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Radiobiological end-points for the theoretical evaluation of the effectiveness of carbon ions and photons in treating tumours with dynamic hypoxia
Stockholm University, Faculty of Science, Department of Physics. (Medicinsk Strålningsfysik)
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Tumours are characterised by unorganised vasculature, which often results in hypoxic regions. Hypoxia is a common cause for photon radiotherapy (RT) treatment failure, as hypoxic cells require up to 2-3 times higher doses compared to well-oxygenated cells for the same effect in terms of cell kill. The increase in dose that would be required to treat the tumours of cancer patients is limited by the radiation sensitivity of surrounding normal tissues. Using carbon ions instead of photons, the radiation dose can be conformed to the tumour to a much higher degree, resulting in an improved sparing of normal tissues. In addition, carbon ions have a much higher radiobiological effectiveness near the end of their range, which is positioned in the tumour. Also, the radiation modes of action leading to cell death when carbon ions interact with living tissues, are less sensitive to the oxygen status compared with the action modes of photons.

The focus of this thesis lies in the development of models for the computation of the cell surviving fraction and tumour control probability (TCP) in hypoxic tumours after photon and carbon ion RT. The impact of fractionation was evaluated with regard to possible spatial changes in oxygenation, both for stereotactic body RT and for carbon ion RT. The feasibility of a method to determine and deliver the optimal photon dose for achieving a high TCP according to spatial variations in radiation sensitivity was evaluated in a treatment planning study. The radiobiological models were finally used for the theoretical quantification of the gain in using carbon ions instead of photons.

The results show that there are great possibilities to increase the number of positive outcomes of radiation treatment of tumours if the key influential factors are taken into account, such as level and distribution of hypoxia, radiation quality and choice of fractionation schedule.

Place, publisher, year, edition, pages
Stockholm: Department of Physics, Stockholm University , 2014. , 50 p.
Keyword [en]
OER, hypoxia, LOC, RCR, hypofractionation, SBRT, carbon ion, fractionation, TCP, SF, RCE, RBE
National Category
Other Physics Topics
Research subject
Medical Radiation Physics
Identifiers
URN: urn:nbn:se:su:diva-102731ISBN: 978-91-7447-835-8 (print)OAI: oai:DiVA.org:su-102731DiVA: diva2:713575
Public defence
2014-05-27, CCK Lecture Hall, R8:00, Karolinska Sjukhuset, Solna, 13:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defence the following papers were unpublished and had a status as follows; Paper 3: Manuscript; Paper 4: Epubl ahead of print; Paper 5: Manuscript

Available from: 2014-05-05 Created: 2014-04-17 Last updated: 2014-05-05Bibliographically approved
List of papers
1. Dose prescription and treatment planning based on FMISO-PET hypoxia
Open this publication in new window or tab >>Dose prescription and treatment planning based on FMISO-PET hypoxia
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2012 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 2, 222-230 p.Article in journal (Refereed) Published
Abstract [en]

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

National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:su:diva-76341 (URN)10.3109/0284186X.2011.599815 (DOI)000299385600010 ()
Note

8

Available from: 2012-05-11 Created: 2012-05-10 Last updated: 2017-12-07Bibliographically approved
2. Radiobiological description of the LET dependence of the cell survival of oxic and anoxic cells irradiated by carbon ions
Open this publication in new window or tab >>Radiobiological description of the LET dependence of the cell survival of oxic and anoxic cells irradiated by carbon ions
2013 (English)In: Journal of radiation research, ISSN 0449-3060, E-ISSN 1349-9157, Vol. 54, no 1, 18-26 p.Article in journal (Refereed) Published
Abstract [en]

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

Keyword
Hypoxia, LET dependence, Carbon ions
National Category
Cancer and Oncology
Research subject
Radiation Physics; Oncology; Medical Radiation Physics
Identifiers
urn:nbn:se:su:diva-79121 (URN)10.1093/jrr/rrs070 (DOI)000313127200002 ()
Available from: 2012-08-28 Created: 2012-08-28 Last updated: 2017-12-07Bibliographically approved
3. Treatment fractionation for stereotactic radiotherapy of lung tumours: a modelling study of the influence of chronic and acute hypoxia on tumour control probability
Open this publication in new window or tab >>Treatment fractionation for stereotactic radiotherapy of lung tumours: a modelling study of the influence of chronic and acute hypoxia on tumour control probability
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2014 (English)In: Radiation Oncology, ISSN 1748-717X, E-ISSN 1748-717X, Vol. 9, 149Article in journal (Refereed) Published
Abstract [en]

Background: Stereotactic body radiotherapy (SBRT) for non-small-cell lung cancer (NSCLC) has led to promising local control and overall survival for fractionation schemes with increasingly high fractional doses. A point has however been reached where the number of fractions used might be too low to allow efficient local inter-fraction reoxygenation of the hypoxic cells residing in the tumour. It was therefore the purpose of this study to investigate the impact of hypoxia and extreme hypofractionation on the tumour control probability (TCP) from SBRT.

Methods: A three-dimensional model of tumour oxygenation able to simulate oxygenation changes on the microscale was used. The TCP was determined for clinically relevant SBRT fractionation schedules of 1, 3 and 5 fractions assuming either static tumour oxygenation or that the oxygenation changes locally between fractions due to fast reoxygenation of acute hypoxia without an overall reduction in chronic hypoxia.

Results: For the schedules applying three or five fractions the doses required to achieve satisfying levels of TCP were considerably lower when local oxygenation changes were assumed compared to the case of static oxygenation; a decrease in D50 of 17.7 Gy was observed for a five-fractions schedule applied to a 20% hypoxic tumour when fast reoxygenation was modelled. Assuming local oxygenation changes, the total doses required for a tumor control probability of 50% were of similar size for one, three and five fractions.

Conclusions: Although attractive from a practical point of view, extreme hypofractionation using just one single fraction may result in impaired local control of hypoxic tumours, as it eliminates the possibility for any kind of reoxygenation.

Keyword
Hypoxia, Hypofractionation, SBRT, NSCLC
National Category
Cancer and Oncology
Research subject
Radiation Physics; Medical Radiation Physics
Identifiers
urn:nbn:se:su:diva-102721 (URN)10.1186/1748-717X-9-149 (DOI)000338791300001 ()
Available from: 2014-04-16 Created: 2014-04-16 Last updated: 2017-10-22Bibliographically approved
4. Clinical oxygen enhancement ratio of tumors in carbon ion radiotherapy: the influence of local oxygenation changes
Open this publication in new window or tab >>Clinical oxygen enhancement ratio of tumors in carbon ion radiotherapy: the influence of local oxygenation changes
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2014 (English)In: Journal of radiation research, ISSN 0449-3060, E-ISSN 1349-9157, Vol. 55, no 5, 902-911 p.Article in journal (Refereed) Published
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.

Keyword
hypoxia, OER, TCP, RCR, carbon ion, fractionation, LOC
National Category
Cancer and Oncology
Research subject
Medical Radiation Physics; Radiation Physics; Oncology
Identifiers
urn:nbn:se:su:diva-101434 (URN)10.1093/jrr/rru020 (DOI)000342223100008 ()
Available from: 2014-03-08 Created: 2014-03-08 Last updated: 2017-10-11Bibliographically approved
5. Relative clinical effectiveness of carbon ion radiotherapy: theoretical modelling for H&N tumours
Open this publication in new window or tab >>Relative clinical effectiveness of carbon ion radiotherapy: theoretical modelling for H&N tumours
2015 (English)In: Journal of radiation research, ISSN 0449-3060, E-ISSN 1349-9157, Vol. 56, no 4, 639-645 p.Article in journal (Refereed) Published
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.

Keyword
hypoxia, RBE, TCP, carbon ion, fractionation, RCE
National Category
Physical Sciences
Identifiers
urn:nbn:se:su:diva-102720 (URN)10.1093/jrr/rrv016 (DOI)000360990700005 ()
Available from: 2014-04-16 Created: 2014-04-16 Last updated: 2017-12-05Bibliographically approved

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