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Time, dose and fractionation: accounting for hypoxia in the search for optimal radiotherapy treatment parameters
Stockholm University, Faculty of Science, Department of Physics. (Medical Radiation Physics)
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 [en]
Hypoxia, radiobiological modelling, radiotherapy, functional imaging
National Category
Physical Sciences
Research subject
Medical Radiation Physics
Identifiers
URN: urn:nbn:se:su:diva-148301ISBN: 978-91-7797-031-6 (print)ISBN: 978-91-7797-032-3 (electronic)OAI: oai:DiVA.org:su-148301DiVA: diva2:1151147
Public defence
2017-12-05, CCK lecture hall, building R8, Karolinska University Hospital Solna, Solna, 10:00 (English)
Opponent
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
List of papers
1. Survival and tumour control probability in tumours with heterogeneous oxygenation: A comparison between the linear-quadratic and the universal survival curve models for high doses
Open this publication in new window or tab >>Survival and tumour control probability in tumours with heterogeneous oxygenation: A comparison between the linear-quadratic and the universal survival curve models for high doses
2014 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, no 8, 1035-1040 p.Article in journal (Refereed) Published
Abstract [en]

Background: The validity of the linear-quadratic (LQ) model at high doses has been questioned due to a decreasing agreement between predicted survival and experimental cell survival data. A frequently proposed alternative is the universal survival curve (USC) model, thought to provide a better fit in the high-dose region. The comparison between the predictions of the models has mostly been performed for uniform populations of cells with respect to sensitivity to radiation. This study aimed to compare the two models in terms of cell survival and tumour control probability (TCP) for cell populations with mixed sensitivities related to their oxygenation.

Methods: The study was performed in two parts. For the first part, cell survival curves were calculated with both models assuming various homogeneous populations of cells irradiated with uniform doses. For the second part, a realistic 3D-model of complex tumour oxygenation was used to study the impact of the differences in cell survival on the modelled tumour control probability. Cellular response was assessed with the LQ and USC models at voxel level and a Poisson TCP model at tumour level.

Results: For hypoxic tumours, the disputed continuous bend of the LQ survival curve was counteracted by the increased radio-resistance of the hypoxic cells and the survival curves started to diverge only at much higher doses than for oxic tumours. This was also reflected by the TCP curves for hypoxic tumours for which the difference in D50 values for the LQ and USC models was reduced from 5.4 to 0.2 Gy for 1 and 3 fractions respectively in a tumour with only 1.1% hypoxia and from 9.5 to 0.4 Gy in a tumour with 11.1% hypoxia.

Conclusions: For a large range of fractional doses including hypofractionated schemes, the difference in predicted survival and tumour control probability between the LQ and USC models for tumours with heterogeneous oxygenation was found to be negligible.

National Category
Cancer and Oncology
Research subject
Medical Radiation Physics
Identifiers
urn:nbn:se:su:diva-103440 (URN)10.3109/0284186X.2014.925582 (DOI)000340892900007 ()
Available from: 2014-05-16 Created: 2014-05-16 Last updated: 2017-10-22Bibliographically approved
2. Accounting for two forms of hypoxia for predicting tumour control probability in radiotherapy – an in silico study
Open this publication in new window or tab >>Accounting for two forms of hypoxia for predicting tumour control probability in radiotherapy – an in silico study
(English)Manuscript (preprint) (Other academic)
National Category
Physical Sciences
Research subject
Medical Radiation Physics
Identifiers
urn:nbn:se:su:diva-148299 (URN)
Available from: 2017-10-22 Created: 2017-10-22 Last updated: 2017-10-24Bibliographically 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
Show others...
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. Optimal fractionation in radiotherapy for non-small cell lung cancer - a modelling approach
Open this publication in new window or tab >>Optimal fractionation in radiotherapy for non-small cell lung cancer - a modelling approach
2015 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 9, 1592-1598 p.Article in journal (Refereed) Published
Abstract [en]

Background. Conventionally fractionated radiotherapy (CFRT) has proven ineffective in treating non-small cell lung cancer while more promising results have been obtained with stereotactic body radiotherapy (SBRT). Hypoxic tumours, however, might present a challenge to extremely hypofractionated schedules due to the decreased possibility for inter-fraction fast reoxygenation. A potentially successful compromise might be found in schedules employing several fractions of varying fractional doses. In this modelling study, a wide range of fractionation schedules from single-fraction treatments to heterogeneous, multifraction schedules taking into account repair, repopulation, reoxygenation and radiosensitivity of the tumour cells, has been explored with respect to the probability of controlling lung tumours.

Material and methods. The response to radiation of tumours with heterogeneous spatial and temporal oxygenation was simulated including the effects of accelerated repopulation and intra-fraction repair. Various treatments with respect to time, dose and fractionation were considered and the outcome was estimated as Poisson-based tumour control probability for local control.

Results. For well oxygenated tumours, heterogeneous fractionation could increase local control while hypoxic tumours are not efficiently targeted by such treatments despite reoxygenation. For hypofractionated treatments employing large doses per fraction, a synergistic effect was observed between intra-fraction repair and inter-fraction fast reoxygenation of the hypoxic cells as demonstrated by a reduction in D50 from 53.3 Gy for 2 fractions to 52.7 Gy for 5 fractions.

Conclusions. For well oxygenated tumours, heterogeneous fractionation schedules could increase local control rates substantially compared to CFRT. For hypoxic tumours, SBRT-like hypofractionated schedules might be optimal despite the increased risk of intra-fraction repair due to a synergistic effect with inter-fraction reoxygenation.

National Category
Cancer and Oncology
Research subject
Medical Radiation Physics
Identifiers
urn:nbn:se:su:diva-119100 (URN)10.3109/0284186X.2015.1061207 (DOI)000366674700049 ()
Available from: 2015-07-28 Created: 2015-07-28 Last updated: 2017-10-22Bibliographically approved
5. 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
Open this publication in new window or tab >>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
Show others...
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.

National Category
Cancer and Oncology
Research subject
Medical Radiation Physics
Identifiers
urn:nbn:se:su:diva-139929 (URN)10.1080/0284186X.2017.1293289 (DOI)000400796200011 ()28464740 (PubMedID)2-s2.0-85014551887 (Scopus ID)
Available from: 2017-02-20 Created: 2017-02-20 Last updated: 2017-10-22Bibliographically approved
6. Non-linear conversion of HX4 uptake for automatic segmentation of hypoxic volumes and dose prescription
Open this publication in new window or tab >>Non-linear conversion of HX4 uptake for automatic segmentation of hypoxic volumes and dose prescription
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Physical Sciences
Research subject
Medical Radiation Physics
Identifiers
urn:nbn:se:su:diva-148300 (URN)
Available from: 2017-10-22 Created: 2017-10-22 Last updated: 2017-10-24Bibliographically approved

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