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Defining the hypoxic target volume based on positron emission tomography for image guided radiotherapy – the influence of the choice of the reference region and conversion function
Stockholm University, Faculty of Science, Department of Physics.
The Skandion Clinic, Sweden; Linköping University, Sweden.ORCID iD: 0000-0001-8171-2541
RaySearch Laboratories AB, Sweden.
Maastricht University Medical Center, The Netherlands.
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2017 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 6, 819-825 p.Article in journal (Refereed) Published
Abstract [en]

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

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

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

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

Place, publisher, year, edition, pages
2017. Vol. 56, no 6, 819-825 p.
National Category
Cancer and Oncology
Research subject
Medical Radiation Physics
Identifiers
URN: urn:nbn:se:su:diva-139929DOI: 10.1080/0284186X.2017.1293289ISI: 000400796200011PubMedID: 28464740Scopus ID: 2-s2.0-85014551887OAI: oai:DiVA.org:su-139929DiVA: diva2:1075733
Available from: 2017-02-20 Created: 2017-02-20 Last updated: 2017-10-22Bibliographically approved
In thesis
1. Time, dose and fractionation: accounting for hypoxia in the search for optimal radiotherapy treatment parameters
Open this publication in new window or tab >>Time, dose and fractionation: accounting for hypoxia in the search for optimal radiotherapy treatment parameters
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The search for the optimal choice of treatment time, dose and fractionation regimen is one of the major challenges in radiation therapy. Several aspects of the radiation response of tumours and normal tissues give different indications of how the parameters defining a fractionation schedule should be altered relative to each other which often results in contradictory conclusions. For example, the increased sensitivity to fractionation in late-reacting as opposed to early-reacting tissues indicates that a large number of fractions is beneficial, while the issue of accelerated repopulation of tumour cells starting at about three weeks into a radiotherapy treatment would suggest as short overall treatment time as possible. Another tumour-to-normal tissue differential relevant to the sensitivity as well as the fractionation and overall treatment time is the issue of tumour hypoxia and reoxygenation.

The tumour oxygenation is one of the most influential factors impacting on the outcome of many types of treatment modalities. Hypoxic cells are up to three times as resistant to radiation as well-oxygenated cells, presenting a significant obstacle to overcome in radiotherapy as solid tumours often contain hypoxic areas as a result of their poorly functioning vasculature. Furthermore, the oxygenation is highly dynamic, with changes being observed both from fraction to  fraction and over a time period of weeks as a result of fast and slow reoxygenation of acute and chronic hypoxia. With an increasing number of patients treated with hypofractionated stereotactic body radiotherapy (SBRT), the clinical implications of a substantially reduced number of fractions and hence also treatment time thus have to be evaluated with respect to the oxygenation status of the tumour.

One of the most promising tools available for the type of study aiming at determining the optimal radiotherapy approach with respect to fractionation is radiobiological modelling. With clinically validated in vitro-derived tissue-specific radiobiological parameters and well-established survival models, in silico modelling offers a wide range of opportunities to test various hypotheses with respect to time, dose, fractionation and details of the tumour microenvironment. Any type of radiobiological modelling study intended to provide a realistic representation of a clinical tumour should therefore take into account details of both the spatial and temporal tumour oxygenation.

This thesis presents the results of three-dimensional radiobiological modelling of the response of tumours with heterogeneous oxygenation to various fractionation schemes, and oxygenation levels and dynamics using different survival models. The results of this work indicate that hypoxia and its dynamics play a major role in the outcome of radiotherapy, and that neglecting the oxygenation status of tumours treated with e.g. SBRT may compromise the treatment outcome substantially. Furthermore, the possibilities offered by incorporating modelling into the clinical routine are explored and demonstrated by the development of a new calibration function for converting the uptake of the hypoxia-PET tracer 18F-HX4 to oxygen partial pressure, and applying it for calculations of the doses needed to overcome hypoxia-induced radiation resistance. By hence demonstrating how the clinical impact of hypoxia on dose prescription and the choice of fractionation schedule can be investigated, this project will hopefully advance the evolution towards routinely incorporating functional imaging of hypoxia into treatment planning. This is ultimately expected to result in increased levels of local control with more patients being cured from their cancer.

Place, publisher, year, edition, pages
Stockholm: Department of Physics, Stockholm University, 2017. 54 p.
Keyword
Hypoxia, radiobiological modelling, radiotherapy, functional imaging
National Category
Physical Sciences
Research subject
Medical Radiation Physics
Identifiers
urn:nbn:se:su:diva-148301 (URN)978-91-7797-031-6 (ISBN)978-91-7797-032-3 (ISBN)
Public defence
2017-12-05, CCK lecture hall, building R8, Karolinska University Hospital Solna, Solna, 10:00 (English)
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Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 6: Manuscript.

Available from: 2017-11-10 Created: 2017-10-22 Last updated: 2017-11-03Bibliographically approved

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