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  • 1. Anderlind, Eva
    et al.
    Noz, Marilyn E.
    Sallnas, Eva-Lotta
    Lind, Bengt K.
    Stockholm University.
    Maguire, Gerald Q., Jr.
    Will haptic feedback speed up medical imaging?: An application to radiation treatment planning2008In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 47, no 1, p. 32-37Article in journal (Refereed)
    Abstract [en]

    Haptic technology enables us to incorporate the sense of touch into computer applications, providing an additional input/output channel. The purpose of this study was to examine if haptic feedback can help physicians and other practitioners to interact with medical imaging and treatment planning systems. A haptic application for outlining target areas (a key task in radiation therapy treatment planning) was implemented and then evaluated via a controlled experiment with ten subjects. Even though the sample size was small, and the application only a prototype, results showed that haptic feedback can significantly increase (p0.05) the speed of outlining target volumes and organs at risk. No significant differences were found regarding precision or perceived usability. This promising result warrants further development of a full haptic application for this task. Improvements to the usability of the application as well as to the forces generated have been implemented and an experiment with more subjects is planned.

  • 2.
    Ardenfors, Oscar
    et al.
    Stockholm University, Faculty of Science, Department of Physics. Linköping University, Sweden; Karolinska Institutet, Sweden.
    Josefsson, Dan
    Dasu, Alexandru
    Are IMRT treatments in the head and neck region increasing the risk of secondary cancers?2014In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, no 8, p. 1041-1047Article in journal (Refereed)
    Abstract [en]

    Background. Intensity-modulated radiation therapy (IMRT) has been increasingly employed for treating head and neck (H&N) tumours due to its ability to produce isodoses suitable for the complex anatomy of the region. The aim of this study was to assess possible differences between IMRT and conformal radiation therapy (CRT) with regard to risk of radiation-induced secondary malignancies for H&N tumours. Material and methods. IMRT and CRT plans were made for 10 H&N adult patients and the resulting treatment planning data were used to calculate the risk of radiation-induced malignancies in four different tissues. Three risk models with biologically relevant parameters were used for calculations. The influence of scatter radiation and repeated imaging sessions has also been investigated. Results. The results showed that the total lifetime risks of developing radiation-induced secondary malignancies from the two treatment techniques, CRT and IMRT, were comparable and in the interval 0.9-2.5%. The risk contributions from the primary beam and scatter radiation were comparable, whereas the contribution from repeated diagnostic imaging was considerably smaller. Conclusion. The results indicated that the redistribution of the dose characteristic to IMRT leads to a redistribution of the risks in individual tissues. However, the total levels of risk were similar between the two irradiation techniques considered.

  • 3.
    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, p. 829-835Article 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.

  • 4.
    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, p. 963-974Article, 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.

  • 5.
    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, p. 896-905Article in journal (Refereed)
    Abstract [en]

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

  • 6.
    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, p. 563-571Article 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.

  • 7.
    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, p. 339-347Article 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.

  • 8.
    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, p. 712-715Article in journal (Refereed)
  • 9. Friberg, Sten
    et al.
    Ruden, Bengt-Inge
    Stockholm University.
    Hypofractionation in radiotherapy: An investigation of injured Swedish women, treated for cancer of the breast2009In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 48, no 6, p. 822-831Article in journal (Refereed)
    Abstract [en]

    Background. The Swedish Insurance Company for Patient Injuries asked the two authors of this report to identify the Swedish women with cancer of the breast who had been injured by radiotherapy with a hypofractionated schedule. The purpose was to provide a basis on which the Company could decide if indemnification could be given. Material and methods. We define hypo-fractionation as any fraction dose exceeding 2.0 gray (Gy) per day. We set the lower limit for the ""late effect"" at 53.0 Gy with 2 Gy/fraction. All departments of radiotherapy in Sweden were asked to identify women who had developed brachial plexus neuropathy (BPN). Their medical records were obtained. The clinical picture of their injuries was recorded, and the absorbed dose was calculated or reconstructed. All doses, no matter in what way they were expressed, were recalculated to ""late effect"", presented in EQD(2Gy) (Equalized Total Dose in 2 Gy/fraction). The latency period from therapy to onset of symptoms was also noted. Results. A variety of treatment techniques was used, fractions ranging in size from 2.5 to 6.0 Gy. Absorbed doses up to a Biologically Equivalent Dose (BED) 146 EQD(2Gy) in late effects were recorded (6 Gy x 13). More than 95% of the injured women had a combination of stiff shoulder, paralysis, pain, oedema and atrophy of the muscles to the arm and/or hand. Latency from end of radiotherapy to onset of symptoms could be as long as 30 years. Discussion. Hypofractionated radiotherapy has injured severely numerous patients. The lesions have become a medico-legal issue in some countries. The life of many of these women has been ruined: physically, mentally, socially and economically. Conclusion. Hypofractionated radiotherapy can cause injuries if the target volume is not exact, or the total dose is not adjusted to a tolerable level as compared to conventional treatments employing 2 Gy/day fractions.

  • 10. Gudmundsdottir, Eyglo
    et al.
    Schirren, Maria
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Boman, Krister K.
    Psychological resilience and long-term distress in Swedish and Icelandic parents' adjustment to childhood cancer2011In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 50, no 3, p. 373-380Article in journal (Refereed)
    Abstract [en]

    Aim. Studies of parental reactions to a child's cancer have traditionally been carried out within the framework of psychiatry and psychopathology. We studied the significance of individual resource factors strengthening parents' resilience to long-term cancer-related distress, a focus that has rarely been used. Participants and methods. The two-nation Nordic sample included 398 parents; 190 of whom had experienced a child's cancer, and 208 reference parents. We studied the sense of coherence (SOC) using the SOC-13 questionnaire. For assessing distress reactions we used a primarily illness-specific 11-dimensional Parental Psychosocial Distress in Cancer (PPD-C) self-report questionnaire developed for use with parents of childhood cancer patients, and the General Health Questionnaire (GHQ). Resilience was defined as absence of/less severe distress. Results. Low SOC was significantly associated with more severe distress in all dimensions of the PPD-C and GHQ. The protective effect of SOC was indicated by it being most negatively related to general psychiatric symptoms, physical and psychological stress symptoms, anxiety and depression. The influence of SOC varied with parents' gender, showing a stronger modifying influence among mothers. Mothers and fathers also differed in their utilisation of professional psychosocial support when confronted with the child's cancer. Conclusion. Parental resilience to cancer-related distress varies with identifiable strength factors. A strengths-oriented approach helps in understanding parental adjustment to childhood cancer. In order to counteract psychological vulnerability, addressing resilience instead of pathology helps to identify parents at risk and in need of professional support when faced with a child's cancer.

  • 11.
    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, p. 1035-1040Article 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.

  • 12.
    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, p. 1592-1598Article 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.

  • 13.
    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, p. 819-825Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 14.
    Mondlane, Gracinda
    et al.
    Stockholm University, Faculty of Science, Department of Physics. Universidade Eduardo Mondlane, Mozambique.
    Gubanski, Michael
    Lind, Pehr A.
    Ureba, Ana
    Stockholm University, Faculty of Science, Department of Physics.
    Siegbahn, Albert
    Stockholm University, Faculty of Science, Department of Physics.
    Comparison of gastric-cancer radiotherapy performed with volumetric modulated arc therapy or single-field uniform-dose proton therapy2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 6, p. 832-838Article in journal (Refereed)
    Abstract [en]

    Background: Proton-beam therapy of large abdominal cancers has been questioned due to the large variations in tissue density in the abdomen. The aim of this study was to evaluate the importance of these variations for the dose distributions produced in adjuvant radiotherapy of gastric cancer (GC), implemented with photon-based volumetric modulated arc therapy (VMAT) or with proton-beam single-field uniform-dose (SFUD) method. Material and methods: Eight GC patients were included in this study. For each patient, a VMAT- and an SFUD-plan were created. The prescription dose was 45 Gy (IsoE) given in 25 fractions. The plans were prepared on the original CT studies and the doses were thereafter recalculated on two modified CT studies (one with extra water filling and the other with expanded abdominal air-cavity volumes). Results: Compared to the original VMAT plans, the SFUD plans resulted in reduced median values for the V18 of the left kidney (26%), the liver mean dose (14.8 Gy (IsoE)) and the maximum dose given to the spinal cord (26.6 Gy (IsoE)). However, the PTV coverage decreased when the SFUD plans were recalculated on CT sets with extra air- (86%) and water-filling (87%). The added water filling only led to minor dosimetric changes for the OARs, but the extra air caused significant increases of the median values of V18 for the right and left kidneys (10% and 12%, respectively) and of V10 for the liver (12%). The density changes influenced the dose distributions in the VMAT plans to a minor extent. Conclusions: SFUD was found to be superior to VMAT for the plans prepared on the original CT sets. However, SFUD was inferior to VMAT for the modified CT sets.

  • 15. Nielsen, Steffen
    et al.
    Bassler, Niels
    Stockholm University, Faculty of Science, Department of Physics.
    Grzanka, Leszek
    Swakon, Jan
    Olko, Pawel
    Andreassen, Christian Nicolaj
    Overgaard, Jens
    Alsner, Jan
    Singers Sørensen, Brita
    Differential gene expression in primary fibroblasts induced by proton and cobalt-60 beam irradiation2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 11, p. 1406-1412Article in journal (Refereed)
    Abstract [en]

    Introduction: Proton beam therapy delivers a more conformal dose distribution than conventional radiotherapy, thus improving normal tissue sparring. Increasing linear energy transfer (LET) along the proton track increases the relative biological effectiveness (RBE) near the distal edge of the Spread-out Bragg peak (SOBP). The severity of normal tissue side effects following photon beam radiotherapy vary considerably between patients.

    Aim: The dual study aim was to identify gene expression patterns specific to radiation type and proton beam position, and to assess whether individual radiation sensitivity influences gene expression levels in fibroblast cultures irradiated in vitro.

    Methods: The study includes 30 primary fibroblast cell cultures from patients previously classified as either radiosensitive or radioresistant. Cells were irradiated at three different positions in the proton beam profile: entrance, mid-SOBP and at the SOBP distal edge. Dose was delivered in three fractions × 3.5 Gy(RBE) (RBE 1.1). Cobalt-60 (Co-60) irradiation was used as reference. Real-time qPCR was performed to determine gene expression levels for 17 genes associated with inflammation response, fibrosis and angiogenesis.

    Results: Differences in median gene expression levels were observed for multiple genes such as IL6, IL8 and CXCL12. Median IL6 expression was 30%, 24% and 47% lower in entrance, mid-SOBP and SOBP distal edge groups than in Co-60 irradiated cells. No genes were found to be oppositely regulated by different radiation qualities. Radiosensitive patient samples had the strongest regulation of gene expression; irrespective of radiation type.

    Conclusions: Our findings indicate that the increased LET at the SOBP distal edge position did not generally lead to increased transcriptive response in primary fibroblast cultures. Inflammatory factors were generally less extensively upregulated by proton irradiation compared with Co-60 photon irradiation. These effects may possibly influence the development of normal tissue damage in patients treated with proton beam therapy.

  • 16. 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, p. 1012-1018Article 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.

  • 17. Roshanai, Afsaneh Hayat
    et al.
    Nordin, Karin
    Berglund, Gunilla
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Factors influencing primary care physicians' decision to order prostate-specific antigen (PSA) test for men without prostate cancer2013In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 8, p. 1602-1608Article in journal (Refereed)
    Abstract [en]

    Background. Despite extensive ongoing clinical trials investigating appropriateness of prostate-specific antigen (PSA)-screening, the benefit of PSA-based screening for prostate cancer remains controversial due to the lack of clear evidence for effectiveness of population-based PSA-screening. Notwithstanding, the need to identify the determinants behind PSA-testing decisions, the number of studies that have examined factors affecting the physicians' decision as to whether PSA-testing should be ordered are few. The aim of the current study was to investigate how physician-and patient-related factors influence Swedish primary care physicians' decision to order a PSA test for men harboring no symptoms of prostate cancer within different age groups. Methods. A total of 305 physicians filled out the study questionnaire containing items about physicians' attitudes towards PSA-testing and the probability of screening men within different age groups. Results. The majority of physicians reported positive attitude towards PSA-testing. However, the likelihood of offering PSA-testing to young men was low, but increased with age. Physicians' opinion about PSA-test as a sufficient screening tool was the only variable affecting physicians' decision of ordering PSA-test regardless of patient age. The level of the patients' worry, and patients request were the most influential factors in age groups between 40 and 70 years old. Patients' physical symptoms were an indicator in age groups above 60 years. Conclusion. The decision to screen for prostate cancer using the PSA-test is influenced by several factors and not only those having direct clinical indication for prostate disease. This may lead to unnecessary treatment of some patients.

  • 18. Singers Sørensen, Brita
    et al.
    Bassler, Niels
    Stockholm University, Faculty of Science, Department of Physics.
    Nielsen, Steffen
    Horsman,, Michael R.
    Grzanka, Leszek
    Spejlborg, Harald
    Swakoń, Jan
    Olko, Paweł
    Overgaard, Jens
    Relative biological effectiveness (RBE) and distal edge effects of proton radiation on early damage in vivo2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 11, p. 1387-1391Article in journal (Refereed)
    Abstract [en]

    Introduction: The aim of the present study was to examine the RBE for early damage in an in vivo mouse model, and the effect of the increased linear energy transfer (LET) towards the distal edge of the spread-out Bragg peak (SOBP).

    Method: The lower part of the right hind limb of CDF1 mice was irradiated with single fractions of either 6 MV photons, 240 kV photons or scanning beam protons and graded doses were applied. For the proton irradiation, the leg was either placed in the middle of a 30-mm SOBP, or to assess the effect in different positions, irradiated in 4 mm intervals from the middle of the SOBP to behind the distal dose fall-off. Irradiations were performed with the same dose plan at all positions, corresponding to a dose of 31.25 Gy in the middle of the SOBP. Endpoint of the study was early skin damage of the foot, assessed by a mouse foot skin scoring system.

    Results: The MDD50 values with 95% confidence intervals were 36.1 (34.2–38.1) Gy for protons in the middle of the SOBP for score 3.5. For 6 MV photons, it was 35.9 (34.5–37.5) Gy and 32.6 (30.7–34.7) Gy for 240 kV photons for score 3.5. The corresponding RBE was 1.00 (0.94–1.05), relative to 6 MV photons and 0.9 (0.85–0.97) relative to 240 kV photons. In the mice group positioned at the SOBP distal dose fall-off, 25% of the mice developed early skin damage compared with 0–8% in other groups. LETd,z = 1 was 8.4 keV/μm at the distal dose fall-off and the physical dose delivered was 7% lower than in the central SOBP position, where LETd,z =1 was 3.3 keV/μm.

    Conclusions: Although there is a need to expand the current study to be able to calculate an exact enhancement ratio, an enhanced biological effect in vivo for early skin damage in the distal edge was demonstrated.

  • 19.
    Thomas, Henry
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Bassler, Niels
    Stockholm University, Faculty of Science, Department of Physics.
    Ureba, Ana
    Stockholm University, Faculty of Science, Department of Physics.
    Tsubouchi, Toshiro
    Valdman, Alexander
    Siegbahn, Albert
    Stockholm University, Faculty of Science, Department of Physics.
    Development of an interlaced-crossfiring geometry for proton grid therapy2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 11, p. 1437-1443Article in journal (Refereed)
    Abstract [en]

    Background: Grid therapy has in the past normally been performed with single field photon-beamgrids. In this work, we evaluated a method to deliver grid therapy based on interlacing and crossfiringgrids of mm-wide proton beamlets over a target volume, by Monte Carlo simulations.

    Material and methods: Dose profiles for single mm-wide proton beamlets (1, 2 and 3 mm FWHM) inwater were simulated with the Monte Carlo code TOPAS. Thereafter, grids of proton beamlets weredirected toward a cubic target volume, located at the center of a water tank. The aim was to deliver anearly homogeneous dose to the target, while creating high dose heterogeneity in the normal tissue,i.e., high gradients between valley and peak doses in the grids, down to the close vicinity of thetarget.

    Results: The relative increase of the beam width with depth was largest for the smallest beams(þ6.9mm for 1 mm wide and 150MeV proton beamlets). Satisfying dose coverage of the cubic targetvolume (r< ±5%) was obtained with the interlaced-crossfiring setup, while keeping the grid pattern ofthe dose distribution down to the target (valley-to-peak dose ratio<0.5 less than 1 cm before the tar-get). Center-to-center distances around 7–8 mm between the beams were found to give the best com-promise between target dose homogeneity and low peak doses outside of the target.

    Conclusions: A nearly homogeneous dose distribution can be obtained in a target volume by crossfir-ing grids of mm-wide proton-beamlets, while maintaining the grid pattern of the dose distribution atlarge depths in the normal tissue, close to the target volume. We expect that the use of this methodwill increase the tumor control probability and improve the normal tissue sparing in grid therapy.

  • 20.
    Toma-Dasu, Iuliana
    et al.
    Stockholm University, Faculty of Science, Medical Radiation Physics (together with KI).
    Dasu, Alexandru
    Umeå University.
    Brahme, Anders
    Stockholm University, Faculty of Science, Medical Radiation Physics (together with KI).
    Dose prescription and optimisation based on tumour hypoxia2009In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 48, no 8, p. 1181-1192Article in journal (Refereed)
    Abstract [en]

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

  • 21.
    Toma-Dasu, Iuliana
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Uhrdin, Johan
    RaySearch Laboratories AB, Stockholm, Sweden.
    Antonovic, Laura
    Stockholm University, Faculty of Science, Department of Physics.
    Dasu, Alexandru
    Linköping University, Sweden.
    Nuyts, Sandra
    Dirix, Piet
    Haustermans, Karin
    Brahme, Anders
    Dose prescription and treatment planning based on FMISO-PET hypoxia2012In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 2, p. 222-230Article in journal (Refereed)
    Abstract [en]

    Purpose. The study presents the implementation of a novel method for incorporating hypoxia information from PET-CT imaging into treatment planning and estimates the efficiency of various optimization approaches. Its focuses on the feasibility of optimizing treatment plans based on the non-linear conversion of PET hypoxia images into radiosensitivity maps from the uptake properties of the tracers used. Material and methods. PET hypoxia images of seven head-and-neck cancer patients were used to determine optimal dose distributions needed to counteract the radiation resistance associated with tumor hypoxia assuming various scenarios regarding the evolution of the hypoxic compartment during the treatment. A research planning system for advanced studies has been used to optimize IMRT plans based on hypoxia information from patient PET images. These resulting plans were compared in terms of target coverage for the same fulfilled constraints regarding the organs at risk. Results. The results of a planning study indicated the clinical feasibility of the proposed method for treatment planning based on PET hypoxia. Antihypoxic strategies would lead to small improvements in all the patients, but higher effects are expected for the fraction of patients with hypoxic tumors. For these, individualization of the treatment based on hypoxia PET imaging could lead to improved treatment outcome while creating the premises for limiting the irradiation of the surrounding normal tissues. Conclusions. The proposed approach offers the possibility of improved treatment results as it takes into consideration the heterogeneity and the dynamics of the hypoxic regions. It also provides early identification of the clinical cases that might benefit from dose escalation as well as the cases that could benefit from other counter-hypoxic measures.

  • 22.
    Ureba, Ana
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Lindblom, Emely
    Stockholm University, Faculty of Science, Department of Physics.
    Dasu, Alexandru
    The Skandion Clinic, 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.
    Non-linear conversion of HX4 uptake for automatic segmentation of hypoxic volumes and dose prescription2018In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 4, p. 485-490Article in journal (Other academic)
    Abstract [en]

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

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

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

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

  • 23.
    Ödén, Jakob
    et al.
    Stockholm University, Faculty of Science, Department of Physics. RaySearch Laboratories, Sweden.
    Eriksson, Kjell
    RaySearch Laboratories, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Incorporation of relative biological effectiveness uncertainties into proton plan robustness evaluation2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 6, p. 769-778Article in journal (Refereed)
    Abstract [en]

    Background: The constant relative biological effectiveness (RBE) of 1.1 is typically assumed in proton therapy. This study presents a method of incorporating the variable RBE and its uncertainties into the proton plan robustness evaluation.

    Material and methods: The robustness evaluation was split into two parts. In part one, the worst-case physical dose was estimated using setup and range errors, including the fractionation dependence. The results were fed into part two, in which the worst-case RBE-weighted doses were estimated using a Monte Carlo method for sampling the input parameters of the chosen RBE model. The method was applied to three prostate, breast and head and neck (H&N) plans for several fractionation schedules using two RBE models. The uncertainties in the model parameters, linear energy transfer and α/β were included. The resulting DVH error bands were compared with the use of a constant RBE without uncertainties.

    Results: All plans were evaluated as robust using the constant RBE. Applying the proposed methodology using the variable RBE models broadens the DVH error bands for all structures studied. The uncertainty in α/β was the dominant factor. The variable RBE also shifted the nominal DVHs towards higher doses for most OARs, whereas the direction of this shift for the clinical target volumes (CTVs) depended on the treatment site, RBE model and fractionation schedule. The average RBE within the CTV, using one of the RBE models and 2 Gy(RBE) per fraction, varied between 1.11–1.26, 1.06–1.16 and 1.14–1.25 for the breast, H&N and prostate patients, respectively.

    Conclusions: A method of incorporating RBE uncertainties into the robustness evaluation has been proposed. By disregarding the variable RBE and its uncertainties, the variation in the RBE-weighted CTV and OAR doses may be underestimated. This could be an essential factor to take into account, especially in normal tissue complication probabilities based comparisons between proton and photon plans.

  • 24.
    Ödén, Jakob
    et al.
    Stockholm University, Faculty of Science, Department of Physics. RaySearch Laboratories, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Eriksson, Kjell
    Flejmer, Anna Maria
    Dasu, Alexandru
    The influence of breathing motion and a variable relative biological effectiveness in proton therapy of left-sided breast cancer2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 11, p. 1428-1436Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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