spatial changes in oxygenation, both for stereotactic body RT and for carbon ion RT. The feasibility of a method to determine and deliver the optimal photon dose for achieving a high TCP according to spatial variations in radiation sensitivity was evaluated in a treatment planning study. The radiobiological models were finally used for the theoretical quantification of the gain in using carbon ions instead of photons. The results show that there are great possibilities to increase the number of positive outcomes of radiation treatment of tumours if the key influential factors are taken into account, such as level and distribution of hypoxia, radiation quality and choice of fractionation schedule.At the time of the doctoral defence the following papers were unpublished and had a status as follows; Paper 3: Manuscript; Paper 4: Epubl ahead of print; Paper 5: Manuscript</p

Evaluation of the lithium formate EPR dosimetry system for dose measurements around 192Ir brachytherapy sources

The dose distribution around brachytherapy (BT) sources is characterized by steep dose gradients and an energy spectrum varying rapidly with depth in water around the source. These two properties make experimental verification of the dose distribution difficult, and put high demands on the dosimetry system in use regarding precision, size and energy dependence. The American Association of Physicists in Medicine (AAPM) recommends lithium fluoride (LiF) thermo-luminescence dosimetry (TLD) to be used for verification measurements, as it is the only dosimetry system meeting the requirements, but still the total combined uncertainty in dose-rate determination is as high as 7-9 % (1 σ). Lithium formate is a new dosimetry material that is less energy dependent than LiF, but more sensitive than the most common EPR (electron paramagnetic resonance) dosimetry material, alanine. In order to evaluate lithium formate EPR for BT dosimetry, dosimeters were produced for experimental dose determination around BT source 192Ir. The dosimeters were calibrated against an ionization chamber in a high energy photon beam. Dose to water was determined at 1, 3 and 5 cm radial distance from the source, which was stepped along a straight line in a PMMA phantom. The experiments were performed twice using 4 dosimeters per distance and experiment. Methods to correct for energy dependence were developed and evaluated. The uncertainty in measured dose was estimated. The experimental dose values agreed with the values from the treatment planning system with a maximum deviation of 3.3 %, and an average 1 σ uncertainty of 3 % at 3 and 5 cm and 5 % at 1cm. Uncertainty in radial distance from the source as well as source calibration were the dominating contributions to the total combined uncertainty. Lithium formate EPR has been shown to be a promising alternative to LiF TLD for BT dosimetry

Evaluation of a lithium formate EPR dosimetry system for dose measurements around Ir-192 brachytherapy sources

A dosimetry system using lithium formate monohydrate (HCO2Li center dot H2O) as detector material and electron paramagnetic resonance (EPR) spectroscopy for readout has been used to measure absorbed dose distributions around clinical Ir-192 sources. Cylindrical tablets with diameter of 4.5 mm, height of 4.8 mm, and density of 1.26 g/cm(3) were manufactured. Homogeneity test and calibration of the dosimeters were performed in a 6 MV photon beam. Ir-192 irradiations were performed in a PMMA phantom using two different source models, the GammaMed Plus HDR and the microSelectron PDR-v1 model. Measured absorbed doses to water in the PMMA phantom were converted to the corresponding absorbed doses to water in water phantoms of dimensions used by the treatment planning systems (TPSs) using correction factors explicitly derived for this experiment. Experimentally determined absorbed doses agreed with the absorbed doses to water calculated by the TPS to within +/- 2.9%. Relative standard uncertainties in the experimentally determined absorbed doses were estimated to be within the range of 1.7%-1.3% depending on the radial distance from the source, the type of source (HDR or PDR), and the particular absorbed doses used. This work shows that a lithium formate dosimetry system is well suited for measurements of absorbed dose to water around clinical HDR and PDR Ir-192 sources. Being less energy dependent than the commonly used thermoluminescent lithium fluoride (LiF) dosimeters, lithium formate monohydrate dosimeters are well suited to measure absorbed doses in situations where the energy dependence cannot easily be accounted for such as in multiple-source irradiations to verify treatment plans. Their wide dynamic range and linear dose response over the dose interval of 0.2-1000 Gy make them suitable for measurements on sources of the strengths used in clinical applications. The dosimeter size needs, however, to be reduced for application to single-source dosimetry.Original Publication: Laura Antonovic, Håkan Gustafsson, Gudrun Alm Carlsson and Åsa Carlsson Tedgren, Evaluation of a lithium formate EPR dosimetry system for dose measurements around Ir-192 brachytherapy sources, 2009, MEDICAL PHYSICS, (36), 6, 2236-2247. http://dx.doi.org/10.1118/1.3110068 Copyright: American Institute of Physics http://www.aip.org/</p

Relative clinical effectiveness of carbon ion radiotherapy: theoretical modelling for H&N tumours

Comparison of the efficiency of photon and carbon ion radiotherapy (RT) administered with the same number of fractions might be of limited clinical interest, since a wide range of fractionation patterns are used clinically today. Due to advanced photon treatment techniques, hypofractionation is becoming increasingly accepted for prostate and lung tumours, whereas patients with head and neck tumours still benefit from hyperfractionated treatments. In general, the number of fractions is considerably lower in carbon ion RT. A clinically relevant comparison would be between fractionation schedules that are optimal within each treatment modality category. In this in silico study, the relative clinical effectiveness (RCE) of carbon ions was investigated for human salivary gland tumours, assuming various radiation sensitivities related to their oxygenation. The results indicate that, for hypoxic tumours in the absence of reoxygenation, the RCE (defined as the ratio of D50 for photons to carbon ions) ranges from 3.5 to 5.7, corresponding to carbon ion treatments given in 36 and 3 fractions, respectively, and 30 fractions for photons. Assuming that interfraction local oxygenation changes take place, results for RCE are lower than that for an oxic tumour if only a few fractions of carbon ions are used. If the carbon ion treatment is given in more than 12 frac- tions, the RCE is larger for the hypoxic than for the well-oxygenated tumour. In conclusion, this study showed that in silico modelling enables the study of a wide range of factors in the clinical considerations and could be an import- ant step towards individualisation of RT treatments

Treatment fractionation for stereotactic radiotherapy of lung tumours: a modelling study of the influence of chronic and acute hypoxia on tumour control probability

Background: Stereotactic body radiotherapy (SBRT) for non-small-cell lung cancer (NSCLC) has led to promising local control and overall survival for fractionation schemes with increasingly high fractional doses. A point has however been reached where the number of fractions used might be too low to allow efficient local inter-fraction reoxygenation of the hypoxic cells residing in the tumour. It was therefore the purpose of this study to investigate the impact of hypoxia and extreme hypofractionation on the tumour control probability (TCP) from SBRT. Methods: A three-dimensional model of tumour oxygenation able to simulate oxygenation changes on the microscale was used. The TCP was determined for clinically relevant SBRT fractionation schedules of 1, 3 and 5 fractions assuming either static tumour oxygenation or that the oxygenation changes locally between fractions due to fast reoxygenation of acute hypoxia without an overall reduction in chronic hypoxia. Results: For the schedules applying three or five fractions the doses required to achieve satisfying levels of TCP were considerably lower when local oxygenation changes were assumed compared to the case of static oxygenation; a decrease in D50 of 17.7 Gy was observed for a five-fractions schedule applied to a 20% hypoxic tumour when fast reoxygenation was modelled. Assuming local oxygenation changes, the total doses required for a tumor control probability of 50% were of similar size for one, three and five fractions. Conclusions: Although attractive from a practical point of view, extreme hypofractionation using just one single fraction may result in impaired local control of hypoxic tumours, as it eliminates the possibility for any kind of reoxygenation

Clinical oxygen enhancement ratio of tumors in carbon ion radiotherapy: the influence of local oxygenation changes

The effect of carbon ion radiotherapy on hypoxic tumors has recently been questioned because of low linear energy transfer (LET) values in the spread-out Bragg peak (SOBP). The aim of this study was to investigate the role of hypoxia and local oxygenation changes (LOCs) in fractionated carbon ion radiotherapy. Three-dimensional tumors with hypoxic subvolumes were simulated assuming interfraction LOCs. Different fractionations were applied using a clinically relevant treatment plan with a known LET distribution. The surviving fraction was calculated, taking oxygen tension, dose and LET into account, using the repairable–conditionally repairable (RCR) damage model with parameters for human salivary gland tumor cells. The clinical oxygen enhancement ratio (OER) was defined as the ratio of doses required for a tumor control probability of 50% for hypoxic and well-oxygenated tumors. The resulting OER was well above unity for all fractionations. For the hypoxic tumor, the tumor control probability was considerably higher if LOCs were assumed, rather than static oxygenation. The beneficial effect of LOCs increased with the number of fractions. However, for very low fraction doses, the improvement related to LOCs did not compensate for the increase in total dose required  for tumor control. In conclusion, our results suggest that hypoxia can influence the outcome of carbon ion radiotherapy because of the non-negligible oxygen effect at the low LETs in the SOBP. However, if LOCs occur, a relatively high level of tumor control probability is achievable with a large range of fractionation schedules for tumors with hypoxic subvolumes, but both hyperfractionation and hypofractionation should be pursued with caution

Η παραλία του Μυλοπόταμου Πηλίου

Η παραλία του Μυλοπόταμου Πηλίο

Treatment fractionation for stereotactic radiotherapy of lung tumours: a modelling study of the influence of chronic and acute hypoxia on tumour control probability

Background: Stereotactic body radiotherapy (SBRT) for non-small-cell lung cancer (NSCLC) has led to promising local control and overall survival for fractionation schemes with increasingly high fractional doses. A point has however been reached where the number of fractions used might be too low to allow efficient local inter-fraction reoxygenation of the hypoxic cells residing in the tumour. It was therefore the purpose of this study to investigate the impact of hypoxia and extreme hypofractionation on the tumour control probability (TCP) from SBRT. Methods: A three-dimensional model of tumour oxygenation able to simulate oxygenation changes on the microscale was used. The TCP was determined for clinically relevant SBRT fractionation schedules of 1, 3 and 5 fractions assuming either static tumour oxygenation or that the oxygenation changes locally between fractions due to fast reoxygenation of acute hypoxia without an overall reduction in chronic hypoxia. Results: For the schedules applying three or five fractions the doses required to achieve satisfying levels of TCP were considerably lower when local oxygenation changes were assumed compared to the case of static oxygenation; a decrease in D50 of 17.7 Gy was observed for a five-fractions schedule applied to a 20% hypoxic tumour when fast reoxygenation was modelled. Assuming local oxygenation changes, the total doses required for a tumor control probability of 50% were of similar size for one, three and five fractions. Conclusions: Although attractive from a practical point of view, extreme hypofractionation using just one single fraction may result in impaired local control of hypoxic tumours, as it eliminates the possibility for any kind of reoxygenation