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Searching for the optimal radiotherapy treatment time, dose and fractionation - the role of hypoxia and reoxygenation: A modelling study
Stockholm University, Faculty of Science, Department of Physics.
2014 (English)Licentiate 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.

The perhaps most promising tool available for the type of study aiming at determining the optimal SBRT approach with respect to fractionation is radiobiological modelling. With clinically-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, consisting of papers I-III and a summary, presents the results of three-dimensional radiobiological modelling of the response of tumours with heterogeneous oxygenation to various radiation qualities, fractionation schemes, 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 both photon and carbon ion radiotherapy, and that neglecting the oxygenation status of tumours treated with SBRT may compromise the treatment outcome substantially. Continued to include clinical studies on the impact of hypoxia on the treatment outcome in lung cancer patients treated with SBRT, 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 , 2014. , 30 p.
Keyword [en]
Hypoxia, Reoxygenation, SBRT, Fractionation
National Category
Other Physics Topics
Research subject
Medical Radiation Physics
Identifiers
URN: urn:nbn:se:su:diva-109348OAI: oai:DiVA.org:su-109348DiVA: diva2:764569
Presentation
2014-12-10, CCK Lecture Hall, Karolinska Universitetssjukhuset Solna, hus R8, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2014-12-01 Created: 2014-11-18 Last updated: 2017-10-20Bibliographically 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. 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
3. 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

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