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

    Comparison of the efficiency of photon and carbon ion radiotherapy (RT) administered with the same number of fractions might be of limited clinical interest, since a wide range of fractionation patterns are used clinically today. Due to advanced photon treatment techniques, hypofractionation is becoming increasingly accepted for prostate and lung tumours, whereas patients with head and neck tumours still benefit from hyperfractionated treatments. In general, the number of fractions is considerably lower in carbon ion RT. A clinically relevant comparison would be between fractionation schedules that are optimal within each treatment modality category. In this in silico study, the relative clinical effectiveness (RCE) of carbon ions was investigated for human salivary gland tumours, assuming various radiation sensitivities related to their oxygenation. The results indicate that, for hypoxic tumours in the absence of reoxygenation, the RCE (defined as the ratio of D50 for photons to carbon ions) ranges from 3.5 to 5.7, corresponding to carbon ion treatments given in 36 and 3 fractions, respectively, and 30 fractions for photons. Assuming that interfraction local oxygenation changes take place, results for RCE are lower than that for an oxic tumour if only a few fractions of carbon ions are used. If the carbon ion treatment is given in more than 12 fractions, the RCE is larger for the hypoxic than for the well-oxygenated tumour. In conclusion, this study showed that in silico modelling enables the study of a wide range of factors in the clinical considerations and could be an important step towards individualisation of RT treatments.

  • 2.
    Antonovic, Laura
    et al.
    Stockholm University, 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, p. 639-645Article 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, p. 902-911Article 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.
    Antonovic, Laura
    et al.
    Stockholm University, Sweden.
    Lindblom, Emely
    Stockholm University, Sweden.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Bassler, Niels
    Aarhus University, Denmark.
    Furusawa, Yoshiya
    National Institute of Radiological Sciences, Chiba, Japan.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet, Stockholm, Sweden.
    Clinical oxygen enhancement ratio of tumors in carbon ion radiotherapy: the influence of local oxygenation changes2014In: Journal of radiation research, ISSN 0449-3060, E-ISSN 1349-9157, Vol. 55, no 5, p. 902-911Article 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.

  • 5.
    Ardenfors, Oscar
    et al.
    Stockholm University, Stockholm, Sweden.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. The Skandion Clinic, Uppsala, Sweden.
    Kopeć, Mariusz
    University of Science and Technology, Krakow, Poland.
    Gudowska, Irena
    Stockholm University, Stockholm, Sweden.
    Modelling of a proton spot scanning system using MCNP62017In: INTERNATIONAL NUCLEAR SCIENCE AND TECHNOLOGY CONFERENCE 2016, Institute of Physics (IOP), 2017, Vol. 860, article id 012025Conference paper (Refereed)
    Abstract [en]

    The aim of this work was to model the characteristics of a clinical proton spot scanning beam using Monte Carlo simulations with the code MCNP6. The proton beam was defined using parameters obtained from beam commissioning at the Skandion Clinic, Uppsala, Sweden. Simulations were evaluated against measurements for proton energies between 60 and 226 MeV with regard to range in water, lateral spot sizes in air and absorbed dose depth profiles in water. The model was also used to evaluate the experimental impact of lateral signal losses in an ionization chamber through simulations using different detector radii. Simulated and measured distal ranges agreed within 0.1 mm for R90 and R80, and within 0.2 mm for R50. The average absolute difference of all spot sizes was 0.1 mm. The average agreement of absorbed dose integrals and Bragg-peak heights was 0.9%. Lateral signal losses increased with incident proton energy with a maximum signal loss of 7% for 226 MeV protons. The good agreement between simulations and measurements supports the assumptions and parameters employed in the presented Monte Carlo model. The characteristics of the proton spot scanning beam were accurately reproduced and the model will prove useful in future studies on secondary neutrons.

  • 6. Ardenfors, Oscar
    et al.
    Dasu, Alexandru
    Kopeć, Mariusz
    Gudowska, Irena
    Modelling of a proton spot scanning system using MCNP62017In: Journal of Physics: Conference Series, ISSN 1742-6588, Vol. 860, p. 012025-Article in journal (Refereed)
  • 7. Ardenfors, Oscar
    et al.
    Dasu, Alexandru
    Lillhök, Jan
    Persson, Linda
    Gudowska, Irena
    Out-of-field doses from secondary radiation produced in proton therapy and the associated risk of radiation-induced cancer from a brain tumor treatment.2018In: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 53, p. 129-136Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To determine out-of-field doses produced in proton pencil beam scanning (PBS) therapy using Monte Carlo simulations and to estimate the associated risk of radiation-induced second cancer from a brain tumor treatment.

    METHODS: Simulations of out-of-field absorbed doses were performed with MCNP6 and benchmarked against measurements with tissue-equivalent proportional counters (TEPC) for three irradiation setups: two irradiations of a water phantom using proton energies of 78-147 MeV and 177-223 MeV, and one brain tumor irradiation of a whole-body phantom. Out-of-field absorbed and equivalent doses to organs in a whole-body phantom following a brain tumor treatment were subsequently simulated and used to estimate the risk of radiation-induced cancer. Additionally, the contribution of absorbed dose originating from radiation produced in the nozzle was calculated from simulations.

    RESULTS: Out-of-field absorbed doses to the TEPC ranged from 0.4 to 135 µGy/Gy. The average deviation between simulations and measurements of the water phantom irradiations was about 17%. The absorbed dose contribution from radiation produced in the nozzle ranged between 0 and 70% of the total dose; the contribution was however small in absolute terms. The absorbed and equivalent doses to the organs ranged between 0.2 and 60 µGy/Gy and 0.5-151 µSv/Gy. The estimated lifetime risk of radiation-induced second cancer was approximately 0.01%.

    CONCLUSIONS: The agreement of out-of-field absorbed doses between measurements and simulations was good given the sources of uncertainties. Calculations of out-of-field organ doses following a brain tumor treatment indicated that proton PBS therapy of brain tumors is associated with a low risk of radiation-induced cancer.

  • 8.
    Ardenfors, Oscar
    et al.
    Stockholm University, Sweden.
    Gudowska, Irena
    Stockholm University, Sweden.
    Flejmer, Anna M.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Dasu, Alexandru
    The Skandion Clinic, Sweden.
    Impact of irradiation setup in proton spot scanning brain therapy on organ doses from secondary radiation2018In: Radiation Protection Dosimetry, ISSN 0144-8420, E-ISSN 1742-3406, Vol. 180, no 1-4, p. 261-266Article in journal (Refereed)
    Abstract [en]

    A Monte Carlo model of a proton spot scanning pencil beam was used to simulate organ doses from secondary radiation produced from brain tumour treatments delivered with either a lateral field or a vertex field to one adult and one paediatric patient. Absorbed doses from secondary neutrons, photons and protons and neutron equivalent doses were higher for the vertex field in both patients, but the differences were low in absolute terms. Absorbed doses ranged between 0.1 and 43 μGy.Gy−1 in both patients with the paediatric patient receiving higher doses. The neutron equivalent doses to the organs ranged between 0.5 and 141 μSv.Gy−1 for the paediatric patient and between 0.2 and 134 μSv.Gy−1 for the adult. The highest neutron equivalent dose from the entire treatment was 7 mSv regardless of field setup and patient size. The results indicate that different field setups do not introduce large absolute variations in out-of-field doses produced in patients undergoing proton pencil beam scanning of centrally located brain tumours.

  • 9.
    Ardenfors, Oscar
    et al.
    Stockholm University, Faculty of Science, Department of Physics.
    Gudowska, Irena
    Stockholm University, Faculty of Science, Department of Physics.
    Flejmer, Anna Maria
    Dasu, Alexandru
    IMPACT OF IRRADIATION SETUP IN PROTON SPOT SCANNING BRAIN THERAPY ON ORGAN DOSES FROM SECONDARY RADIATION2018In: Radiation Protection Dosimetry, ISSN 0144-8420, E-ISSN 1742-3406, Vol. 180, no 1-4, p. 261-266Article in journal (Refereed)
    Abstract [en]

    A Monte Carlo model of a proton spot scanning pencil beam was used to simulate organ doses from secondary radiation produced from brain tumour treatments delivered with either a lateral field or a vertex field to one adult and one paediatric patient. Absorbed doses from secondary neutrons, photons and protons and neutron equivalent doses were higher for the vertex field in both patients, but the differences were low in absolute terms. Absorbed doses ranged between 0.1 and 43 mu Gy. Gy(-1) in both patients with the paediatric patient receiving higher doses. The neutron equivalent doses to the organs ranged between 0.5 and 141 mu Sv. Gy(-1) for the paediatric patient and between 0.2 and 134 mu Sv. Gy(-1) for the adult. The highest neutron equivalent dose from the entire treatment was 7 mSv regardless of field setup and patient size. The results indicate that different field setups do not introduce large absolute variations in out-of-field doses produced in patients undergoing proton pencil beam scanning of centrally located brain tumours.

  • 10. Ardenfors, Oscar
    et al.
    Gudowska, Irena
    Flejmer, Anna Maria
    Dasu, Alexandru
    Impact of irradiation setup in proton spot scanning brain therapy on organ doses from secondary radiation2018In: Radiation Protection Dosimetry, ISSN 0144-8420, E-ISSN 1742-3406, Vol. 180, no 1-4, p. 261-266Article in journal (Refereed)
    Abstract [en]

    A Monte Carlo model of a proton spot scanning pencil beam was used to simulate organ doses from secondary radiation produced from brain tumour treatments delivered with either a lateral field or a vertex field to one adult and one paediatric patient. Absorbed doses from secondary neutrons, photons and protons and neutron equivalent doses were higher for the vertex field in both patients, but the differences were low in absolute terms. Absorbed doses ranged between 0.1 and 43 μGy.Gy-1 in both patients with the paediatric patient receiving higher doses. The neutron equivalent doses to the organs ranged between 0.5 and 141 μSv.Gy-1 for the paediatric patient and between 0.2 and 134 μSv.Gy-1 for the adult. The highest neutron equivalent dose from the entire treatment was 7 mSv regardless of field setup and patient size. The results indicate that different field setups do not introduce large absolute variations in out-of-field doses produced in patients undergoing proton pencil beam scanning of centrally located brain tumours.

  • 11. Ardenfors, Oscar
    et al.
    Henry, Thomas
    Gudowska, Irena
    Poludniowski, Gavin
    Dasu, Alexandru
    Organ doses from a proton gantry-mounted cone-beam computed tomography system characterized with MCNP6 and GATE2018In: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 53, p. 56-61Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To determine organ doses from a proton gantry-mounted cone-beam computed tomography (CBCT) system using two Monte Carlo codes and to study the influence on organ doses from different acquisition modes and repeated imaging.

    METHODS: The CBCT system was characterized with MCNP6 and GATE using measurements of depth doses in water and spatial profiles in air. The beam models were validated against absolute dose measurements and used to simulate organ doses from CBCT imaging with head, thorax and pelvis protocols. Anterior and posterior 190° scans were simulated and the resulting organ doses per mAs were compared to those from 360° scans. The influence on organ doses from repeated imaging with different imaging schedules was also investigated.

    RESULTS: The agreement between MCNP6, GATE and measurements with regard to depth doses and beam profiles was within 4% for all protocols and the corresponding average agreement in absolute dose validation was 4%. Absorbed doses for in-field organs from 360° scans ranged between 6 and 8 mGy, 15-17 mGy and 24-54 mGy for the head, thorax and pelvis protocols, respectively. Cumulative organ doses from repeated CBCT imaging ranged between 0.04 and 0.32 Gy for weekly imaging and 0.2-1.6 Gy for daily imaging. The anterior scans resulted in an average increase in dose per mAs of 24% to the organs of interest relative to the 360° scan, while the posterior scan showed a 37% decrease.

    CONCLUSIONS: A proton gantry-mounted CBCT system was accurately characterized with MCNP6 and GATE. Organ doses varied greatly depending on acquisition mode, favoring posterior scans.

  • 12.
    Ardenfors, Oscar
    et al.
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Stockholm University.
    Josefsson, Dan
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Dasu, Alexandru
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    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.

  • 13.
    Bennati, Paolo
    et al.
    KTH, Royal Institute of Technology, Stockholm, Sweden.
    Dasu, Alexandru
    The Skandion Clinic, Uppsala, Sweden.
    Colarieti-Tosti, Massimiliano
    KTH, Royal Institute of Technology, Stockholm, Sweden.
    Lönn, Gustaf
    KTH, Royal Institute of Technology, Stockholm, Sweden.
    Larsson, David
    KTH, Royal Institute of Technology, Stockholm, Sweden.
    Fabbri, Andrea
    INFN, National Institute for Nuclear Physics, Rome, Italy.
    Galasso, Matteo
    INFN, National Institute for Nuclear Physics, Rome, Italy.
    Cinti, Maria Nerina
    Sapienza University, Rome, Italy.
    Pellegrini, Rosanna
    Sapienza University, Rome, Italy.
    Pani, Roberto
    Sapienza University, Rome, Italy.
    Preliminary study of a new gamma imager for on-line proton range monitoring during proton radiotherapy2017In: Journal of Instrumentation, ISSN 1748-0221, E-ISSN 1748-0221, Vol. 12, no 5, article id C05009Article in journal (Refereed)
    Abstract [en]

    We designed and tested new concept imaging devices, based on a thin scintillating crystal, aimed at the online monitoring of the range of protons in tissue during proton radiotherapy. The proposed crystal can guarantee better spatial resolution and lower sensitivity with respect to a thicker one, at the cost of a coarser energy resolution. Two different samples of thin crystals were coupled to a position sensitive photo multiplier tube read out by 64 independent channels electronics. The detector was equipped with a knife-edge Lead collimator that defined a reasonable field of view of about 10 cm in the target. Geant4 Monte Carlo simulations were used to optimize the design of the experimental setup and assess the accuracy of the results. Experimental measurements were carried out at the Skandion Clinic, the recently opened proton beam facility in Uppsala, Sweden. PMMA and water phantoms studies were performed with a first prototype based on a round 6.0 mm thick Cry019 crystal and with a second detector based on a thinner 5 × 5 cm2, 2.0 mm thick LFS crystal. Phantoms were irradiated with mono-energetic proton beams whose energy was in the range between 110 and 160 MeV. According with the simulations and the experimental data, the detector based on LFS crystal seems able to identify the peak of prompt-gamma radiation and its results are in fair agreement with the expected shift of the proton range as a function of energy. The count rate remains one of the most critical limitations of our system, which was able to cope with only about 20% of the clinical dose rate. Nevertheless, we are confident that our study might provide the basis for developing a new full-functional system.

  • 14. Bennati, Paolo
    et al.
    Dasu, Alexandru
    Colarieti-Tosti, Massimiliano
    Lönn, Gustaf
    Larsson, David
    Fabbri, Andrea
    Galasso, Matteo
    Cinti, Maria Nerina
    Pellegrini, Rosanna
    Pani, Roberto
    Preliminary study of a new gamma imager for on-line proton range monitoring during proton radiotherapy2017In: Journal of Instrumentation, ISSN 1748-0221, E-ISSN 1748-0221, Vol. 12, no 5, p. C05009-Article in journal (Refereed)
  • 15.
    Bolsi, Alessandra
    et al.
    Paul Scherrer Institute, Switzerland.
    Peroni, Marta
    Paul Scherrer Institute, Switzerland.
    Amelio, Dante
    Proton Therapy Centre Azienda Provinciale per I Servizi Sanitari (APSS), Italy.
    Dasu, Alexandru
    The Skandion Clinic, Sweden.
    Stock, Markus
    MedAustron Ion Therapy Center, Austria.
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.
    Witt Nyström, Petra
    The Skandion Clinic, Sweden; Danish Centre for Particle Therapy, Denmark.
    Hoffmann, Aswin
    Technische Universität Dresden, Germany; OncoRay, Germany.
    Practice patterns of image guided particle therapy in Europe: A 2016 survey of the European Particle Therapy Network (EPTN)2018In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 128, no 1, p. 4-8Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

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

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

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

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

  • 17.
    Dasu, Alexandru
    Norrlands University Hospital.
    Is the alpha/beta value for prostate tumours low enough to be safely used in clinical trials?2007In: Clinical Oncology, ISSN 0936-6555, E-ISSN 1433-2981, Vol. 19, no 5, p. 289-301Article, review/survey (Refereed)
    Abstract [en]

    There has been an intense debate over the past several years on the relevant alpha/beta value that could be used to describe the fractionation response of prostate tumours. Previously it has been assumed that prostate tumours have high alpha/beta values, similar to most other tumours and the early reacting normal tissues. However, the proliferation behaviour of the prostate tumours is more like that of the late reacting tissues, with slow doubling times and low alpha/beta values. The analyses of clinical results carried out in the past few years have indeed suggested that the alpha/beta value that characterises the fractionation response of the prostate is low, possibly even below the 3 Gy commonly assumed for most late complications, and hence that hypofractionation of the radiation treatment might improve the therapeutic ratio (better control at the same or lower complication rate). However, hypofractionation might also increase the complication rates in the surrounding late responding tissues and if their alpha/beta value is not larger that of prostate tumours it could even lead to a decrease in the therapeutic ratio. Therefore, the important question is whether the alpha/beta value for the prostate is lower than the alpha/beta values of the surrounding late responding tissues at risk. This paper reviews the clinical and experimental data regarding the radiobiological differential that might exist between prostate tumours and the late normal tissues around them. Several prospective hypofractionated trials that have been initiated recently in order to determine the alpha/beta value or the range of values that describe the fractionation response of prostate tumours are also reviewed. In spite of several confounding factors that interfere with the derivation of a precise value, it seems that most data support a trend towards lower alpha/beta values for prostate tumours than for rectum or bladder.

  • 18.
    Dasu, Alexandru
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Radiobiology of prostate cancer2012In: Robotic Radiosurgery. Treating Prostate Cancer and Related Genitourinary Applications / [ed] Ponsky LE, Fuller DB, Meier RM, Ma C-MC, Springer Berlin/Heidelberg, 2012, p. 79-101Chapter in book (Refereed)
    Abstract [en]

    The 1999 proposal of Brenner and Hall of an alpha/beta value of 1.5 Gy for prostate tumors has rekindled the interest in the traditional radiobiological aspects of time, dose, and fractionation as effective means of modulating the therapeutic window in radiation therapy. It is well established that, depending on the fractionation sensitivity of normal and tumor tissues, one could depart from the usual fractionation pattern and devise schedules that lead to the same tumor results with less complications, or better tumor control with the same level of complications. Nevertheless, radiobiology experience indicates that the success of any fractionation schedule depends on the temporal pattern of dose delivery. From this perspective, the present chapter aims to review the radiobiological aspects that may be relevant for the design of treatment schedules for prostate tumors.

  • 19.
    Dasu, Alexandru
    Norrlands University Hospital, Umeå.
    Treatment planning optimisation based on imaging tumour proliferation and cell density2008In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 47, no 7, p. 1221-1228Article in journal (Refereed)
    Abstract [en]

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

  • 20. Dasu, Alexandru
    et al.
    Flejmer, Anna M.
    Dohlmar, Frida
    Josefsson, Dan
    Witt Nyström, Petra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    The Potential Benefit of Scanned Proton Beam Versus Intensity Modulated Photon Therapy as Adjuvant Radiation Therapy in Breast Cancer2014In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 34, no 10, p. 5873-5874Article in journal (Other academic)
  • 21.
    Dasu, Alexandru
    et al.
    The Skandion Clinic, Uppsala, Sweden.
    Flejmer, Anna M.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. The Skandion Clinic, Uppsala, Sweden.
    Edvardsson, Anneli
    Medical Radiation Physics, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
    Witt Nyström, Petra
    The Skandion Clinic, Uppsala, Sweden.
    Normal tissue sparing potential of scanned proton beams with and without respiratory gating for the treatment of internal mammary nodes in breast cancer radiotherapy2018In: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 52, p. 81-85Article in journal (Refereed)
    Abstract [en]

    Proton therapy has shown potential for reducing doses to normal tissues in breast cancer radiotherapy. However data on the impact of protons when including internal mammary nodes (IMN) in the target for breast radiotherapy is comparatively scarce. This study aimed to evaluate normal tissue doses when including the IMN in regional RT with scanned proton beams, with and without respiratory gating. The study cohort was composed of ten left-sided breast patients CT-scanned during enhanced inspiration gating (EIG) and free-breathing (FB). Proton plans were designed for the target including or excluding the IMN. Targets and organs-at-risk were delineated according to RTOG guidelines. Comparison was performed between dosimetric parameters characterizing target coverage and OAR radiation burden. Statistical significance of differences was tested using a paired, two-tailed Student’s t-test. Inclusion of the IMN in the target volume led to a small increase of the cardiopulmonary burden. The largest differences were seen for the ipsilateral lung where the mean dose increased from 6.1 to 6.6 Gy (RBE) (P < 0.0001) in FB plans and from 6.9 to 7.4 Gy (RBE) (P = 0.003) in EIG plans. Target coverage parameters were very little affected by the inclusion of IMN into the treatment target. Radiotherapy with scanned proton beams has the potential of maintaining low cardiovascular burden when including the IMN into the target, irrespective of whether respiratory gating is used or not.

  • 22. Dasu, Alexandru
    et al.
    Flejmer, Anna M.
    Edvardsson, Anneli
    Witt Nyström, Petra
    Normal tissue sparing potential of scanned proton beams with and without respiratory gating for the treatment of internal mammary nodes in breast cancer radiotherapy2018In: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 52, p. 81-85Article in journal (Refereed)
    Abstract [en]

    Proton therapy has shown potential for reducing doses to normal tissues in breast cancer radiotherapy. However data on the impact of protons when including internal mammary nodes (IMN) in the target for breast radiotherapy is comparatively scarce. This study aimed to evaluate normal tissue doses when including the IMN in regional RT with scanned proton beams, with and without respiratory gating. The study cohort was composed of ten left-sided breast patients CT-scanned during enhanced inspiration gating (EIG) and free-breathing (FB). Proton plans were designed for the target including or excluding the IMN. Targets and organs-at-risk were delineated according to RTOG guidelines. Comparison was performed between dosimetric parameters characterizing target coverage and OAR radiation burden. Statistical significance of differences was tested using a paired, two-tailed Student's t-test. Inclusion of the IMN in the target volume led to a small increase of the cardiopulmonary burden. The largest differences were seen for the ipsilateral lung where the mean dose increased from 6.1 to 6.6 Gy (RBE) (P < 0.0001) in FB plans and from 6.9 to 7.4 Gy (RBE) (P = 0.003) in EIG plans. Target coverage parameters were very little affected by the inclusion of IMN into the treatment target. Radiotherapy with scanned proton beams has the potential of maintaining low cardiovascular burden when including the IMN into the target, irrespective of whether respiratory gating is used or not.

  • 23.
    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, p. 1731-1734Article 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.

  • 24.
    Dasu, Alexandru
    et al.
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Dose painting by numbers - do the practical limitations of the technique decrease or increase the probability of controlling tumours?2013In: IFMBE Proceedings / [ed] Long Mian, Springer, 2013, Vol. 39, p. 1731-1734Conference paper (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.

  • 25.
    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.

  • 26.
    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, p. 490-493Article 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.

  • 27.
    Dasu, Alexandru
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Toma-Dasu, Iuliana
    Stockholm University, Sweden.
    Impact of increasing irradiation time on the treatment of prostate cancers2015In: World Congress on Medical Physics and Biomedical Engineering, June 7-12, 2015, Toronto, Canada / [ed] Jaffray David A., Springer, 2015, Vol. 51, p. 490-493Conference paper (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.

  • 28.
    Dasu, Alexandru
    et al.
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Impact of variable RBE on proton fractionation2013In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 40, no 1, p. Article ID 011705-Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 29.
    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, article id 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.

  • 30.
    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, p. 1614-1615Article in journal (Refereed)
  • 31.
    Dasu, Alexandru
    et al.
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet, Stockholm, Sweden.
    Long-term effects and secondary tumors2014In: Comprehensive Biomedical Physics, Volume 9: Radiation Therapy Physics and Treatment Optimization / [ed] Anders Brahme, Amsterdam: Elsevier, 2014, p. 223-233Chapter 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.

  • 32.
    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, p. 223-233Chapter 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.

  • 33.
    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, p. 232-238Article in journal (Refereed)
    Abstract [en]

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

  • 34.
    Dasu, Alexandru
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. The Skandion Clinic, Uppsala, Sweden.
    Toma-Dasu, Iuliana
    Stockholm University, Sweden; 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, p. 232-238Article in journal (Refereed)
    Abstract [en]

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

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

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

  • 36.
    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.

  • 37.
    Dasu, Alexandru
    et al.
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Toma-Dasu, Iuliana
    Stockholm University and Karolinska Institutet.
    Prostate alpha/beta revisited – an analysis of clinical results from 14168 patients2012In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 8, 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.

  • 38.
    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, p. 255-260Article 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.

  • 39.
    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, p. 357-362Article 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.

  • 40.
    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.

  • 41.
    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, p. 539-545Article 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.

  • 42.
    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, p. 867-874Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To study the clinically relevant relative biologic effectiveness (RBE) of fractionated treatments with high linear energy transfer (LET) radiation and to identify the important factors that might influence the transfer of tolerance and curative levels from low LET radiation. These are important questions in the light of the growing interest for the therapeutic use of radiation with higher LET than electrons or photons. METHODS AND MATERIALS: The RBE of various fractionated schedules was analyzed with theoretical models for radiation effect, and the resulting predictions were compared with the published clinical and experimental data regarding fractionated irradiation with high LET radiation. RESULTS: The clinically relevant RBE increased for greater doses per fraction, in contrast to the predictions from single-dose experiments. Furthermore, the RBE for late-reacting tissues appeared to modify more quickly than that for early-reacting tissues. These aspects have quite important clinical implications, because the increased biologic effectiveness reported for this type of radiation would otherwise support the use of hypofractionation. Thus, the differential between acute and late-reacting tissues could put the late-reacting normal tissues at more risk from high LET irradiation; however, at the same time, it could increase the therapeutic window for slow-growing tumors. CONCLUSIONS: The modification of the RBE with the dose per fraction must be carefully taken into consideration when devising fractionated treatments with high LET radiation. Neglecting to do so might result in an avalanche of complications that could obscure the potential advantages of the therapeutic use of this type of radiation.

  • 43.
    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, article id 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.

  • 44.
    Dasu, Alexandru
    et al.
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences.
    Toma-Dasu, Iuliana
    Stockholm University.
    Will intrafraction repair have negative consequences on extreme hypofractionation in prostate radiation therapy?2015In: British Journal of Radiology, ISSN 0007-1285, E-ISSN 1748-880X, Vol. 88, no 1056, p. Article ID 20150588-Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

  • 45.
    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, p. 387-397Article 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.

  • 46.
    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, p. 738-746Article 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.

  • 47.
    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, p. 237-240Article 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.

  • 48.
    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.

  • 49.
    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, p. 2829-2842Article 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.

  • 50.
    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.

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