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  • 1.
    Dasu, Alexandru
    Umeå University, Faculty of Medicine, Radiation Sciences, Radiation Physics.
    Is the alpha/beta value for prostate tumours low enough to be safely used in clinical trials?2007In: Clin Oncol (R Coll Radiol), ISSN 0936-6555, Vol. 19, no 5, p. 289-301Article in journal (Refereed)
  • 2.
    Dasu, Alexandru
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Toma-Dasu, Iuliana
    Franzen, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nilsson, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    The risk of secondary cancers in patients treated for prostate carcinoma: an analysis with competition dose response model2009In: IFMBE Proceedings, Berlin: Springer , 2009, p. 237-240Conference paper (Refereed)
    Abstract [en]

    The risk for radiation-induced cancers has become increasingly important as patient survival following radiotherapy has increased due to the advent of new methods for early detection and advanced treatment. Attempts have been made to quantify the risk of cancer that may be associated with various treatment approaches, but the accuracy of predictions is rather low due to the influence of many confouding factors. It is the aim of this paper to investigate the impact of dose heterogeneity and inter-patient anatomical heterogeneity that may be encountered in a population of patients undergoing radiotheray and are thought to influence risk predictions. Dose volume histograms from patients treated with radiation for the carcinoma of the prostate have been used to calculate the risk for secondary malignancies using a competition dose-response model previously developed. Biologically-relevant parameters derived from clinical and experimental data have been used for the model. The results suggested that dose heterogeneity plays an important role in predicting the risk for secondary cancer and that it should be taken into account throught the use of dose volume histograms. Consequently, dose-response relationships derived for uniform relationships should be used with care to predict the risk for secondary malignancies in heterogeneously irradiated tissues. Inter-patient differences could lead to considerable uncertainties in the shape of the relationship between predicted risk and average tissue dose, as seen in epidemiological studies. They also lead to rather weak correlations between the risk for secondary malignancies and target volumes. The results stress the importance of taking into account the details of the clinical delivery of dose in radiotherapy plan evaluation or for retrospective analyses of the induction of secondary cancers. Nevertheless, the levels of risks are generally low and they could be regarded as teh price of success for the advances in the radiotherapy of the prostate.

  • 3.
    Dasu, Alexandru
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Toma-Dasu, Iuliana
    Franzén, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nilsson, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    The risk for secondary cancers in patients treated for prostate carcinoma: an analysis with completion dose response model2009In: IFMBE Proceedings of the World Congress on Medical Physics and Biomedical Engineering, September 7 - 12, 2009, Munich, Germany / [ed] Olaf Dössel, Wolfgang C. Schlegel, Springer Verlag , 2009, p. 237-240Conference paper (Refereed)
    Abstract [en]

    The risk for radiation-induced cancers has become increasingly important as patient survival following radiotherapy has increased due to the advent of new methods for early detection and advanced treatment. Attempts have been made to quantify the risk of cancer that may be associated with various treatment approaches, but the accuracy of predictions is rather low due to the influence of many confounding factors. It is the aim of this paper to investigate the impact of dose heterogeneity and inter-patient anatomical heterogeneity that may be encountered in a population of patients undergoing radiotherapy and are thought to influence risk predictions. Dose volume histograms from patients treated with radiation for the carcinoma of the prostate have been used to calculate the risk for secondary malignancies using a competition dose-response model previously developed. Biologically-relevant parameters derived from clinical and experimental data have been used for the model. The results suggested that dose heterogeneity plays an important role in predicting the risk for secondary cancer and that it should be taken into account through the use of dose volume histograms. Consequently, dose-response relationships derived for uniform relationships should be used with care to predict the risk for secondary malignancies in heterogeneously irradiated tissues. Inter-patient differences could lead to considerable uncertainties in the shape of the relationship between predicted risk and average tissue dose, as seen in epidemiological studies. They also lead to rather weak correlations between the risk for secondary malignancies and target volumes. The results stress the importance of taking into account the details of the clinical delivery of dose in radiotherapy for treatment plan evaluation or for retrospective analyses of the induction of secondary cancers. Nevertheless, the levels of risks are generally low and they could be regarded as the price of success for the advances in the radiotherapy of the prostate.

  • 4.
    Dasu, Alexandru
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Toma-Daşu, Iuliana
    Treatment modelling: The influence of micro-environmental conditions2008In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 47, no 5, p. 896-905Article in journal (Refereed)
    Abstract [en]

    The interest in theoretical modelling of radiation response has grown steadily from a fast method to estimate the gain of new treatment strategies to an individualisation tool that may be used as part of the treatment planning algorithms. While the advantages of biological optimisation of plans are obvious, accurate theoretical models and realistic information about the micro-environmental conditions in tissues are needed. This paper aimed to investigate the clinical implications of taking into consideration the details of the tumour microenvironmental conditions. The focus was on the availability of oxygen and other nutrients to tumour cells and the relationship between cellular energy reserves and DNA repair ability as this is thought to influence the response of the various hypoxic cells. The choice of the theoretical models for predicting the response (the linear quadratic model or the inducible repair model) was also addressed. The modelling performed in this project has shown that the postulated radiobiological differences between acute and chronic hypoxia have some important clinical implications which may help to understand the mechanism behind the current success rates of radiotherapy. The results also suggested that it is important to distinguish between the two types of hypoxia in predictive assays and other treatment simulations.

  • 5.
    Dasu, Alexandru
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Toma-Daşu, Iuliana
    Vascular oxygen content and the tissue oxygenation - a theoretical analysis2008In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 35, no 2, p. 539-455Article in journal (Refereed)
    Abstract [en]

    Several methods exist for evaluating tumor oxygenation as hypoxia is an important prognostic factor for cancer patients. They use different measuring principles that highlight various aspects of oxygenation. The results could be empirically correlated, but it has been suspected that there could be discordances in some cases. This study describes an analysis of the relationship between vascular and tissue oxygenations. Theoretical simulation has been employed to characterize tissue oxygenations for a broad range of distributions of intervessel distances and vascular oxygenations. The results were evaluated with respect to the implications for practical measurements of tissue oxygenations. The findings showed that although the tissue oxygenation is deterministically related to vascular oxygenation, the relationship between them is not unequivocal. Variability also exists between the fractions of values below the sensitivity thresholds of various measurement methods which in turn could be reflected in the power of correlations between results from different methods or in the selection of patients for prognostic studies. The study has also identified potential difficulties that may be encountered at the quantitative evaluation of the results from oxygenation measurements. These could improve the understanding of oxygenation measurements and the interpretation of comparisons between results from various measurement methods.

  • 6.
    Dasu, Alexandru
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Toma-Daşu, Iuliana
    What is the Clinically Relevant Relative Biologic Effectiveness? A Warning for Fractionated Treatments With High Linear Energy Transfer Radiation2008In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 70, no 3, p. 867-874Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To study the clinically relevant relative biologic effectiveness (RBE) of fractionated treatments with high linear energy transfer (LET) radiation and to identify the important factors that might influence the transfer of tolerance and curative levels from low LET radiation. These are important questions in the light of the growing interest for the therapeutic use of radiation with higher LET than electrons or photons.

    METHODS AND MATERIALS: The RBE of various fractionated schedules was analyzed with theoretical models for radiation effect, and the resulting predictions were compared with the published clinical and experimental data regarding fractionated irradiation with high LET radiation.

    RESULTS: The clinically relevant RBE increased for greater doses per fraction, in contrast to the predictions from single-dose experiments. Furthermore, the RBE for late-reacting tissues appeared to modify more quickly than that for early-reacting tissues. These aspects have quite important clinical implications, because the increased biologic effectiveness reported for this type of radiation would otherwise support the use of hypofractionation. Thus, the differential between acute and late-reacting tissues could put the late-reacting normal tissues at more risk from high LET irradiation; however, at the same time, it could increase the therapeutic window for slow-growing tumors.

    CONCLUSIONS: The modification of the RBE with the dose per fraction must be carefully taken into consideration when devising fractionated treatments with high LET radiation. Neglecting to do so might result in an avalanche of complications that could obscure the potential advantages of the therapeutic use of this type of radiation.

  • 7.
    Daşu, Alexandru
    Umeå University, Faculty of Medicine, Radiation Sciences, Radiation Physics.
    Treatment planning optimisation based on imaging tumour proliferation and cell density.2008In: Acta oncologica (Stockholm, Sweden), ISSN 1651-226X, Vol. 47, no 7, p. 1221-8Article in journal (Refereed)
    Abstract [en]

    Functional imaging could provide valuable information on the distribution of biological factors that influence the outcome of radiation therapy. Tumour proliferation and cell density in particular could be imaged with dedicated metabolic tracers and could thus be used for the biological optimisation of the treatment plans. The feasibility of individualising treatment planning using proliferation and density information has been investigated through simulations of heterogeneous tumours taking into account the cell density and proliferation rates. The predicted outcome was used to estimate the success of the individualisation of dose distributions. The results have shown that tumour control could be increased through the escalation of doses to proliferating foci with a relative reduction of doses to slowly proliferating regions of the tumour. This suggests that individualisation of treatment planning taking into account proliferation information creates the premises for further reduction of the doses to the surrounding regions which would consequently lead to an increased sparing of the normal tissues. Cell density has been shown to be another important factor that could be used for optimisation, albeit of a lower weight than proliferation. However, associated with proliferation it could lead to treatment failure if the trouble foci are underdosed. In conclusion, treatment optimisation based on imaged proliferation could improve both tumour control and normal tissue sparing.

  • 8.
    Daşu, Alexandru
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences.
    Fowler, Jack F
    Comments on "Comparison of in vitro and in vivo alpha/beta ratios for prostate cancer".2005In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 50, no 6, p. L1-4; author reply L5Article in journal (Refereed)
  • 9.
    Daşu, Alexandru
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Radiation Physics.
    Toma-Daşu, Iuliana
    The relationship between vascular oxygen distribution and tissue oxygenation.2009In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 645, p. 255-60Article in journal (Refereed)
    Abstract [en]

    Tumour oxygenation could be investigated through several methods that use various measuring principles and can therefore highlight its different aspects. The results have to be subsequently correlated, but this might not be straightforward due to intrinsic limitations of the measurement methods. This study describes an analysis of the relationship between vascular and tissue oxygenations that may help the interpretation of results. Simulations have been performed with a mathematical model that calculates the tissue oxygenation for complex vascular arrangements by taking into consideration the oxygen diffusion into the tissue and its consumption at the cells. The results showed that while vascular and tissue oxygenations are deterministically related, the relationship between them is not unequivocal and this could lead to uncertainties when attempting to correlate them. However, theoretical simulation could bridge the gap between the results obtained with various methods.

  • 10.
    Daşu, Alexandru
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Toma-Daşu, Iuliana
    Franzén, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nilsson, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Secondary malignancies from prostate cancer radiation treatment: a risk analysis of the influence of target margins and fractionation patterns2011In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 79, no 3, p. 738-746Article in journal (Refereed)
    Abstract [en]

    The results have shown the complex interplay between the risk for secondary malignancies, the details of the treatment delivery, and the patient heterogeneity that may influence comparisons between the long-term effects of various treatment techniques. Nevertheless, absolute risk levels seem very small and comparable to mortality risks from surgical interventions, thus supporting the robustness of radiation therapy as a successful treatment modality for prostate carcinomas.

  • 11. Toma-Dasu, Iuliana
    et al.
    Uhrdin, J
    Dasu, Alexandru
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Brahme, Anders
    Therapy optimization based on non-linear uptake of PET tracers versus "linear dose painting"2009In: IFMBE Proceedings 25/1 / [ed] O Dössel, W C Schlegel, R Magjarevic, Springer Verlag , 2009, p. 221-224Chapter in book (Refereed)
    Abstract [en]

    Treatment optimization based on positron emission tomography (PET) images of tumor hypoxia has been proposed as a method to improve the cure rates in radiotherapy through the increased dose delivery to tumor regions with increased radioresistance. One of the major advantages of PET imaging of hypoxia is that it can provide information on both the extent and the spatial distribution of the resistant regions. One of the key issues for the practical implementation of this approach is the accurate conversion of the intensities in the recorded images into radiosensitivity maps that could then be used for dose escalation. The present paper explores the influence of the conversion from uptake to prescribed doses. Transformation functions derived from the uptake properties of the PET tracers were taken into consideration. The results have shown that the available tracers have different uptake properties and therefore they could interpret differently the gradients in the images which in turn would lead to different dose predictions. Best results in terms of dose prescription would therefore be achieved by carefully taking into account the uptake characteristics of the imaged tracers. Linear approximations could lead to unnecessary over-estimations of the doses for cases of partial hypoxia in tumors. This highlights the need for more experimental studies of the uptake properties of PET tracers proposed to image tissue hypoxia. These would eventually provide more reliable methods for dose prescription that could be used with optimization algorithms for the successful individualization of radiation therapy.

  • 12. Toma-Dasu, Iuliana
    et al.
    Uhrdin, J
    Dasu, Alexandru
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Brahme, Anders
    Therapy optimization based on non-linear uptake of PET tracers versus "linear dose painting"2009In: IFMBE Proceedings, Berlin: Springer , 2009, p. 221-224Conference paper (Refereed)
    Abstract [en]

    Treatment optimization based on positron emission tomography (PET) images of tumor hypoxia has been proposed as a method to improve the cure rates in radiotherapy through the increased dose delivery to tumor regions with increased radioresistance. One of the major advantages of PET imaging of hypoxia is that it can provide information on both the extent and the spatial distribution of the resistant regions. One of the key issues for the practical implementation of this approach is the accurate conversion of the intensities in the recorded images into radiosensitivity maps that could then be used for dose escalation. The present paper explores the influence of the conversion from uptake to prescribed doses. Transformation functions derived from the uptake properties of the PET tracers were taken into consideration. The results have shown that the available tracers have different uptake properties and therefore they could interpret differently the gradients in the images which in turn would lead to different dose predictions. Best results in terms of dose prescription would therefore be achieved by carefully taking into account the uptake characteristics of the imaged tracers. Linear approximations could lead to unnecessary over-estimations of the doses for cases of partial hypoxia in tumors. This highlights the need for more experimental studies of the uptake properties of PET tracers proposed to image tissue hypoxia. These would eventually provide more reliable methods for dose prescription that could be used with optimization algorithms for the successful individualization of radiation therapy.

  • 13. Toma-Daşu, Iuliana
    et al.
    Daşu, Alexandru
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Brahme, Anders
    Dose prescription and optimisation based on tumour hypoxia.2009In: Acta oncologica (Stockholm, Sweden), ISSN 1651-226X, Vol. 48, no 8, p. 1181-1192Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION. Tumour hypoxia is an important factor that confers radioresistance to the affected cells and could thus decrease the tumour response to radiotherapy. The development of advanced imaging methods that quantify both the extent and the spatial distribution of the hypoxic regions has created the premises to devise therapies that target the hypoxic regions in the tumour. MATERIALS AND METHODS. The present study proposes an original method to prescribe objectively dose distributions that focus the radiation dose to the radioresistant tumour regions and could therefore spare adjacent normal tissues. The effectiveness of the method was tested for clinically relevant simulations of tumour hypoxia that take into consideration dynamics and heterogeneity of oxygenation. RESULTS AND DISCUSSION. The results have shown that highly heterogeneous dose distributions may lead to significant improvements of the outcome only for static oxygenations. In contrast, the proposed method that involves the segmentation of the dose distributions and the optimisation of the dose prescribed to each segment to account for local heterogeneity may lead to significantly improved local control for clinically-relevant patterns of oxygenation. The clinical applicability of the method is warranted by its relatively easy adaptation to functional imaging of tumour hypoxia obtained with markers with known uptake properties.

  • 14. Toma-Daşu, Iuliana
    et al.
    Daşu, Alexandru
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Brahme, Anders
    Quantifying tumour hypoxia by PET imaging--a theoretical analysis.2009In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 645, p. 267-272Article in journal (Refereed)
    Abstract [en]

    Information on tumour oxygenation could be obtained from various imaging methods, but the success of incorporating it into treatment planning depends on the accuracy of quantifying it. This study presents a theoretical analysis of the efficiency of measuring tumour hypoxia by PET imaging. Tissue oxygenations were calculated for ranges of biologically relevant physiological parameters and were then used to simulate PET images for markers with different uptake characteristics. The resulting images were used to calculate dose distributions that could lead to predefined tumour control levels. The results have shown that quantification of tumour hypoxia with PET may lead to different values according to the tracer used and the tumour site investigated. This would in turn be reflected into the dose distributions recommended by the optimisation algorithms. However, irrespective of marker-specific differences, focusing the radiation dose to the hypoxic areas appears to reduce the average tumour dose needed to achieve a certain control level.

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