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  • 1. Bolsi, Alessandra
    et al.
    Peroni, Marta
    Amelio, Dante
    Dasu, Alexandru
    Stock, Markus
    Toma-Dasu, Iuliana
    Witt Nyström, Petra
    Hoffmann, Aswin
    Practice patterns of image guided particle therapy in Europe: A 2016 survey of the European Particle Therapy Network (EPTN)2018In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 128, no 1, p. 4-8Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Image guidance is critical in achieving accurate and precise radiation delivery in particle therapy, even more than in photon therapy. However, equipment, quality assurance procedures and clinical workflows for image-guided particle therapy (IGPT) may vary substantially between centres due to a lack of standardization. A survey was conducted to evaluate the current practice of IGPT in European particle therapy centres.

    MATERIAL AND METHODS: In 2016, a questionnaire was distributed among 19 particle therapy centres in 12 European countries. The questionnaire consisted of 30 open and 37 closed questions related to image guidance in the general clinical workflow, for moving targets, current research activities and future perspectives of IGPT.

    RESULTS: All centres completed the questionnaire. The IGPT methods used by the 10 treating centres varied substantially. The 9 non-treating centres were in the process to introduce IGPT. Most centres have developed their own IGPT strategies, being tightly connected to their specific technical implementation and dose delivery methods.

    CONCLUSIONS: Insight into the current clinical practice of IGPT in European particle therapy centres was obtained. A variety in IGPT practices and procedures was confirmed, which underlines the need for harmonisation of practice parameters and consensus guidelines.

  • 2. Dasu, Alexandru
    et al.
    Toma-Dasu, Iuliana
    Models for the risk of secondary cancers from radiation therapy2017In: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 42, p. 232-238Article in journal (Refereed)
    Abstract [en]

    The interest in the induction of secondary tumours following radiotherapy has greatly increased as developments in detecting and treating the primary tumours have improved the life expectancy of cancer patients. However, most of the knowledge on the current levels of risk comes from patients treated many decades ago. As developments of irradiation techniques take place at a much faster pace than the progression of the carcinogenesis process, the earlier results could not be easily extrapolated to modern treatments. Indeed, the patterns of irradiation from historically-used orthovoltage radiotherapy and from contemporary techniques like conformal radiotherapy with megavoltage radiation, intensity modulated radiation therapy with photons or with particles are quite different. Furthermore, the increased interest in individualised treatment options raises the question of evaluating and ranking the different treatment plan options from the point of view of the risk for cancer induction, in parallel with the quantification of other long-term effects. It is therefore inevitable that models for risk assessment will have to be used to complement the knowledge from epidemiological studies and to make predictions for newer forms of treatment for which clinical evidence is not yet available. This work reviews the mathematical models that could be used to predict the risk of secondary cancers from radiotherapy-relevant dose levels, as well as the approaches and factors that have to be taken into account when including these models in the clinical evaluation process. These include the effects of heterogeneous irradiation, secondary particles production, imaging techniques, interpatient variability and other confounding factors.

  • 3. Flejmer, Anna M.
    et al.
    Chehrazi, Behnaz
    Josefsson, Dan
    Toma-Dasu, Iuliana
    Dasu, Alexandru
    Impact of physiological breathing motion for breast cancer radiotherapy with proton beam scanning - An in silico study2017In: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 39, p. 88-94Article in journal (Refereed)
    Abstract [en]

    This study investigates the impact of breathing motion on proton breast treatment plans. Twelve patients with CT datasets acquired during breath-hold-at-inhalation (BHI), breath-hold-at-exhalation (BHE) and in free-breathing (FB) were included in the study. Proton plans were designed for the left breast for BHI and subsequently recalculated for BHE or designed for FB and recalculated for the extreme breath-hold phases. The plans were compared from the point of view of their target coverage and doses to organs-at-risk. The median amplitude of breathing motion determined from the positions of the sternum was 4.7mm (range 0.5-14.6mm). Breathing motion led to a degradation of the dose coverage of the target (heterogeneity index increased from 4-7% to 8-11%), but the degraded values of the dosimetric parameters of interest fulfilled the clinical criteria for plan acceptance. Exhalation decreased the lung burden [average dose 3.1-4.5Gy (RBE)], while inhalation increased it [average dose 5.8-6.8Gy (RBE)]. The individual values depended on the field arrangement. Smaller differences were seen for the heart [average dose 0.1-0.2Gy (RBE)] and the LAD [1.9-4.6Gy (RBE)]. Weak correlations were generally found between changes in dosimetric parameters and respiratory motion. The differences between dosimetric parameters for various breathing phases were small and their expected clinical impact is consequently quite small. The results indicated that the dosimetric parameters of the plans corresponding to the extreme breathing phases are little affected by breathing motion, thus suggesting that this motion might have little impact for the chosen beam orientations with scanned proton beams.

  • 4. Kjellsson Lindblom, Emely
    et al.
    Dasu, Alexandru
    Toma-Dasu, Iuliana
    Hypoxia induced by vascular damage at high doses could compromise the outcome of radiotherapy2019In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 39, no 5, p. 2337-2340Article in journal (Refereed)
  • 5. Kjellsson Lindblom, Emely
    et al.
    Ureba, Ana
    Dasu, Alexandru
    Wersäll, Peter
    Even, Aniek J. G.
    van Elmpt, Wouter
    Lambin, Philippe
    Toma-Dasu, Iuliana
    Impact of SBRT fractionation in hypoxia dose painting - accounting for heterogeneous and dynamic tumour oxygenation2019In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 46, no 5, p. 2512-2521Article in journal (Refereed)
  • 6. Lazzeroni, Marta
    et al.
    Bunea, Hatice
    Grosu, Anca L.
    Baltas, Dimos
    Toma-Dasu, Iuliana
    Dasu, Alexandru
    Mathematical Description of Changes in Tumour Oxygenation from Repeated Functional Imaging2018In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 1072, p. 195-200Article in journal (Refereed)
    Abstract [en]

    Functional imaging of tumour hypoxia has been suggested as a tool for refining target definition and treatment optimization in radiotherapy. The approach, however, has been slow to be adopted clinically as most of the studies on the topic do not take into account the in-treatment changes of hypoxia. The present study aimed to introduce a function that quantifies the changes of oxygen distributions in repeated PET images taken during treatment. The proposed approach for determining the reoxygenation function was tested for feasibility on patients with head and neck cancer, repeatedly imaged with FMISO PET during radiotherapy. Reoxygenation functions were derived by solving the convolution between functions describing the oxygen distributions of successive images. The method was found to be mathematically feasible. The results indicate that the reoxygenation functions describing the change in oxygenation have distinct shapes prompting the hypothesis that oxygenation changes reflected by them might have predictive power for treatment outcome. Future studies on a larger patient population to search for predictive correlations based on the reoxygenation function are planned.

  • 7. Lazzeroni, Marta
    et al.
    Uhrdin, Johan
    Carvalho, Sara
    van Elmpt, Wouter
    Lambin, Philippe
    Dasu, Alexandru
    Wersäll, Peter
    Toma-Dasu, Iuliana
    Evaluation of third treatment week as temporal window for assessing responsiveness on repeated FDG-PET-CT scans in Non-Small Cell Lung Cancer patients2018In: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 46, p. 45-51Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Early assessment of tumour response to treatment with repeated FDG-PET-CT imaging has potential for treatment adaptation but it is unclear what the optimal time window for this evaluation is. Previous studies indicate that changes in SUVmean and the effective radiosensitivity (αeff, accounting for uptake variations and accumulated dose until the second FDG-PET-CT scan) are predictive of 2-year overall survival (OS) when imaging is performed before radiotherapy and during the second week. This study aims to investigate if multiple FDG-PET-derived quantities determined during the third treatment week have stronger predictive power.

    METHODS: Twenty-eight lung cancer patients were imaged with FDG-PET-CT before radiotherapy (PET1) and during the third week (PET2). SUVmean, SUVmax, SUVpeak, MTV41%-50% (Metabolic Tumour Volume), TLG41%-50% (Total Lesion Glycolysis) in PET1 and PET2 and their change (), as well as average αeff (α¯eff) and the negative fraction of αeff values [Formula: see text] ) were determined. Correlations were sought between FDG-PET-derived quantities and OS with ROC analysis.

    RESULTS: Neither SUVmean, SUVmax, SUVpeak in PET1 and PET2 (AUC = 0.5-0.6), nor their changes (AUC = 0.5-0.6) were significant for outcome prediction purposes. Lack of correlation with OS was also found for α¯eff (AUC = 0.5) and [Formula: see text] (AUC = 0.5). Threshold-based quantities (MTV41%-50%, TLG41%-50%) and their changes had AUC = 0.5-0.7. P-values were in all cases ≫0.05.

    CONCLUSIONS: The poor OS predictive power of the quantities determined from repeated FDG-PET-CT images indicates that the third week of treatment might not be suitable for treatment response assessment. Comparatively, the second week during the treatment appears to be a better time window.

  • 8. Lindblom, Emely
    et al.
    Dasu, Alexandru
    Beskow, Catharina
    Toma-Dasu, Iuliana
    High brachytherapy doses can counteract hypoxia in cervical cancer - a modelling study2017In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 62, no 2, p. 560-572Article in journal (Refereed)
    Abstract [en]

    Tumour hypoxia is a well-known adverse factor for the outcome of radiotherapy. For cervical tumours in particular, several studies indicate large variability in tumour oxygenation. However, clinical evidence shows that the management of cervical cancer including brachytherapy leads to high rate of success. It was the purpose of this study to investigate whether the success of brachytherapy for cervical cancer, seemingly regardless of oxygenation status, could be explained by the characteristics of the brachytherapy dose distributions. To this end, a previously used in silico model of tumour oxygenation and radiation response was further developed to simulate the treatment of cervical cancer employing a combination of external beam radiotherapy and intracavitary brachytherapy. Using a clinically-derived brachytherapy dose distribution and assuming a homogeneous dose delivered by external radiotherapy, cell survival was assessed on voxel level by taking into account the variation of sensitivity with oxygenation as well as the effects of repair, repopulation and reoxygenation during treatment. Various scenarios were considered for the conformity of the brachytherapy dose distribution to the hypoxic region in the target. By using the clinically-prescribed brachytherapy dose distribution and varying the total dose delivered with external beam radiotherapy in 25 fractions, the resulting values of the dose for 50% tumour control, D 50, were in agreement with clinically-observed values for high cure rates if fast reoxygenation was assumed. The D 50 was furthermore similar for the different degrees of conformity of the brachytherapy dose distribution to the tumour, regardless of whether the hypoxic fraction was 10%, 25%, or 40%. To achieve 50% control with external RT only, a total dose of more than 70 Gy in 25 fractions would be required for all cases considered. It can thus be concluded that the high doses delivered in brachytherapy can counteract the increased radioresistance caused by hypoxia if fast reoxygenation is assumed.

  • 9. Lindblom, Emely
    et al.
    Dasu, Alexandru
    Uhrdin, Johan
    Even, Aniek
    van Elmpt, Wouter
    Lambin, Philippe
    Wersäll, Peter
    Toma-Dasu, Iuliana
    Defining the hypoxic target volume based on positron emission tomography for image guided radiotherapy - the influence of the choice of the reference region and conversion function2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 6, p. 819-825Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Hypoxia imaged by positron emission tomography (PET) is a potential target for optimization in radiotherapy. However, the implementation of this approach with respect to the conversion of intensities in the images into oxygenation and radiosensitivity maps is not straightforward. This study investigated the feasibility of applying two conversion approaches previously derived for 18F-labeled fluoromisonidazole (18F-FMISO)-PET images for the hypoxia tracer 18F-flortanidazole (18F-HX4).

    MATERIAL AND METHODS: Ten non-small-cell lung cancer patients imaged with 18F-HX4 before the start of radiotherapy were considered in this study. PET image uptake was normalized to a well-oxygenated reference region and subsequently linear and non-linear conversions were used to determine tissue oxygenations maps. These were subsequently used to delineate hypoxic volumes based partial oxygen pressure (pO2) thresholds. The results were compared to hypoxic volumes segmented using a tissue-to-background ratio of 1.4 for 18F-HX4 uptake.

    RESULTS: While the linear conversion function was not found to result in realistic oxygenation maps, the non-linear function resulted in reasonably sized sub-volumes in good agreement with uptake-based segmented volumes for a limited range of pO2 thresholds. However, the pO2 values corresponding to this range were significantly higher than what is normally considered as hypoxia. The similarity in size, shape, and relative location between uptake-based sub-volumes and volumes based on the conversion to pO2 suggests that the relationship between uptake and pO2 is similar for 18F-FMISO and 18F-HX4, but that the model parameters need to be adjusted for the latter.

    CONCLUSIONS: A non-linear conversion function between uptake and oxygen partial pressure for 18F-FMISO-PET could be applied to 18F-HX4 images to delineate hypoxic sub-volumes of similar size, shape, and relative location as based directly on the uptake. In order to apply the model for e.g., dose-painting, new parameters need to be derived for the accurate calculation of dose-modifying factors for this tracer.

  • 10. Lindblom, Emely
    et al.
    Toma-Dasu, Iuliana
    Dasu, Alexandru
    Accounting for Two Forms of Hypoxia for Predicting Tumour Control Probability in Radiotherapy: An In Silico Study2018In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 1072, p. 183-187Article in journal (Refereed)
    Abstract [en]

    The progress in functional imaging and dose delivery has opened the possibility of targeting tumour hypoxia with radiotherapy. Advanced approaches apply quantitative information on tumour oxygenation retrieved from imaging in dose prescription. These do not, however, take into account the potential difference in radiosensitivity of chronically and acutely hypoxic cells. It was the aim of this study to evaluate the implications of assuming the same or different sensitivities for the hypoxic cells. An in silico 3D-model of a hypoxic tumour with heterogeneous oxygenation was used to model the probabilities of tumour control with different radiotherapy regimens. The results show that by taking into account the potential lower radioresistance of chronically hypoxic cells deprived of oxygen and nutrients, the total dose required to achieve a certain level of control is substantially reduced for a given fractionation scheme in comparison to the case when chronically and acutely hypoxic cells are assumed to have similar features. The results also suggest that the presence of chronic hypoxia could explain the success of radiotherapy for some hypoxic tumours. Given the implications for clinical dose escalation trials, further exploration of the influence of the different forms of hypoxia on treatment outcome is therefore warranted.

  • 11. Marcu, Loredana G.
    et al.
    Toma-Dasu, Iuliana
    Dasu, Alexandru
    Mercke, Claes
    Radiotherapy and clinical radiobiology of head and neck cancer2018Book (Refereed)
  • 12. Ureba, Ana
    et al.
    Lindblom, Emely
    Dasu, Alexandru
    Uhrdin, Johan
    Even, Aniek J. G.
    van Elmpt, Wouter
    Lambin, Philippe
    Wersäll, Peter
    Toma-Dasu, Iuliana
    Non-linear conversion of HX4 uptake for automatic segmentation of hypoxic volumes and dose prescription2018In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 4, p. 485-490Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Tumour hypoxia is associated with increased radioresistance and poor response to radiotherapy. Pre-treatment assessment of tumour oxygenation could therefore give the possibility to tailor the treatment by calculating the required boost dose needed to overcome the increased radioresistance in hypoxic tumours. This study concerned the derivation of a non-linear conversion function between the uptake of the hypoxia-PET tracer 18F-HX4 and oxygen partial pressure (pO2).

    MATERIAL AND METHODS: Building on previous experience with FMISO including experimental data on tracer uptake and pO2, tracer-specific model parameters were derived for converting the normalised HX4-uptake at the optimal imaging time point to pO2. The conversion function was implemented in a Python-based computational platform utilising the scripting and the registration modules of the treatment planning system RayStation. Subsequently, the conversion function was applied to determine the pO2 in eight non-small-cell lung cancer (NSCLC) patients imaged with HX4-PET before the start of radiotherapy. Automatic segmentation of hypoxic target volumes (HTVs) was then performed using thresholds around 10 mmHg. The HTVs were compared to sub-volumes segmented based on a tumour-to-blood ratio (TBR) of 1.4 using the aortic arch as the reference oxygenated region. The boost dose required to achieve 95% local control was then calculated based on the calibrated levels of hypoxia, assuming inter-fraction reoxygenation due to changes in acute hypoxia but no overall improvement of the oxygenation status.

    RESULTS: Using the developed conversion tool, HTVs could be obtained using pO2 a threshold of 10 mmHg which were in agreement with the TBR segmentation. The dose levels required to the HTVs to achieve local control were feasible, being around 70-80 Gy in 24 fractions.

    CONCLUSIONS: Non-linear conversion of tracer uptake to pO2 in NSCLC imaged with HX4-PET allows a quantitative determination of the dose-boost needed to achieve a high probability of local control.

  • 13. Ödén, Jakob
    et al.
    Toma-Dasu, Iuliana
    Eriksson, Kjell
    Flejmer, Anna Maria
    Dasu, Alexandru
    The influence of breathing motion and a variable relative biological effectiveness in proton therapy of left-sided breast cancer2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 11, p. 1428-1436Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Proton breast radiotherapy has been suggested to improve target coverage as well as reduce cardiopulmonary and integral dose compared with photon therapy. This study aims to assess this potential when accounting for breathing motion and a variable relative biological effectiveness (RBE).

    METHODS: Photon and robustly optimized proton plans were generated to deliver 50 Gy (RBE) in 25 fractions (RBE = 1.1) to the CTV (whole left breast) for 12 patients. The plan evaluation was performed using the constant RBE and a variable RBE model. Robustness against breathing motion, setup, range and RBE uncertainties was analyzed using CT data obtained at free-breathing, breath-hold-at-inhalation and breath-hold-at-exhalation.

    RESULTS: All photon and proton plans (RBE = 1.1) met the clinical goals. The variable RBE model predicted an average RBE of 1.18 for the CTVs (range 1.14-1.21) and even higher RBEs in organs at risk (OARs). However, the dosimetric impact of this latter aspect was minor due to low OAR doses. The normal tissue complication probability (NTCP) for the lungs was low for all patients (<1%), and similar for photons and protons. The proton plans were generally considered robust for all patients. However, in the most extreme scenarios, the lowest dose received by 98% of the CTV dropped from 96 to 99% of the prescribed dose to around 92-94% for both protons and photons. Including RBE uncertainties in the robustness analysis resulted in substantially higher worst-case OAR doses.

    CONCLUSIONS: Breathing motion seems to have a minor effect on the plan quality for breast cancer. The variable RBE might impact the potential benefit of protons, but could probably be neglected in most cases where the physical OAR doses are low. However, to be able to identify outlier cases at risk for high OAR doses, the biological evaluation of proton plans taking into account the variable RBE is recommended.

  • 14. Ödén, Jakob
    et al.
    Toma-Dasu, Iuliana
    Witt Nyström, Petra
    Traneus, Erik
    Dasu, Alexandru
    Spatial correlation of linear energy transfer and relative biological effectiveness with suspected treatment related toxicities following proton therapy for intracranial tumors2019In: Medical physics (Lancaster), ISSN 0094-2405Article in journal (Refereed)
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