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  • 1.
    Antonovic, Laura
    et al.
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Brahme, Anders
    Furusawa, Yoshiya
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Radiobiological description of the LET dependence of the cell survival of oxic and anoxic cells irradiated by carbon ions2013In: Journal of radiation research, ISSN 0449-3060, E-ISSN 1349-9157, Vol. 54, no 1, 18-26 p.Article in journal (Refereed)
    Abstract [en]

    Light-ion radiation therapy against hypoxic tumors is highly curative due to reduced dependence on the presence of oxygen in the tumor at elevated linear energy transfer (LET) towards the Bragg peak. Clinical ion beams using spread-out Bragg peak (SOBP) are characterized by a wide spectrum of LET values. Accurate treatment optimization requires a method that can account for influence of the variation in response for a broad range of tumor hypoxia, absorbed doses and LETs. This paper presents a parameterization of the Repairable Conditionally-Repairable (RCR) cell survival model that can describe the survival of oxic and hypoxic cells over a wide range of LET values, and investigates the relationship between hypoxic radiation resistance and LET. The biological response model was tested by fitting cell survival data under oxic and anoxic conditions for V79 cells irradiated with LETs within the range of 30 – 500 keV/μm. The model provides good agreement with experimental cell survival data for the range of LET investigated, confirming the robustness of the parameterization method. This new version of the RCR model is suitable for describing the biological response of mixed populations of oxic and hypoxic cells and at the same time taking into account the distribution of doses and LETs in the incident beam and its variation with depth in tissue. The model offers a versatile tool for the selection of LET and dose required in the optimization of the therapeutic effect, without severely affecting normal tissue in realistic tumors presenting highly heterogeneous oxic and hypoxic regions.

  • 2.
    Antonovic, Laura
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Dasu, Alexandru
    Linköping University, Sweden.
    Furusawa, Yoshiya
    National Institute of Radiological Sciences, Japan.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    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.

  • 3.
    Antonovic, Laura
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Lindblom, Emely
    Stockholm University, Faculty of Science, Department of Physics.
    Dasu, Alexandru
    Bassler, Niels
    Furusawa, Yoshiya
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, 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.

  • 4. Beskow, Catharina
    et al.
    Ågren-Cronqvist, Anna-Karin
    Lewensohn, Rolf
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics.
    Biological effective dose evaluation and assessment of rectal and bladder complications for cervical cancer treated with radiotherapy and surgery2012In: Journal of Contemporary Brachytherapy, ISSN 1689-832X, E-ISSN 2081-2841, Vol. 4, no 4, 205-212 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: This study aims to retrospectively evaluate dosimetric parameters calculated as biological effective dose in relation to outcome in patients with cervical cancer treated with various treatment approaches including radiotherapy, with and without surgery.

    Methods and Materials: Calculations of biological effective dose (BED) were performed on data from a retrospective analysis of 171 patients with cervical carcinoma stages IB-IIB treated with curative intent between January 1989 and December 1991. 43 patients were treated only with radiotherapy and 128 patients were treated with a combination of radiotherapy and surgery. External beam radiotherapy was delivered with 6-21 MV photons from linear accelerators. Brachytherapy was delivered either with a manual radium technique or with a remote afterloading technique. The treatment outcome was evaluated at 5 years.

    Results: The disease-specific survival rate was 87% for stage IB, 75% for stage IIA and 54% for stage IIB, while the overall survival rates were 84% for stage IB, 68% for stage IIA and 43% for stage IIB. Patients treated only with radiotherapy had a local control rate of 77% which was comparable to that for radiotherapy and surgery patients (78%). Late complications were recorded in 25 patients (15%). Among patients treated with radiotherapy and surgery, differences in radiation dose calculated as BED10 did not seem to influence survival. For patients treated with radiotherapy only, a higher BED10 was correlated to a higher overall survival (p=0.0075). The dose response parameters found based on biological effective dose calculations were D50=85.2 Gy10 and γ=1.62 for survival and D50=61.6 Gy10 and γ=0.92 for local control.

    Conclusions: The outcome correlates with biological effective dose for patients treated with radiation therapy alone, but not for patients treated with radiotherapy and surgery. No correlations were found between BED and late toxicity from bladder and rectum.

  • 5.
    Dasu, Alexandru
    et al.
    Linköping University, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Dose painting by numbers - do the practical limitations of the technique decrease or increase the probability of controlling tumours?2013In: IFMBE Proceedings, ISSN 1680-0737, 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.

  • 6.
    Dasu, Alexandru
    et al.
    Umeå University.
    Toma-Dasu, 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.

  • 7.
    Dasu, Alexandru
    et al.
    Linköping University, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Impact of increasing irradiation time on the treatment of prostate cancers2015In: IFMBE Proceedings, ISSN 1680-0737, 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.

  • 8.
    Dasu, Alexandru
    et al.
    Linköping University, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Impact of variable RBE on proton fractionation2013In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 40, no 1, 011705Article 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.

  • 9.
    Dasu, Alexandru
    et al.
    Umeå University.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Medical Radiation Physics (together with KI).
    In response to Dr. Karger et al.2008In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 70, no 5, 1614-1615 p.Article in journal (Refereed)
  • 10.
    Dasu, Alexandru
    et al.
    Linköping University, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, 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.

  • 11.
    Dasu, Alexandru
    et al.
    The Skandion Clinic.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Models for the risk of secondary cancers from radiation therapy2017In: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 42, 232-238 p.Article 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.

  • 12.
    Dasu, Alexandru
    et al.
    Linköping University, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    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.

  • 13.
    Dasu, Alexandru
    et al.
    Norrlands University Hospital.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Medical Radiation Physics (together with KI).
    The relationship between vascular oxygen distribution and tissue oxygenation2009In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, 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.

  • 14.
    Dasu, Alexandru
    et al.
    Umeå University.
    Toma-Dasu, Iuliana
    Umeå University.
    Theoretical simulation of tumour oxygenation--practical applications2006In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, 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.

  • 15.
    Dasu, Alexandru
    et al.
    Norrland University Hospital, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Medical Radiation Physics (together with KI).
    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.

  • 16.
    Dasu, Alexandru
    et al.
    Norrland University Hospital, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Medical Radiation Physics (together with KI).
    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.

  • 17.
    Dasu, Alexandru
    et al.
    Norrland University Hospital, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Medical Radiation Physics (together with KI). Karolinska Insitutet, Sweden.
    What is the clinically relevant relative biologic effectiveness? A warning for fractionated treatments with high linear energy transfer radiation2008In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 70, no 3, 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.

  • 18.
    Dasu, Alexandru
    et al.
    Linköping University, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    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, 20150588Article 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.

  • 19.
    Dasu, Alexandru
    et al.
    Umeå University.
    Toma-Dasu, Iuliana
    Umeå University.
    Fowler, Jack F.
    University of Wisconsin.
    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.

  • 20.
    Dasu, Alexandru
    et al.
    Umeå University, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Medical Radiation Physics (together with KI).
    Franzén, Lars
    Umeå University, Sweden.
    Widmark, Anders
    Umeå University, Sweden.
    Nilsson, Per
    Umeå University, Sweden; Lund University, Sweden.
    Secondary malignancies from prostate cancer radiation treatment: a risk analysis of the influence of target margins and fractionation patterns2011In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 79, no 3, 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.

  • 21.
    Dasu, Alexandru
    et al.
    Umeå University, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Medical Radiation Physics (together with KI).
    Franzén, Lars
    Umeå University, Sweden.
    Widmark, Anders
    Umeå University, Sweden.
    Nilsson, Per
    Umeå University, Sweden; Lund University, Sweden.
    The risk for secondary cancers in patients treated for prostate carcinoma – An analysis with the competition dose response model2009In: IFMBE Proceedings, ISSN 1680-0737, Vol. 25/3, 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.

  • 22.
    Dasu, Alexandru
    et al.
    Umeå University.
    Toma-Dasu, 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.

  • 23.
    Dasu, Alexandru
    et al.
    Umeå University.
    Toma-Dasu, 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.

  • 24.
    Dasu, Alexandru
    et al.
    Umeå University.
    Toma-Dasu, 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.

  • 25.
    Dasu, Iuliana Livia
    et al.
    Umeå University.
    Dasu, Alexandru
    Umeå University.
    Denekamp, Juliana
    Umeå University.
    Fowler, Jack F.
    University of Wisconsin.
    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)
  • 26.
    dos S. Matias, Lucilio
    et al.
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Lind, Bengt
    Maphossa, Alexandre M.
    Gudowska, Irena
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Cancer incidence and radiation therapy in Mozambique - a comparative study to Sweden2014In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, no 5, 712-715 p.Article in journal (Refereed)
  • 27.
    dos Santos Matias, Lucílio
    et al.
    Stockholm University, Faculty of Science, Department of Physics. Eduardo Mondlane University, Mozambique.
    Palmqvist, Tomas
    Wolke, Jeanette
    Nilsson, Josef
    Beskow, Catharina
    Maphossa, Alexandre M.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics.
    Dosimetric and radiobiological evaluation of hybrid inverse planning and optimization for cervical cancer brachytherapy2015In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 35, no 11, 6091-6096 p.Article in journal (Refereed)
    Abstract [en]

    Aim: To compare manual graphical optimization (GrO) with hybrid inverse planning optimization (HIPO) of cervical cancer brachytherapy treatment plans using physical and radiobiological tools. Patients and Methods: Ten patients suffering from cervical cancer, treated with pulsed brachytherapy using GrO plans, were included in the study. For each patient, four different HIPO class solutions with different dose objectives to the target and constraints to the organs at risk (OAR) produced four optimized plans, that were each compared to the corresponding GrO plan. Class solution in HIPO is a set of parameters consisting of dose constraints and penalty weights, which are used for optimization. The comparison was based on the following dosimetric parameters: conformity index (COIN), minimum dose received by 98% and 90% of the high-risk clinical target volume (represented by D98 and D90, respectively), and the minimum dose imparted to 2 cm3 (D2cm3) of the most exposed OAR i.e. bladder, sigmoid colon or rectum. The HIPO class solution which produced plans with overall better dosimetric parameters was selected and its plans were compared with manual GrO plans from a radiobiological viewpoint based on the calculated complication-free tumour control probability, P+. Results: The average COIN for the GrO and the selected HIPO plans were 0.22 and 0.30, respectively. The median COIN of the GrO and the HIPO plans were not statistically different (p>0.05, Wilcoxon test). The relative percentage difference of the averaged P+ values between the HIPO and GrO plans evaluated together with the external beam radiation therapy plans was 0.01%, 0.37% and 0.98% for the bladder, sigmoid colon and rectum, respectively. The lowest P+ value for all the plans was 98.44% for sigmoid colon. Conclusion: HIPO presented comparable results in relation to manual planning with respect to dosimetric and radiobiological parameters.

  • 28.
    Fager, Marcus
    et al.
    Stockholm University, Faculty of Science, Department of Physics. University of Pennsylvania, Philadelphia.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Kirk, Maura
    Dolney, Derek
    Diffenderfer, Eric S.
    Vapiwala, Neha
    Carabe, Alejandro
    Linear energy transfer painting with proton therapy: a means of reducing radiation doses with equivalent clinical effectiveness2015In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 91, no 5, 1057-1064 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: The purpose of this study was to propose a proton treatment planning method that trades physical dose (D) for dose-averaged linear energy transfer (LETd) while keeping the radiobiologically weighted dose (DRBE) to the target the same.

    Methods and Materials: The target is painted with LETd by using 2, 4, and 7 fields aimed at the proximal segment of the target (split target planning [STP]). As the LETd within the target increases with increasing number of fields, D decreases to maintain the DRBE the same as the conventional treatment planning method by using beams treating the full target (full target planning [FTP]).

    Results: The LETd increased 61% for 2-field STP (2STP) compared to FTP, 72% for 4STP, and 82% for 7STP inside the target. This increase in LETd led to a decrease of D with 5.3 ± 0.6 Gy for 2STP, 4.4 ± 0.7 Gy for 4STP, and 5.3 ± 1.1 Gy for 7STP, keeping the DRBE at 90% of the volume (DRBE, 90) constant to FTP.

    Conclusions: LETd painting offers a method to reduce prescribed dose at no cost to the biological effectiveness of the treatment.

  • 29.
    Flejmer, Anna M.
    et al.
    Linköping University, Sweden.
    Chehrazi, Behnaz
    Stockholm University, Faculty of Science, Department of Physics.
    Josefsson, Dan
    Linköping University, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Dasu, Alexandru
    Linköping University, Sweden; The Skandion Clinic, 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.

  • 30. Fowler, Jack
    et al.
    Dasu, Alexandru
    Linköping University.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics.
    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.

  • 31. Fowler, Jack F.
    et al.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Dasu, Alexandru
    Linköping University, Sweden.
    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.

  • 32.
    Gudowska, Irena
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Ardenfors, Oscar
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics.
    Dasu, Alexandru
    Linköping University, Sweden.
    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.

  • 33. Hedman, Mattias
    et al.
    Björk-Eriksson, Thomas
    Brodin, Ola
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Predictive value of modelled tumour control probability based on individual measurements of in vitro radiosensitivity and potential doubling time2013In: British Journal of Radiology, ISSN 0007-1285, E-ISSN 1748-880X, Vol. 86, no 1025, 20130015Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of this study was to compare patient-specific radiobiological parameters to population averages in predicting clinical outcome after radiotherapy using a tumor control probability (TCP) model based on BED.

    Methods: A previously published material of forty-six head and neck carcinomas with individually identified radiobiological parameters; SF2 and Tpot, and known tumor size was investigated. These patients had all been treated with external beam radiotherapy and the majority had also received brachytherapy. TCP for each individual based on BED using patient-specific radiobiological parameters was compared to TCP based on BED using average radiobiological parameters (α = 0.3 Gy-1 and Tpot = 3 days).

    Results: Forty-three patients remained in the final analysis. There was only a weak trend for increasing local tumor control with increasing BED in both groups. However, when TCP was calculated the use of patient-specific parameters was better to identify local control correctly. Sensitivity and specificity for tumor-specific parameters were 63% and 80%, respectively. The corresponding values for population-based averages were 0% and 91%, respectively. Positive predictive value was 92% when tumor-specific parameters were used compared to 0 % for population-based. A receiver operating characteristic (ROC) curve confirmed the superiority of patient-specific parameters over population averages in predicting local control.

    Conclusions: Individual radiobiological parameters are better than population derived averages when used in a mathematical model to predict tumor control probability after curative radiotherapy in head and neck carcinomas.

    Advances in knowledge: TCP based on individual radiobiological parameters are better than TCP based on population based averages.

  • 34.
    Huss, Marie
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Barsoum, Pierre
    Karolinska University Hospital, Sweden.
    Dodoo, Ernest
    Karolinska University Hospital, Sweden.
    Sinclair, Georges
    Karolinska University Hospital, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institute, Sweden.
    Fractionated SRT using VMAT and Gamma Knife for brain metastases and gliomas - a planning study2015In: Journal of Applied Clinical Medical Physics, ISSN 1526-9914, E-ISSN 1526-9914, Vol. 16, no 6, 3-16 p.Article in journal (Refereed)
    Abstract [en]

    Stereotactic radiosurgery using Gamma Knife (GK) or linear accelerators has been used for decades to treat brain tumors in one fraction. A new positioning system, Extend™, was introduced by Elekta AB for fractionated stereotactic radiotherapy (SRT) with GK. Another option for fractionated SRT is advanced planning and delivery using linacs and volumetric modulated arc therapy (VMAT). This project aims to assess the performance of GK Extend™ for delivering fractionated SRT by comparing GK treatments plans for brain targets performed using Leksell GammaPlan (LGP) with VMAT treatment plans. Several targets were considered for the planning: simulated metastasis- and glioma-like targets surrounding an organ at risk (OAR), as well as three clinical cases of metastases. Physical parameters such as conformity, gradient index, dose to OARs, and brain volume receiving doses above the threshold associated with risk of damaging healthy tissue, were determined and compared for the treatment plans. The results showed that GK produced better dose distributions for target volumes below 15 cm3, while VMAT results in better dose conformity to the target and lower doses to the OARs in case of fractionated treatments for large or irregular volumes. The volume receiving doses above a threshold associated with increased risk of damage to normal brain tissue was also smaller for VMAT. The GK consistently performed better than VMAT in producing a lower dose-bath to the brain. The above is subjected only to margin-dependent fractionated radiotherapy (CTV/PTV). The results of this study could lead to clinically significant decisions regarding the choice of the radiotherapy technique for brain targets.

  • 35.
    Lindblom, Emely
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Antonovic, Laura
    Stockholm University, Faculty of Science, Department of Physics.
    Dasu, Alexandru
    Lax, Ingmar
    Wersäll, Peter
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    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, E-ISSN 1748-717X, Vol. 9, 149Article 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.

  • 36.
    Lindblom, Emely
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Dasu, Alexandru
    The Skandion Clinic, Sweden.
    Beskow, Catharina
    Karolinska University Hospital, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, 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, D 50, were in agreement with clinically-observed values for high cure rates if fast reoxygenation was assumed. The D 50 was furthermore similar for the different degrees of conformity of the brachytherapy dose distribution to the tumour, regardless of whether the hypoxic fraction was 10%, 25%, or 40%. To achieve 50% control with external RT only, a total dose of more than 70 Gy in 25 fractions would be required for all cases considered.

    It can thus be concluded that the high doses delivered in brachytherapy can counteract the increased radioresistance caused by hypoxia if fast reoxygenation is assumed.

  • 37.
    Lindblom, Emely
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Dasu, Alexandru
    Lax, Ingmar
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Survival and tumour control probability in tumours with heterogeneous oxygenation: 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.

  • 38.
    Lindblom, Emely
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Dasu, Alexandru
    Linköping University, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    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.

  • 39.
    Lindblom, Emely
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Dasu, Alexandru
    The Skandion Clinic, Sweden; Linköping University, Sweden.
    Uhrdin, Johan
    RaySearch Laboratories AB, Sweden.
    Even, Aniek J. G.
    Maastricht University Medical Center, The Netherlands.
    van Elmpt, Wouter
    Maastricht University Medical Center, The Netherlands.
    Lambin, Philippe
    Maastricht University Medical Center, The Netherlands.
    Wersäll, Peter
    Karolinska University Hospital, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. 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.

  • 40.
    Lindblom, Emely
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics.
    Dasu, Alexandru
    The Skandion Clinic, Sweden; Linköping University, Sweden.
    Accounting for two forms of hypoxia for predicting tumour control probability in radiotherapy – an in silico studyManuscript (preprint) (Other academic)
  • 41. Marcu, Loredana G.
    et al.
    Bezak, Eva
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Dasu, Alexandru
    Linköping University, Sweden.
    Predictive models of tumour response to treatment using functional imaging techniques2015In: Computational & Mathematical Methods in Medicine, ISSN 1748-670X, E-ISSN 1748-6718, 571351Article in journal (Refereed)
  • 42.
    Marcu, Loredana G.
    et al.
    University of Oradea, Romania; University of Adelaide, Australia.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Dasu, Alexandru
    Linköping University, Sweden.
    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)
  • 43.
    Marcu, Loredana G.
    et al.
    University of Oradea and University of South Australia.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics.
    Dasu, Alexandru
    The Skandion Clinic.
    Mercke, Claes
    Karolinska University Hospital.
    Radiotherapy and clinical radiobiology of head and neck cancer2018Book (Refereed)
    Abstract [en]

    Common factors that lead to treatment failure in head and neck cancer are the lack of tumour oxygenation, the accelerated division of cancer cells during treatment, and radioresistance. These tumour-related challenges and possible ways to overcome them are covered in this book, authored by three medical physicists and a clinical oncologist who explain how different radiobiological findings have led to the development of various treatment techniques for head and neck cancer. Novel treatment techniques as supported by current scientific evidence are comprehensively explored, as well as the major challenges that arise in the retreatment of patients who have already undergone a form of radiotherapy for primary head and neck cancer.

  • 44. Mohanty, Chitralekha
    et al.
    Zielinska-Chomej, Katarzyna
    Edgren, Margareta
    Hirayama, Ryoichi
    Murakami, Takeshi
    Lind, Bengt
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Predicting the sensitivity to ion therapy based on the response to photon irradiation - experimental evidence and mathematical modelling2014In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 34, no 6, 2801-2806 p.Article in journal (Refereed)
    Abstract [en]

    Background/Aim: The use of ion radiation therapy is growing due to the continuously increasing positive clinical experience obtained. Therefore, there is a high interest in radio-biological experiments comparing the relative efficiency in cell killing of ions and photons as the photons are currently the main radiation modality used for cancer treatment. This comparison is particularly important since the treatment planning systems (TPSs) used at the main ion therapy centres make use of parameters describing the cellular response to photons, respectively ions, determined in vitro. It was therefore the aim of this paper to compare the effects of high LET ion radiation with low LET photons and determine whether the cellular response to low LET could predict the response to high LET irradiation. Materials and Methods: Clonogenic cell survival data of five tumor cell lines irradiated with different ion beams of similar, clinically-relevant, LET were studied in relation to the response to low LET photons. Two mathematical models were used to fit the data, the repairable-conditionally repairable damage (RCR) model and the linear quadratic (LQ) model. Results: The results indicate that the relative biological efficiency of the high LET radiation assessed with the RCR model could be predicted based only on the response to the low LET irradiation. Conclusion: The particular features of the RCR model indicate thus that tumor cells showing a large capacity for repairing the damage will have the larger benefit from radiation therapy with ions beams.

  • 45. Palmqvist, Tomas
    et al.
    dos S. Matias, Lucílio
    Stockholm University, Faculty of Science, Department of Physics. Eduardo Mondlane University, Mozambique.
    Langeland Marthinsen, Anne Beate
    Sundset, Marit
    Dybdahl Wanderås, Anne
    Danielsen, Signe
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics.
    Radiobiological treatment planning evaluation of inverse planning simulated annealing for cervical cancer high-dose-rate brachytherapy2015In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 35, no 2, 935-939 p.Article in journal (Refereed)
    Abstract [en]

    Aim: To compare five inverse treatment plans with one conventional manually optimized plan for cervical cancer brachytherapy (BT) using radiobiological parameters combined with dosimetric and volumetric parameters.

    Materials and Methods: Five inverse treatment plans were calculated using an inverse planning simulated annealing (IPSA) algorithm for each of four fractions for 12 cervical cancer patients treated with high-dose-rate (HDR) brachytherapy. The inverse treatment plans were compared with a manually optimized plan used for the actual treatment of the patients. The comparison of the plans was performed with respect to the probability of cure without complication.

    Results: Overall, the manually optimized plan scored the best results; however, the probability of cure without complication is within an acceptable clinical range for all the plans.

    Conclusion: Although there are still considerable uncertainties in the radiobiological parameters, the radiobiological plan evaluation method presents itself as a potential complement to physical dosimetric methods.

  • 46. Palmqvist, Tomas
    et al.
    Dybdahl Wanderås, Anne
    Langeland Marthinsen, Anne Beate
    Sundset, Marit
    Langdal, Ingrid
    Danielsen, Signe
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Dosimetric evaluation of manually and inversely optimized treatment planning for high dose rate brachytherapy of cervical cancer2014In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, no 8, 1012-1018 p.Article in journal (Refereed)
    Abstract [en]

    Background. To compare five inverse treatment planning methods with the conventional manually optimized planning approach for brachytherapy of cervical cancer with respect to dosimetric parameters.

    Material and methods. Eighteen cervical cancer patients treated with magnetic resonance imaging (MRI)-guided high dose rate (HDR) brachytherapy were included in this study. Six plans were created for each of the 4 HDR brachytherapy fractions for each patient: 1 manually optimized and 5 inversely planned. Three of these were based on inverse planning simulated annealing (IPSA) with and without extra constraints on maximum doses of the target volume, and different constraints on doses to the organs at risk (OARs). In addition there were two plans based on dose to target surface points. The resulting dose-volume histograms were analyzed and compared from the dosimetric point of view by quantifying specific dosimetric parameters, such as clinical target volume (CTV) D90, CTV D100, conformal index (COIN), and D2cm3 for rectum, bladder and the sigmoid colon.

    Results. Manual optimization led to a mean target coverage of 78.3% compared to 87.5%, 91.7% and 82.5% with the three IPSA approaches (p < 0.001). Similar COIN values for manual and inverse optimization were found. The manual optimization led to better results with respect to the dose to the OARs expressed as D2cm3. Overall, the best results were obtained with manual optimization and IPSA plans with volumetric constraints including maximum doses to the target volume.

    Conclusions. Dosimetric evaluation of manual and inverse optimization approaches is indicating the potential of IPSA for brachytherapy of cervical cancer. IPSA with constraints of maximum doses to the target volume is closer related to manual optimization than plans with constraints only to minimum dose to the target volume and maximum doses to OARs. IPSA plans with proper constraints performed better than those based on dose to target surface points and manually optimized plans.

  • 47.
    Sandström, Helena
    et al.
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Chung, Caroline
    University of Toronto, Canada.
    Jokura, Hidefumi
    Tohoku University School of Medicine, Japan.
    Torrens, Michael
    Hygeia Hospital, Greece.
    Jaffray, David
    University of Toronto, Canada.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Assessment of organs-at-risk contouring practices in radiosurgery institutions around the world - The first initiative of the OAR Standardization Working Group2016In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 121, no 2, 180-186 p.Article in journal (Refereed)
    Abstract [en]

    Materials and methods

    Imaging datasets for typical lesions (cavernous sinus meningioma, vestibular schwannoma, pituitary adenoma) treated with Leksell Gamma Knife Perfexion were circulated to 12 centers. Observers were asked to contour the target and OARs as per their standard clinical practice. The analyzed parameters were the intersection (AV100), union volumes (AV100/N) and the 50% agreement volume (AV50). The ratio of AV100 and AV100/N (the Agreement Volume Index, AVI) was used as a measure of agreement level together with a generalized conformity index (CIgen) and a pairwise averaged conformity index (CIpairs). The maximum doses were also determined.

    Results

    Results showed a wide variability in terminology, choice of structures contoured and in the size and shape of the contoured structures. The highest variability was observed for the left and right optic tract for cavernous sinus meningioma where the AV100 was zero. The highest consistency was observed for the right optic nerve in the cavernous sinus case followed by the cochlea for the vestibular schwannoma case for which the AVI was still only 0.13 and 0.054, respectively. Corresponding results for the CIgen and CIpairs also showed the highest variability for the right optic tract and the highest consistency in contours for the right optic nerve, both in the cavernous sinus meningioma case.

    Conclusion

    The results quantify the large variability in OAR contouring in clinical practice across Gamma Knife radiosurgery centers with respect to the choice of OARs to be contoured, nomenclature and size and shape of OARs. This motivates future effort to standardize practices to enable more effective collaboration.

  • 48.
    Sandström, Helena
    et al.
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Dasu, Alexandru
    Linköping University, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Radiobiological framework for the evaluation of stereotactic radiosurgery plans for invasive brain tumours2013In: ISRN Oncology, ISSN 2090-5661, E-ISSN 2090-567X, Vol. 2013, 527251Article 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.

  • 49.
    Sandström, Helena
    et al.
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Nordström, Håkan
    Elekta Instrument AB, Sweden.
    Johansson, Jonas
    Elekta Instrument AB, Sweden.
    Kjäll, Per
    Elekta Instrument AB, Sweden.
    Jokura, Hidefumi
    Tohoku University School of Medicine, Japan.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Insitutet, Sweden.
    Variability in target delineation for cavernous sinus meningioma and anaplastic astrocytoma in stereotactic radiosurgery with Leksell Gamma Knife Perfexion2014In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 156, no 12, 2303-2313 p.Article in journal (Refereed)
    Abstract [en]

    Background: Radiosurgery clinical practice relays on empirical observations and the experience of the practitioners involved in determining and delineating the target and therefore variability in target delineation might be expected for all the radiosurgery approaches, independent of the technique and the equipment used for delivering the treatment. The main aim of this study was to quantify the variability of target delineation for two radiosurgery targets expected to be difficult to delineate. The secondary aim was to investigate the dosimetric implications with respect to the plan conformity. The primary aim of the study has therefore a very general character, not being bound to one specific radiosurgery technique.

    Materials and methods: Twenty radiosurgery centers were asked to delineate one cavernous sinus meningioma and one astrocytoma and to plan the treatments for Leksell Gamma Knife Perfexion. The analysis of the delineated targets was based on the calculated 50% agreement volume, AV50. The AV50 was compared to each delineated target by the concordance index and discordance index. The differences in location, size, and shape of the delineated targets were also analyzed using the encompassing volume compared to the common volume, i.e., the AV100, of all delineated structures.

    Results: Target delineation led to major differences between the participating centers and therefore the AV50 was small in comparison to each delineated target volume. For meningioma, the AV50 was 5.90 cm3, the AV100 was 2.60 cm3, and the encompassing volume was 13.14 cm3. For astrocytoma, the AV50 was 2.06 cm3 while the AV100 was extremely small, only 0.05 cm3, and the encompassing volume was 43.27 cm3. These variations translate into corresponding discrepancies in plan conformity.

    Conclusions: Significant differences in shape, size, and location between the targets included in this study were identified and therefore the clinical implications of these differences should be further investigated.

  • 50.
    Toma-Dasu, Iuliana
    et al.
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Dasu, Alexandru
    Linköping University, Sweden.
    Biologically-optimised IMRT based on molecular imaging of tumour hypoxia: the impact of the tracer used2013In: IFMBE Proceedings, ISSN 1680-0737, 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.

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