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  • 1.
    Antonovic, Laura
    et al.
    Stockholm University.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Health Sciences.
    Furusawa, Yoshiya
    National Institute of Radiological Sciences, Chiba, Japan.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Relative clinical effectiveness of carbon ion radiotherapy: theoretical modelling for H&N tumours2015In: Journal of radiation research, ISSN 0449-3060, E-ISSN 1349-9157, Vol. 56, no 4, 639-645 p.Article in journal (Refereed)
    Abstract [en]

    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 fractions, 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 important step towards individualisation of RT treatments.

  • 2.
    Antonovic, Laura
    et al.
    Stockholm University, Sweden.
    Lindblom, Emely
    Stockholm University, Sweden.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Bassler, Niels
    Aarhus University, Denmark.
    Furusawa, Yoshiya
    National Institute of Radiological Sciences, Chiba, Japan.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet, Stockholm, Sweden.
    Clinical oxygen enhancement ratio of tumors in carbon ion radiotherapy: the influence of local oxygenation changes2014In: Journal of radiation research, ISSN 0449-3060, E-ISSN 1349-9157, Vol. 55, no 5, 902-911 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 3.
    Dasu, Alexandru
    et al.
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Dose painting by numbers - do the practical limitations of the technique decrease or increase the probability of controlling tumours?2013In: IFMBE Proceedings, Vol. 39, 1731-1734 p.Article in journal (Refereed)
    Abstract [en]

    One of the important questions regarding the feasibility of dose-painting-by-numbers approaches for treatment planning concerns the influence of the averaging of the imaging techniques used and the resolution of the planned and achieved dose distributions. This study investigates the impact of these aspects on the probability of controlling dynamic tumours. The effectiveness of dose painting approaches to target tumour hypoxia has been investigated in terms of the predicted tumour control probabilities (TCP) for tumours with dynamic oxygenations. Several levels of resolution for the resistance of the tumour or the planned dose distributions have been investigated. A very fine heterogeneous dose distribution ideally calculated at voxel level for a high target TCP would fail to control a tumour with dynamic oxygenation during the course of fractionated radiotherapy as mismatches between hotspots in the dose distribution and resistant hypoxic foci would lead to a significant loss in TCP. Only adaptive treatment would lead to reasonably high TCP. A coarse resolution for imaging or for dose distributions might compensate microscale mismatches in dynamic tumours, but the resulting tumour control could still be below the target levels. These results indicate that there is a complex relationship between the resolution of the dose-painting-by-numbers approaches and the dynamics of tumour oxygenation. Furthermore, the clinical success of hypoxia targeting strategies in the absence of adaptive approaches might be explained by changes in tumour radiation resistance through reoxygenation.

  • 4.
    Dasu, Alexandru
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Toma-Dasu, Iuliana
    Stockholm University, Sweden.
    Impact of increasing irradiation time on the treatment of prostate cancers2015In: IFMBE Proceedings, Vol. 51, 490-493 p.Article in journal (Refereed)
    Abstract [en]

    This study aimed to investigate the expected impact of intrafraction repair during increasing irradiation times for the treatment of prostate cancers. Lengthy sessions are indeed expected for some advanced irradiation techniques capable to deliver the large fractional doses required by the increased fractionation sensitivity of the prostates. For this purpose, clinically-derived parameters characterizing repair rates and dose response curves for prostate tumors have been used to calculate the expected loss of effectiveness when increasing the irradiation time. The results have shown that treatment sessions lasting more than about 20 to 40 minutes could reduce the probability of biochemical control of prostate tumors by more than 20 to 30 percentage points. These results are in agreement with some observed clinical results and therefore they suggest that treatment durations in prostate radiation therapy should be carefully recorded in order to explicitly account for intrafraction repair, especially when irradiation techniques make use of multiple beams and imaging sessions. Failure to do so might overestimate the expected effectiveness of the treatment and could lead to disappointing clinical results precisely from the demanding treatment modalities expected to increase the therapeutic gain in prostate radiotherapy.

  • 5.
    Dasu, Alexandru
    et al.
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Impact of variable RBE on proton fractionation2013In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 40, no 1, Article ID 011705- p.Article in journal (Refereed)
    Abstract [en]

    Purpose: To explore the impact of variable proton RBE on dose fractionation for clinically-relevant situations. A generic RBE=1.1 is generally used for isoeffect calculations, while experimental studies showed that proton RBE varies with tissue type, dose and LET.

    Material and methods: An analytical expression for the LET and α/β dependence of the LQ model has been used for proton simulations in parallel with the assumption of a generic RBE=1.1. Calculations have been performed for ranges of LET values and fractionation sensitivities to describe clinically-relevant cases, like the treatment of H&N and prostate tumors. Isoeffect calculations were compared with predictions from a generic RBE value and reported clinical results.

    Results: The generic RBE=1.1 appears to be a reasonable estimate for the proton RBE of rapidly growing tissues irradiated with low LET radiation. However, the use of a variable RBE predicts larger differences for tissues with low α/β (both tumor and normal) and at low doses per fraction. In some situations these differences may appear in contrast to the findings from photon studies highlighting the importance of accurate accounting for the radiobiological effectiveness of protons. Furthermore, the use of variable RBE leads to closer predictions to clinical results.

    Conclusions: The LET dependence of the RBE has a strong impact on the predicted effectiveness of fractionated proton radiotherapy. The magnitude of the effect is modulated by the fractionation sensitivity and the fractional dose indicating the need for accurate analyses both in the target and around it. Care should therefore be employed for changing clinical fractionation patterns or when analyzing results from clinical studies for this type of radiation.

  • 6.
    Dasu, Alexandru
    et al.
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet, Stockholm, Sweden.
    Long-term effects and secondary tumors2014In: Comprehensive Biomedical Physics, Volume 9: Radiation Therapy Physics and Treatment Optimization / [ed] Anders Brahme, Amsterdam: Elsevier, 2014, 223-233 p.Chapter in book (Refereed)
    Abstract [en]

    The issue of secondary tumours as long-term effects of radiation therapy has gained increased importance as the life expectancy of cancer patients has increased due to improvements in detecting and treating their primary tumours. Current knowledge indicates that radiotherapy leads to a small but significant risk of inducing cancers which is often referred to as the price to pay for the effectiveness of this treatment modality. Nevertheless, the levels of incidence for the long-term effects of radiation therapy may be influenced by many factors that could be both treatment-related and patient-related and therefore proposals have been made to include risk estimations in the process of treatment optimisation. This chapter summarises the current knowledge concerning the induction of secondary cancers after radiotherapy and discusses their consequences for the therapeutic use of ionising radiation.

  • 7.
    Dasu, Alexandru
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. The Skandion Clinic, Uppsala, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Models for the risk of secondary cancers from radiation therapy2017In: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191XArticle 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.

  • 8.
    Dasu, Alexandru
    et al.
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Prostate alpha/beta revisited – an analysis of clinical results from 14168 patients2012In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 8, 963-974 p.Article, review/survey (Refereed)
    Abstract [en]

    Purpose: To determine the dose response parameters and the fractionation sensitivity of prostate tumours from clinical results of patients treated with external beam radiotherapy.

    Material and methods: The study was based on 5-year biochemical results from 14168 patients treated with external beam radiotherapy. Treatment data from 11330 patients treated with conventional fractionation have been corrected for overall treatment time and fitted with a logit equation. The results have been used to determine the optimum α/β values that minimise differences in predictions from 2838 patients treated with hypofractionated schedules.

    Results: Conventional fractionation data yielded logit dose response parameters for all risk groups and for all definitions of biochemical failures. The analysis of hypofractionation data led to very low α/β values (1-1.7 Gy) in all mentioned cases. Neglecting the correction for overall treatment time has little impact on the derivation of α/β values for prostate cancers.

    Conclusions: These results indicate that the high fractionation sensitivity is an intrinsic property of prostate carcinomas and they support the use of hypofractionation to increase the therapeutic gain for these tumours.

  • 9.
    Dasu, Alexandru
    et al.
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Toma-Dasu, Iuliana
    Stockholm University.
    Will intrafraction repair have negative consequences on extreme hypofractionation in prostate radiation therapy?2015In: British Journal of Radiology, ISSN 0007-1285, E-ISSN 1748-880X, Vol. 88, no 1056, Article ID 20150588- p.Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of the present study was to investigate the impact of increasing fraction delivery time on the outcome of hypofractionated radiation therapy for prostate cancer.

    Methods: Monoexponential and biexponential repair models have been used for patients with prostate cancer to study the loss of biochemical control at 5 years for several clinically relevant irradiation times. The theoretical predictions were compared with newly reported clinical results from 4607 patients undergoing conventionally fractionated and hypofractionated prostate radiation therapy.

    Results: Time-demanding irradiation techniques appear to lead to biochemical control rates that sometimes are about 10–20 percentage points below predictions that neglect intrafraction repair. This difference appears to be of the same order of magnitude as that predicted by moderately slow to slow repair taking place during the irradiation time. The impact is largest for the patient risk groups receiving doses corresponding to the steepest part of the dose–response curve. By contrast, for treatment techniques requiring irradiation times shorter than about 20 min, the impact of intrafraction repair appears to be much smaller and probably difficult to be observed in the light of other sources of uncertainty in clinical data.

    Conclusion: Neglecting intrafraction repair might overestimate the effectiveness of some treatment schedules and could also influence any subsequent estimations of fractionation sensitivity for prostate tumours.

    Advances in knowledge: The effect of intrafraction repair for prostate cancer should be taken into account for long irradiation sessions as might be expected from scanned beams and/or from multiple intrafraction imaging sessions to check the positioning of the patient.

  • 10.
    Daşu, Alexandru
    et al.
    Umeå University.
    Toma-Daşu, Iuliana
    Umeå University.
    Dose-effect models for risk - relationship to cell survival parameters2005In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 44, no 8, 829-835 p.Article in journal (Refereed)
    Abstract [en]

    There is an increased interest in estimating the induction of cancers following radiotherapy as the patients have nowadays a much longer life expectancy following the treatment. Clinical investigations have shown that the dose response relationship for cancer induction following radiotherapy has either of two main characteristics: an increase of the risk with dose to a maximum effect followed by a decrease or an increase followed by a levelling-off of the risk. While these behaviours have been described qualitatively, there is no mathematical model that can explain both of them on mechanistic terms. This paper investigates the relationship between the shape of the dose-effect curve and the cell survival parameters of a single risk model. Dose response relationships were described with a competition model which takes into account the probability to induce DNA mutations and the probability of cell survival after irradiation. The shape of the curves was analysed in relation to the parameters that have been used to obtain them. It was found that the two main appearances of clinical data for the induction of secondary cancer following radiotherapy could be the manifestations of the particular sets of parameters that describe the induction of mutations and cell kill for fractionated irradiations. Thus, the levelling off appearance of the dose response curve could be either a sign of moderate to high inducible repair effect in cell survival (but weak for DNA mutations) or the effect of heterogeneity, or both. The bell-shaped appearance encompasses all the other cases. The results also stress the importance of taking into account the details of the clinical delivery of dose in radiotherapy, mainly the fractionated character, as the findings of our study did not appear for single dose models. The results thus indicate that the shapes of clinically observed dose response curves for the induction of secondary cancers can be described by using one single competition model. It was also found that data for cancer induction may be linked to in vivo cell survival parameters that may be used for other modelling applications.

  • 11.
    Daşu, Alexandru
    et al.
    Umeå University.
    Toma-Daşu, Iuliana
    Stockholm University and Karolinska Institutet.
    In response to Dr. Karger et al.2008In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, Vol. 70, no 5, 1614-1615 p.Article in journal (Refereed)
    Abstract [en]

    n/a

  • 12.
    Daşu, Alexandru
    et al.
    Norrland University Hospital, Umeå.
    Toma-Daşu, Iuliana
    Stockholm University and Karolinska Institutet.
    The relationship between vascular oxygen distribution and tissue oxygenation2009In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, Vol. 645, 255-260 p.Article 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.

  • 13.
    Daşu, Alexandru
    et al.
    Umeå University.
    Toma-Daşu, Iuliana
    Umeå University.
    Theoretical simulation of tumour oxygenation--practical applications2006In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, Vol. 578, no 12, 357-362 p.Article in journal (Refereed)
    Abstract [en]

    Theoretical simulation of tissue oxygenation is a robust method that can be used to quantify the tissue oxygenation for a variety of applications. However, it is necessary that the relevant input parameters are used for the model describing the tumour microenvironment. The results of the simulations presented in this article suggest that the accuracy of the simulations depends very much on the method of calculation of the effects of the temporal change of the hypoxic pattern due to the opening and the closure of blood vessels. Thus, the use of average oxygenations might lead to dangerous overestimations of the treatment response. This indicates that care should be taken when incorporating hypoxia information into the biological modelling of tumour response.

  • 14.
    Daşu, Alexandru
    et al.
    Norrland University Hospital.
    Toma-Daşu, Iuliana
    Stockholm University and Karolinska Institutet.
    Treatment modelling: the influence of micro-environmental conditions2008In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 47, no 5, 896-905 p.Article 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.

  • 15.
    Daşu, Alexandru
    et al.
    Norrland University Hospital.
    Toma-Daşu, Iuliana
    Stockholm University and Karolinska Institutet.
    Vascular oxygen content and the tissue oxygenation--a theoretical analysis2008In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 35, no 2, 539-545 p.Article 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.

  • 16.
    Daşu, Alexandru
    et al.
    Norrland University Hospital, Umeå.
    Toma-Daşu, Iuliana
    Stockholm University and Karolinska Institutet.
    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, Vol. 70, no 3, 867-874 p.Article 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.

  • 17.
    Daşu, Alexandru
    et al.
    Umeå University.
    Toma-Daşu, Iuliana
    Umeå University.
    Fowler, Jack F.
    University of Wisconsin Hospital.
    Should single or distributed parameters be used to explain the steepness of tumour control probability curves?2003In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 48, no 3, 387-397 p.Article in journal (Refereed)
    Abstract [en]

    Linear quadratic (LQ) modelling allows easy comparison of different fractionation schedules in radiotherapy. However, estimating the radiation effect of a single fractionated treatment introduces many questions with respect to the parameters to be used in the modelling process. Several studies have used tumour control probability (TCP) curves in order to derive the values for the LQ parameters that may be used further for the analysis and ranking of treatment plans. Unfortunately, little attention has been paid to the biological relevance of these derived parameters, either for the initial number of cells or their intrinsic radiosensitivity, or both. This paper investigates the relationship between single values for the TCP parameters and the resulting dose-response curve. The results of this modelling study show how clinical observations for the position and steepness of the TCP curve can be explained only by the choice of extreme values for the parameters, if they are single values. These extreme values are in contradiction with experimental observations. This contradiction suggests that single values for the parameters are not likely to explain reasonably the clinical observations and that some distributions of input parameters should be taken into consideration.

  • 18.
    Daşu, Alexandru
    et al.
    Umeå University.
    Toma-Daşu, Iuliana
    Stockholm University and Karolinska Institutet.
    Franzén, Lars
    Umeå University.
    Widmark, Anders
    Umeå University.
    Nilsson, Per
    Umeå University.
    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 1879-355X, Vol. 79, no 3, 738-746 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: This study explores the implications for cancer induction of treatment details such as fractionation, planning target volume (PTV) definition, and interpatient variations, which are relevant for the radiation treatment of prostate carcinomas.

    METHODS AND MATERIALS: Treatment planning data from 100 patients have been analyzed with a risk model based on the United Nations Scientific Committee on the Effects of Atomic Radiation competition model. The risk model can account for dose heterogeneity and fractionation effects characteristic for modern radiotherapy. Biologically relevant parameters from clinical and experimental data have been used with the model.

    RESULTS: The results suggested that changes in prescribed dose could lead to a modification of the risks for individual organs surrounding the clinical target volume (CTV) but that the total risk appears to be less affected by changes in the target dose. Larger differences are observed for modifications of the margins between the CTV and the PTV because these have direct impact onto the dose level and dose heterogeneity in the healthy tissues surrounding the CTV. Interpatient anatomic variations also have to be taken into consideration for studies of the risk for cancer induction from radiotherapy.

    CONCLUSIONS: 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.

  • 19.
    Daşu, Alexandru
    et al.
    Umeå University.
    Toma-Daşu, Iuliana
    Stockholm University and Karolinska Institutet.
    Franzén, Lars
    Umeå University.
    Widmark, Anders
    Umeå University.
    Nilsson, Per
    Umeå University.
    The risk for secondary cancers in patients treated for prostate carcinoma – an analysis with the competition dose response model2009In: IFMBE Proceedings, Vol. 25/III, 237-240 p.Article in journal (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.

  • 20.
    Daşu, Alexandru
    et al.
    Umeå University.
    Toma-Daşu, Iuliana
    Umeå University.
    Karlsson, Mikael
    Umeå University.
    The effects of hypoxia on the theoretical modelling of tumour control probability2005In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 44, no 6, 563-571 p.Article in journal (Refereed)
    Abstract [en]

    Theoretical modelling of tumour response is increasingly used for the prediction of treatment result and has even been proposed as ranking criteria in some algorithms for treatment planning. Tumour response to radiation is greatly influenced by the details of tumour microenvironment, especially hypoxia, that unfortunately are not always taken into consideration for these simulations. This paper intends to investigate the effects of various assumptions regarding hypoxia distribution in tumours on the predictions of treatment outcome. A previously developed model for simulating theoretically the oxygenation in biologically relevant tissues, including results from oxygen diffusion, consumption and perfusion limitations in tumours, was used to investigate the effects of the different aspects of hypoxia on the predictions of treatment outcome. Thus, both the continuous distribution of values and the temporal variation of hypoxia patterns were taken into consideration and were compared with a 'black-and-white' simplification with a fully hypoxic compartment and a fully oxic one. It was found that the full distribution of oxygenation in the tissue is needed for accurate results. The 'black-and-white' simplification, while showing the same general trends for the predictions of radiation response, could lead to serious over-estimations of the tumour control probability. It was also found that the presence of some hypoxia for every treatment fraction leads to a decrease in the predicted local control, regardless of the change of the hypoxic pattern throughout the duration of the whole treatment. The results thus suggest that the assumptions regarding tumour hypoxia influence very much the predictions of treatment outcome and therefore they have to be very carefully incorporated into the theoretical modelling.

  • 21.
    Daşu, Alexandru
    et al.
    Umeå University.
    Toma-Daşu, Iuliana
    Umeå University.
    Karlsson, Mikael
    Umeå University.
    Theoretical simulation of tumour oxygenation and results from acute and chronic hypoxia2003In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 48, no 17, 2829-2842 p.Article in journal (Refereed)
    Abstract [en]

    The tumour microenvironment is considered to be responsible for the outcome of cancer treatment and therefore it is extremely important to characterize and quantify it. Unfortunately, most of the experimental techniques available now are invasive and generally it is not known how this influences the results. Non-invasive methods on the other hand have a geometrical resolution that is not always suited for the modelling of the tumour response. Theoretical simulation of the microenvironment may be an alternative method that can provide quantitative data for accurately describing tumour tissues. This paper presents a computerized model that allows the simulation of the tumour oxygenation. The model simulates numerically the fundamental physical processes of oxygen diffusion and consumption in a two-dimensional geometry in order to study the influence of the different parameters describing the tissue geometry. The paper also presents a novel method to simulate the effects of diffusion-limited (chronic) hypoxia and perfusion-limited (acute) hypoxia. The results show that all the parameters describing tissue vasculature are important for describing tissue oxygenation. Assuming that vascular structure is described by a distribution of inter-vessel distances, both the average and the width of the distribution are needed in order to fully characterize the tissue oxygenation. Incomplete data, such as distributions measured in a non-representative region of the tissue, may not give relevant tissue oxygenation. Theoretical modelling of tumour oxygenation also allows the separation between acutely and chronically hypoxic cells, a distinction that cannot always be seen with other methods. It was observed that the fraction of acutely hypoxic cells depends not only on the fraction of collapsed blood vessels at any particular moment, but also on the distribution of vessels in space as well. All these suggest that theoretical modelling of tissue oxygenation starting from the basic principles is a robust method that can be used to quantify the tissue oxygenation and to provide input parameters for other simulations.

  • 22.
    Daşu, Alexandru
    et al.
    Umeå University.
    Toma-Daşu, Iuliana
    Umeå University.
    Olofsson, Jörgen
    Umeå University.
    Karlsson, Mikael
    Umeå University.
    The use of risk estimation models for the induction of secondary cancers following radiotherapy2005In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 44, no 4, 339-347 p.Article in journal (Refereed)
    Abstract [en]

    Theoretical predictions of cancer risk from radiotherapy may be used as a complementary criterion for the selection of successful treatment plans together with the classical approach of estimating the possible deterministic effects. However, any such attempts must take into consideration the specific features of radiation treatment. This paper explores several possible methods for estimating the risk of cancer following radiotherapy in order to investigate the influences of the fractionation and the non-uniformity of the dose to the irradiated organ. The results indicate that dose inhomogeneity plays an important role in predicting the risk for secondary cancer and therefore for predictive purposes it must be taken into account through the use of the dose volume histograms. They also suggest that the competition between cell killing and the induction of carcinogenic mutations has to be taken into consideration for more realistic risk estimations. Furthermore, more realistic parameters could be obtained if this competition is also included in analyses of epidemiological data from radiotherapy applications.

  • 23.
    Daşu, Iuliana Livia
    et al.
    Umeå University.
    Daşu, Alexandru
    Umeå University.
    Denekamp, Juliana
    Umeå University.
    Fowler, Jack F
    University of Wisconsin Hospital, USA.
    Comments on 'Standard effective doses for proliferative tumours'2000In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 45, no 10, L45-L50 p.Article in journal (Refereed)
    Abstract [en]

    n/a

  • 24.
    Flejmer, Anna M.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Chehrazi, Behnaz
    Department of Physics, Stockholm University, Stockholm, Sweden.
    Josefsson, Dan
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Toma-Dasu, Iuliana
    Medical Radiation Physics, Stockholm University and Karolinska Institutet, Stockholm, Sweden.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. The Skandion Clinic, Uppsala, Sweden / .
    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, 88-94 p.Article 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 4.7 mm (range 0.5-14.6 mm). 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 3.1-4.5 Gy (RBE)], while inhalation increased it [average dose 5.8-6.8 Gy (RBE)]. The individual values depended on the field arrangement. Smaller differences were seen for the heart [average dose 0.1-0.2 Gy (RBE)] and the LAD [1.9-4.6 Gy (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.

  • 25.
    Fowler, Jack F.
    et al.
    University of Wisconsin Medical School, Madison, WI, USA.
    Dasu, Alexandru
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Optimum overall treatment time in radiation oncology2015Book (Refereed)
    Abstract [en]

    John "Jack" Fowler has been a busy radiation biology researcher and teacher. He has written 581 papers over the last 65 plus years. He has also received nearly every honor the medical physics field can bestow. But Jack is not done. He says it is time he wrote a book. Jack's new book, Optimum overall treatment time in radiation oncology, sums up the key concepts relating to optimum fractionation in radiation therapy that have interested him all these years.

  • 26.
    Fowler, Jack F.
    et al.
    University of Wisconsin Medical School, Madison, WI, USA.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet, Stockholm, Sweden .
    Dasu, Alexandru
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Is the α/β ratio for prostate tumours really low and does it vary with the level of risk at diagnosis?2013In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 33, no 3, 1009-1011 p.Article in journal (Refereed)
    Abstract [en]

    Aim: To answer the questions: Is the α/β ratio (radiosensitivity to size of dose-per-fraction) really low enough to justify using a few large dose fractions instead of the traditional many small doses? Does this parameter vary with prognostic risk factors? Methods and Materials: Three large statistical overviews are critiqued, with results for 5,000, 6,000 and 14,000 patients with prostate carcinoma, respectively. Results: These major analyses agree in finding the average α/β ratio to be less than 2 Gy: 1.55 (95% confidence interval=0.46-4.52), 1.4 (0.9-2.2), and the third analysis 1.7 (1.4-2.2) by ASTRO and 1.6 (1.2-2.2) by Phoenix criteria. All agree that α/β values do not vary significantly with the low, intermediate, high and “all included” risk factors. Conclusion: The high sensitivity to dose-per-fraction is an intrinsic property of prostate carcinomas and this supports the use of hypofractionation to increase the therapeutic gain for these tumours with dose-volume modelling to reduce the risk of late complications in rectum and bladder.

  • 27.
    Gudowska, Irena
    et al.
    Stockholm University, Sweden.
    Ardenfors, Oscar
    Stockholm University, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Sweden.
    Dasu, Alexandru
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Radiation burden from secondary doses to patients undergoing radiation therapy with photons and light ions and radiation doses from imaging modalities2014In: Radiation Protection Dosimetry, ISSN 0144-8420, E-ISSN 1742-3406, Vol. 161, no 1-4, 357-362 p.Article in journal (Refereed)
    Abstract [en]

    Ionising radiation is increasingly used for the treatment of cancer, being the source of a considerable fraction of the medical irradiation to patients. With the increasing success rate of cancer treatments and longer life expectancy of the treated patients, the issue of secondary cancer incidence is of growing concern, especially for paediatric patients who may live long after the treatment and be more susceptible to carcinogenesis. Also, additional imaging procedures like CT, kV and MV imaging and PET, alone or in conjunction with radiation therapy, may add to the radiation burden associated with the risk of occurrence of secondary cancers. This work has been based on literature studies and is focussed on the assessment of secondary doses to healthy tissues that are delivered by the use of modern radiation therapy and diagnostic imaging modalities in the clinical environment.

  • 28.
    Lindblom, Emely
    et al.
    Stockholm University.
    Antonovic, Laura
    Stockholm University.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Lax, Ingmar
    Karolinska University Hospital.
    Wersäll, Peter
    Karolinska University Hospital.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Treatment fractionation for stereotactic radiotherapy of lung tumours: a modelling study of the influence of chronic and acute hypoxia on tumour control probability2014In: Radiation Oncology, ISSN 1748-717X, Vol. 9, Article ID 149- p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 29.
    Lindblom, Emely
    et al.
    Stockholm University, Stockholm, Sweden.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. The Skandion Clinic, Uppsala, Sweden.
    Beskow, Catharina
    Karolinska Hospital, Stockholm, Sweden.
    Toma-Dasu, Iuliana
    Stockholm Universitym Stockholm Sweden; Karolinska Institutet, Stockholm, Sweden.
    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, 560-572 p.Article 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, D50, were in agreement with clinically-observed values for high cure rates if fast reoxygenation was assumed. The D50 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.

  • 30.
    Lindblom, Emely
    et al.
    Stockholm University.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Lax, Ingmar
    Karolinska University Hospital.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Survival and tumour control probability in tumours with heterogeneous oxygenations: A comparison between the linear-quadratic and the universal survival curve models for high doses2014In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, no 8, 1035-1040 p.Article in journal (Refereed)
    Abstract [en]

    Background: The validity of the linear-quadratic (LQ) model at high doses has been questioned due to a decreasing agreement between predicted survival and experimental cell survival data. A frequently proposed alternative is the universal survival curve (USC) model, thought to provide a better fit in the high-dose region. The comparison between the predictions of the models has mostly been performed for uniform populations of cells with respect to sensitivity to radiation. This study aimed to compare the two models in terms of cell survival and tumour control probability (TCP) for cell populations with mixed sensitivities related to their oxygenation.

    Methods: The study was performed in two parts. For the first part, cell survival curves were calculated with both models assuming various homogeneous populations of cells irradiated with uniform doses. For the second part, a realistic 3D-model of complex tumour oxygenation was used to study the impact of the differences in cell survival on the modelled tumour control probability. Cellular response was assessed with the LQ and USC models at voxel level and a Poisson TCP model at tumour level.

    Results: For hypoxic tumours, the disputed continuous bend of the LQ survival curve was counteracted by the increased radio-resistance of the hypoxic cells and the survival curves started to diverge only at much higher doses than for oxic tumours. This was also reflected by the TCP curves for hypoxic tumours for which the difference in D50 values for the LQ and USC models was reduced from 5.4 to 0.2 Gy for 1 and 3 fractions respectively in a tumour with only 1.1% hypoxia and from 9.5 to 0.4 Gy in a tumour with 11.1% hypoxia.

    Conclusions: For a large range of fractional doses including hypofractionated schemes, the difference in predicted survival and tumour control probability between the LQ and USC models for tumours with heterogeneous oxygenation was found to be negligible.

  • 31.
    Lindblom, Emely
    et al.
    Stockholm University.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Optimal fractionation in radiotherapy for non-small cell lung cancer - a modelling approach2015In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 9, 1592-1598 p.Article in journal (Refereed)
    Abstract [en]

    Background. Conventionally fractionated radiotherapy (CFRT) has proven ineffective in treating non-small cell lung cancer while more promising results have been obtained with stereotactic body radiotherapy (SBRT). Hypoxic tumours, however, might present a challenge to extremely hypofractionated schedules due to the decreased possibility for inter-fraction fast reoxygenation. A potentially successful compromise might be found in schedules employing several fractions of varying fractional doses. In this modelling study, a wide range of fractionation schedules from single-fraction treatments to heterogeneous, multifraction schedules taking into account repair, repopulation, reoxygenation and radiosensitivity of the tumour cells, has been explored with respect to the probability of controlling lung tumours.

    Material and methods. The response to radiation of tumours with heterogeneous spatial and temporal oxygenation was simulated including the effects of accelerated repopulation and intra-fraction repair. Various treatments with respect to time, dose and fractionation were considered and the outcome was estimated as Poisson-based tumour control probability for local control.

    Results. For well oxygenated tumours, heterogeneous fractionation could increase local control while hypoxic tumours are not efficiently targeted by such treatments despite reoxygenation. For hypofractionated treatments employing large doses per fraction, a synergistic effect was observed between intra-fraction repair and inter-fraction fast reoxygenation of the hypoxic cells as demonstrated by a reduction in D50 from 53.3 Gy for 2 fractions to 52.7 Gy for 5 fractions.

    Conclusions. For well oxygenated tumours, heterogeneous fractionation schedules could increase local control rates substantially compared to CFRT. For hypoxic tumours, SBRT-like hypofractionated schedules might be optimal despite the increased risk of intra-fraction repair due to a synergistic effect with inter-fraction reoxygenation.

  • 32.
    Lindblom, Emely
    et al.
    Stockholm University, Sweden.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. The Skandion Clinic, Uppsala, Sweden.
    Uhrdin, Johan
    RaySearch Laboratories AB.
    Even, Aniek J. G.
    Maastricht University Medical Center, Maastricht, The Netherlands.
    van Elmpt, Wouter
    Maastricht University Medical Center, Maastricht, The Netherlands.
    Lambin, Philippe
    Maastricht University Medical Center, Maastricht, The Netherlands.
    Wersäll, Peter
    Karolinska University Hospital, Stockholm, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet, Sweden.
    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, 819-825 p.Article 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.

  • 33.
    Marcu, Loredana G.
    et al.
    University of Oradea, Romania and University of Adelaide, Australia.
    Bezak, Eva
    Royal Adelaide Hospital, Australia.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet, Sweden.
    Dasu, Alexandru
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Predictive models of tumour response to treatment using functional imaging techniques2015In: Computational & Mathematical Methods in Medicine, ISSN 1748-670X, E-ISSN 1748-6718, Vol. 2015, Article ID 571351- p.Article in journal (Other academic)
  • 34.
    Marcu, Loredana G.
    et al.
    University of Oradea, Romania and University of Adelaide, Australia.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    The six Rs of head and neck cancer radiotherapy2015In: Contemporary Issues in Head and Neck Cancer Management / [ed] Loredana G. Marcu, Rijeka: InTech , 2015, 35-58 p.Chapter in book (Refereed)
    Abstract [en]

    While the management of head and neck cancer has evolved over the last few decades, there are still several challenges and unanswered questions that need solutions. This book is a small compilation of some topical aspects regarding head and neck cancer treatment, including the etiology of HPV-positive oropharyngeal cancers and risk factors in the young population, the challenge of surgical margin definition and the perennial problem of systemic treatment due to distant metastases. Radiobiological aspects are also covered through the Rs of radiotherapy, with a couple of chapters being dedicated to radioresistance and tumour microenvironment. Contemporary Issues in Head and Neck Cancer Management comes as an addition to the existing literature that aims to tackle this radiobiologically challenging tumour.

  • 35.
    Sandström, Helena
    et al.
    Stockholm University and Karolinska Institutet.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Radiobiological framework for the evaluation of stereotactic radiosurgery plans for invasive brain tumours2013In: ISRN Oncology, ISSN 2090-567X, E-ISSN 2090-567X, Vol. 2013, Article ID 527251- p.Article in journal (Refereed)
    Abstract [en]

    This study presents a radiobiological formalism for the evaluation of the treatment plans with respect to the probability of controlling tumours treated with SRS accounting for possible infiltrations of malignant cells beyond the margins of the delineated target.

    Treatments plans devised for three anaplastic astrocytoma cases were assumed for this study representing cases with different difficulties for target coverage. Several scenarios were considered regarding the infiltration patterns. Tumour response was described in terms of tumour control probability (TCP) assuming a Poisson model taking into account the initial number of clonogenic cells and the cell survival.

    The results showed the strong impact of the pattern of infiltration of tumour clonogens outside the delineated target on the outcome of the treatment. The treatment plan has to take into account the existence of the possible microscopic disease around the visible lesion otherwise the high gradients around the target effectively prevent the sterilisation of the microscopic spread leading to low probability of control, in spite of the high dose delivered to the target.

    From this perspective, the proposed framework offers a further criterion for the evaluation of stereotactic radiosurgery plans taking into account the possible infiltration of tumour cells around the visible target.

  • 36.
    Toma-Dasu, Iuliana
    et al.
    Stockholm University and Karolinska Institutet, Sweden.
    Dasu, Alexandru
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Modelling tumour oxygenation, reoxygenation and implications on treatment outcome2013In: Computational and Mathematical Methods in Medicine, ISSN 1748-670X, Vol. 2013, 141087Article in journal (Refereed)
    Abstract [en]

    Oxygenation is an important component of the tumour microenvironment,having a significant impact on the progression and management of cancer. Theoreticaldetermination of tissue oxygenation through simulations of the oxygen transportprocess is a powerful tool to characterise the spatial distribution of oxygenon the microscopic scale and its dynamics and to study its impact on theresponse to radiation. Accurate modelling of tumour oxygenation must take intoaccount important aspects that are specific to tumours, making the quantitativecharacterisation of oxygenation rather difficult. This review aims to discussthe important aspects of modelling tumour oxygenation, reoxygenation andimplications for treatment.

  • 37.
    Toma-Dasu, Iuliana
    et al.
    Stockholm University and Karolinska Institutet, Stockholm, Sweden.
    Dasu, Alexandru
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Quantitative hypoxia imaging for treatment planning of radiotherapy2014In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, Vol. 812, 143-148 p.Article in journal (Refereed)
    Abstract [en]

    Tumour oxygenation is an important determinant of radiotherapy outcome as it could modulate cellular radiation sensitivity. Advanced PET imaging able to characterise this microenvironmental aspect in vivo might be used to devise counteracting therapies as it could provide information on the severity and the spatial distribution of the hypoxic regions. This study reviews the advantages and limitations of PET for imaging and quantifying tumour hypoxia and proposes a novel approach to obtain absolute levels of hypoxia from PET images through the use of EPR oximetry. This would offer a significant advantage over proposals based on empirical conversions of the intensities in the PET images to relative radiosensitivities. Thus, tumour hypoxia must be taken into account at the stage of treatment planning for photons and particle therapy by accounting for its extent and severity through the use of PET imaging combined with absolute EPR measurements.

  • 38.
    Toma-Dasu, Iuliana
    et al.
    Stockholm University and Karolinska Institutet.
    Dasu, Alexandru
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences.
    Towards multidimensional radiotherapy: key challenges for treatment individualisation2015In: Computational & Mathematical Methods in Medicine, ISSN 1748-670X, E-ISSN 1748-6718, Vol. 2015, Article ID 934380- p.Article, review/survey (Refereed)
    Abstract [en]

    Functional and molecular imaging of tumours have offered the possibility of redefining the target in cancer therapy and individualising the treatment with a multidimensional approach that aims to target the adverse processes known to impact negatively upon treatment result. Following the first theoretical attempts to include imaging information into treatment planning, it became clear that the biological features of interest for targeting exhibit considerable heterogeneity with respect to magnitude, spatial, and temporal distribution, both within one patient and between patients, which require more advanced solutions for the way the treatment is planned and adapted. Combining multiparameter information from imaging with predictive information from biopsies and molecular analyses as well as in treatment monitoring of tumour responsiveness appears to be the key approach to maximise the individualisation of treatment. This review paper aims to discuss some of the key challenges for incorporating into treatment planning and optimisation the radiobiological features of the tumour derived from pretreatment PET imaging of tumour metabolism, proliferation, and hypoxia and combining them with intreatment monitoring of responsiveness and other predictive factors with the ultimate aim of individualising the treatment towards the maximisation of response.

  • 39.
    Toma-Dasu, Iuliana
    et al.
    Stockholm University, Sweden.
    Hedman, Mattias
    Karolinska University Hospital, Sweden.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    The value of individual measurements for tumor control probability predictions in head and neck patients2015In: IFMBE Proceedings, Vol. 51, 1675-1678 p.Article in journal (Refereed)
    Abstract [en]

    In the age of personalized cancer medicine, individual measurements of in vitro radiosensitivity and proliferation parameters have great potential for predicting treatment outcome. However, cellular radiosensitivity is quite heterogeneous and therefore concerns exist towards its impact on treatment predictions. It was therefore the purpose of this study to investigate this aspect. Individually-determined radiosensitivities and potential doubling times, as well as tumor volumes from 46 head-and-neck carcinomas treated with radiotherapy, were used to predict tumor control probabilities (TCP) under various biologically-relevant assumptions for heterogeneity in radiosensitivity. TCP predictions were then compared to clinical local control using a ROC curve analysis. The analysis showed that TCP calculated under the assumption of heterogeneous radiosensitivity have the same power of distinguishing between patients with or without local control as from single values for the radiobiological parameters (a sensitivity of 66% and a specificity of 80% for an area under the curve of 0.69). The only difference was in the discrimination criterion (TCP>93% for single parameters and TCP>65% for heterogeneous parameters), illustrating the difference in appearance of the TCP curve under the assumption of heterogeneity. Nevertheless, the results showed that individually determined radiobiological parameters could be quite effective towards predicting treatment outcome for individual patients.

  • 40.
    Toma-Dasu, Iuliana
    et al.
    Stockholm University and Karolinska Institute, Sweden.
    Sandström, Helena
    Stockholm University, Sweden.
    Barsoum, Pierre
    Karolinska University Hospital, Stockholm, Sweden.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    To fractionate or not to fractionate? That is the question for the radiosurgery of hypoxic tumors2014In: Journal of Neurosurgery, ISSN 0022-3085, Vol. 121, no Supplement 2, 110-115 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: This study aimed to investigate the impact of tumour hypoxia on treatment outcome for metastases commonly treated with radiosurgery using one fraction of radiation. It also aimed to investigate the gain that could be expected from reoxygenation if the treatment is delivered in few radiation fractions.

    Methods: In silico metastases-like radiosurgery targets were modelled with respect to size, density of clonogenic cells and oxygenation. Treatment plans were produced for the targets using Leksell GammaPlan delivering clinically relevant doses and evaluating the tumour control probability (TCP) that could be expected in each case. Fractionated schedules with 3, 4 and 5 fractions resulting in similar biological effective doses were also considered for the larger target and TCP was determined under the assumption that local reoxygenation takes place between fractions.

    Results: The results showed that well-oxygenated small and medium-size metastases are well controlled by radiosurgery treatments delivering 20 or 22 Gy at the periphery, the TCP ranging from 90% to 100%. If they are moderately hypoxic the TCP could decrease to 60%. For large metastases, the TCP ranges from 0 to 19% depending on tumour oxygenation. However, for fractionated treatments, the TCP for hypoxic tumours could significantly increase up to 51%, if reoxygenation occurs between fractions.

    Conclusion: This study shows that hypoxia worsens the response to single-fraction radiosurgery, especially for large tumours. However, fractionated therapy for large hypoxic tumours might considerably improve the TCP and might constitute a simple way to improve the outcome of radiosurgery for patients with hypoxic tumours.

  • 41.
    Toma-Dasu, Iuliana
    et al.
    Stockholm University and Karolinska Institutet.
    Uhrdin, Johan
    RaySearch Laboratories AB, Stockholm.
    Antonovic, Laura
    Stockholm University and Karolinska Institutet.
    Dasu, Alexandru
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences.
    Nuyts, Sandra
    Leuven University Hospitals, Gasthuisberg, Belgium.
    Dirix, Piet
    Leuven University Hospitals, Gasthuisberg, Belgium.
    Haustermans, Karin
    Leuven University Hospitals, Gasthuisberg, Belgium.
    Brahme, Anders
    Karolinska Institutet.
    Dose prescription and treatment planning based on FMISO-PET hypoxia2012In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 2, 222-230 p.Article in journal (Refereed)
    Abstract [en]

    Purpose. The study presents the implementation of a novel method for incorporating hypoxia information from PET-CT imaging into treatment planning and estimates the efficiency of various optimization approaches. Its focuses on the feasibility of optimizing treatment plans based on the non-linear conversion of PET hypoxia images into radiosensitivity maps from the uptake properties of the tracers used.

    Material and methods. PET hypoxia images of seven head-and-neck cancer patients were used to determine optimal dose distributions needed to counteract the radiation resistance associated with tumor hypoxia assuming various scenarios regarding the evolution of the hypoxic compartment during the treatment. A research planning system for advanced studies has been used to optimize IMRT plans based on hypoxia information from patient PET images. These resulting plans were compared in terms of target coverage for the same fulfilled constraints regarding the organs at risk.

    Results. The results of a planning study indicated the clinical feasibility of the proposed method for treatment planning based on PET hypoxia. Antihypoxic strategies would lead to small improvements in all the patients, but higher effects are expected for the fraction of patients with hypoxic tumors. For these, individualization of the treatment based on hypoxia PET imaging could lead to improved treatment outcome while creating the premises for limiting the irradiation of the surrounding normal tissues.

    Conclusions. The proposed approach offers the possibility of improved treatment results as it takes into consideration the heterogeneity and the dynamics of the hypoxic regions. It also provides early identification of the clinical cases that might benefit from dose escalation as well as the cases that could benefit from other counter-hypoxic measures.

  • 42.
    Toma-Dasu, Iuliana
    et al.
    Stockholm University and Karolinska Institutet.
    Uhrdin, Johan
    RaySearch Laboratories AB.
    Lazzeroni, Marta
    Karolinska Institutet.
    Carvalho, Sara
    Maastricht University Medical Center, Maastricht, The Netherlands.
    van Elmpt, Wouter
    Maastricht University Medical Center, Maastricht, The Netherlands.
    Lambin, Philippe
    Maastricht University Medical Center, Maastricht, The Netherlands.
    Dasu, Alexandru
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Evaluating tumor response of non-small cell lung cancer patients with 18F-fludeoxyglucose positron emission tomography: potential for treatment individualization2015In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, Vol. 91, no 2, 376-384 p.Article in journal (Refereed)
    Abstract [en]

    Objective: To assess early tumor responsiveness and the corresponding effective radiosensitivity for individual patients with non-small cell lung cancer (NSCLC) based on 2 successive 18F-fludeoxyglucose positron emission tomography (FDG-PET) scans.

    Methods and Materials: Twenty-six NSCLC patients treated in Maastricht were included in the study. Fifteen patients underwent sequential chemoradiation therapy, and 11 patients received concomitant chemoradiation therapy. All patients were imaged with FDG before the start and during the second week of radiation therapy. The sequential images were analyzed in relation to the dose delivered until the second image. An operational quantity, effective radiosensitivity, αeff, was determined at the voxel level. Correlations were sought between the average αeff or the fraction of negative αeff values and the overall survival at 2 years. Separate analyses were performed for the primary gross target volume (GTV), the lymph node GTV, and the clinical target volumes (CTVs).

    Results: Patients receiving sequential treatment could be divided into responders and nonresponders, using a threshold for the average αeff of 0.003 Gy-1 in the primary GTV, with a sensitivity of 75% and a specificity of 100% (P<.0001). Choosing the fraction of negative αeff as a criterion, the threshold 0.3 also had a sensitivity of 75% and a specificity of 100% (P<.0001). Good prognostic potential was maintained for patients receiving concurrent chemotherapy. For lymph node GTV, the correlation had low statistical significance. A cross-validation analysis confirmed the potential of the method.

    Conclusions: Evaluation of the early response in NSCLC patients showed that it is feasible to determine a threshold value for effective radiosensitivity corresponding to good response. It also showed that a threshold value for the fraction of negative αeff could also be correlated with poor response. The proposed method, therefore, has potential to identify candidates for more aggressive strategies to increase the rate of local control and also avoid exposing to unnecessary aggressive therapies the majority of patients responding to standard treatment.

  • 43.
    Toma-Dasu, luliana
    et al.
    Stockholm University and Karolinska Institutet.
    Dasu, Alexandru
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Biologically-optimised IMRT based on molecular imaging of tumour hypoxia - the impact of the tracer used2013In: IFMBE Proceedings, Vol. 39, 1742-1745 p.Article in journal (Refereed)
    Abstract [en]

    One of the most challenging tasks of current radiation therapy is the individualisation of the treatment plans through biological optimisation and adaptation to functional aspects. This study aims to explore the robustness of a newly proposed method of treatment planning optimisation based on patient-specific radiation sensitivity determined by tumour hypoxia. Theoretical three-dimensional tumours with heterogeneous oxygenations were used to investigate the efficiency of various approaches for calculating the optimal dose distribution and the effects of reoxygenation during the treatment duration. The impact of the spatial averaging implied by the imaging method in combination with the binding properties of the tracer used has also been investigated. It has been shown that a newly proposed method for dose prescription based on functional imaging of hypoxia could lead to improved local control for several tracers that could be practically used. The approach for dose prescription appears to have a significant impact for tumours with dynamic hypoxia. Furthermore, the average implied by the imaging method could reduce the effectiveness of the method, but it still has the potential to provide significantly better results than methods employing highly heterogeneous dose distributions. The results showed that planning and optimisation of treatments based on hypoxia information from PET images is feasible and could provide the tool for individualising the planning on biological and molecular bases.

  • 44.
    Toma-Daşu, Iuliana
    et al.
    Stockholm University and Karolinska Institutet.
    Daşu, Alexandru
    Umeå University.
    Brahme, Anders
    Stockholm University and Karolinska Institutet.
    Dose prescription and optimisation based on tumour hypoxia2009In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 48, no 8, 1181-1192 p.Article 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.

  • 45.
    Toma-Daşu, Iuliana
    et al.
    Karolinska Institutet.
    Daşu, Alexandru
    Umeå University.
    Brahme, Anders
    Karolinska Institutet.
    Influence of acute tumour hypoxia on radiation therapy outcome2005In: AAPM Symposium Proceedings No. 14: Physical, Chemical and Biological Targeting in Radiation Oncology, Madison, Wisconsin: Medical Physics Publishing , 2005, 111-117 p.Chapter in book (Refereed)
    Abstract [en]

    One of the most important factors that influence the outcome of cancer treatment is tumor hypoxia that is caused by a deficient vascular network and an increased interstitial pressure. Tumor hypoxia can be divided into two types depending on the underlying mechanism. Thus, chronic hypoxia is caused mainly by the limited diffusion of oxygen into tissue due to cellular consumption and might also be influenced by a high interstitial pressure, and changes very slowly in time. Acute hypoxia might also appear in tumors due to transient perfusion-related events such as the temporary closure of blood vessels and has a finite lifetime ranging from minutes to hours. The temporal variation of acute hypoxia influences the treatment outcome in a more complex way than the chronic hypoxia. The aim of this study is to simulate the influences of various amounts of acute hypoxia on the treatment outcome. The present model for tumor oxygenation allows the simulation of the two forms of tumor hypoxia. We have studied the reduced tumor oxygenations resulting from the temporary shutting down of a given fraction of tumor blood vessels at every radiation fraction throughout the treatment. The particular effect of acute hypoxia on the treatment outcome was evaluated by calculating the effective tumor control probability with or without acute hypoxia. The results suggest that the presence of acute hypoxia during every treatment fraction reduces the tumor control probability significantly. As consequence, higher and higher doses are needed to achieve a certain level of local control in tumors when the fraction of closed vessels increases. These results therefore show that acute hypoxia has to be taken into consideration for accurate simulations of radiation treatments and that an individual approach for each patient might be desirable for maximum improvement of outcome.

  • 46.
    Toma-Daşu, Iuliana
    et al.
    Stockholm University and Karolinska Institutet.
    Daşu, Alexandru
    Norrland University Hospital.
    Brahme, Anders
    Karolinska Institutet.
    Quantifying tumour hypoxia by PET imaging--a theoretical analysis2009In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, Vol. 645, 267-272 p.Article 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.

  • 47.
    Toma-Daşu, Iuliana
    et al.
    Umeå University.
    Daşu, Alexandru
    Umeå University.
    Karlsson, Mikael
    Umeå University.
    Conversion of polarographic electrode measurements--a computer based approach2005In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 50, no 19, 4581-4591 p.Article in journal (Refereed)
    Abstract [en]

    The polarographic measurement of tissue oxygenation is one of the most widely used methods in clinical practice for the quantification of tumour hypoxia. However, due to the particular features of the electrode measuring process, the results of the measurements do not accurately reflect the tumour oxygenation. This study aimed to find a correlation between the electrode measurements and the tumour oxygenation in an attempt to improve the accuracy of the predictions regarding the response to treatment based on electrode measurements. A previously developed computer model that allows the simulation of tumour tissue and electrode measurements was used. The oxygenation of a large number of tumours with biologically relevant distributions of blood vessels was theoretically calculated. Simulations of electrode measurements allowed the comparison between the real tissue oxygenation and the results obtained with the electrode. A semi-empirical relationship between the hypoxic fraction measured by the electrode and the real hypoxic fraction in the tissue has been found. The impact of the correction of the electrode measurements in terms of predictions for tumour control probability was estimated for a few clinical examples. The range of possible true values corresponding to one measurement has also proven useful for explaining the apparently unexpected response to the treatment of some patients. The corrected hypoxic fraction which is believed to be closer to the real value of tissue hypoxia predicts much smaller control probabilities than the raw electrode measurements. This could provide an explanation for the apparently unexpected failure to respond to the treatment of some of the patients with apparently favourable tumour oxygenation. This also means that the electrode measurements cannot be used directly for the quantitative modelling of tumour response to the treatment. The conversion method proposed in this paper might however strengthen the statistical power of the correlations between the electrode measurements and the treatment outcome.

  • 48.
    Toma-Daşu, Iuliana
    et al.
    Umeå University.
    Daşu, Alexandru
    Umeå University.
    Karlsson, Mikael
    Umeå University.
    The relationship between temporal variation of hypoxia, polarographic measurements and predictions of tumour response to radiation2004In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 49, no 19, 4463-4475 p.Article in journal (Refereed)
    Abstract [en]

    The polarographic oxygen sensor is one of the most used devices for in vivo measurements of oxygen and many other measurement techniques for measuring tumour hypoxia are correlated with electrode measurements. Little is known however about the relationship between electrode measurements and the real tissue oxygenation. This paper investigates the influence of the temporal change of the hypoxic pattern on the electrode measurements and the tumour response. Electrode measurements and tumour response were simulated using a computer program that allows both the calculation of the tissue oxygenation with respect to the two types of hypoxia that might arise in tumours and the virtual insertion of the electrode into the tissue. It was therefore possible to control the amount of each type of hypoxia in order to investigate their influence on the measurement results. Tissues with several vascular architectures ranging from well oxygenated to poorly oxygenated were taken into consideration as might be seen in practice. The influence of the electrode measurements on the treatment outcome was estimated by calculating the tumour control probability for the tumours characterized either by the real or by the measured tumour oxygenation. We have simulated electrode oxygen measurements in different types of tissues, covering a wide range of tumour oxygenations. The results of the simulations showed that the measured distribution depends on the details of the vascular network and not on the type of hypoxia. We have also simulated the effects of the temporal change of the acute hypoxic pattern due to the opening and the closure of different blood vessels during a full fractionated treatment. The results of this simulation suggested that the temporal variation of the hypoxic pattern does not lead to significantly different results for the electrode measurements or the predicted tumour control probabilities. In conclusion, it was found that the averaging effect of the electrode leads to a systematic deviation between the actual oxygen distribution and the measured distribution. However, as the electrode reflects the general trends of the tissue oxygenation it has the potential of being used for the general characterization of tumour hypoxia even if the actual type of hypoxia measured by the electrode cannot be determined. Indeed, the change in time of the acute hypoxic region does not compensate for the lack of oxygenation at a specific moment and therefore does not influence the polarographic oxygen measurements.

  • 49.
    Toma-Daşu, Iuliana
    et al.
    Umeå University.
    Daşu, Alexandru
    Umeå University.
    Karlsson, Mikael
    Umeå University.
    Theoretical simulation of tumour hypoxia measurements2006In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, Vol. 578, no 12, 369-374 p.Article in journal (Refereed)
    Abstract [en]

    Our simulations suggested that measurements performed in a limited number of points in the tumour can be representative for the situation in the whole tumour. It has further been shown that the polarographic electrode cannot be used to measure small regions of hypoxia. In fact it has been suggested that the most important factor that determines the efficiency of the polarographic electrode is the spatial distribution of the hypoxic cells and not their type, and therefore the polarographic electrode cannot be used to make the distinction between acute and chronic hypoxia. The simulations have also shown that it is reasonable to assume that the electrode measurement can be correlated to the situation in the whole tissue, even though the correlation is only qualitative. And because the electrode measurements are greatly influenced by the averaging process, the quantitative use of the electrode measurements may lead to erroneous results, especially for modelling the treatment response.

  • 50.
    Toma-Daşu, Iuliana
    et al.
    Umeå University.
    Daşu, Alexandru
    Umeå University.
    Waites, Anthony
    Umeå University.
    Denekamp, Juliana
    Umeå University.
    Computer simulation of oxygen microelectrode measurements in tissues2003In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, Vol. 510, 157-161 p.Article in journal (Refereed)
12 1 - 50 of 54
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