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Clinical oxygen enhancement ratio of tumors in carbon ion radiotherapy: the influence of local oxygenation changes
Stockholm University, Faculty of Science, Department of Physics.
Stockholm University, Faculty of Science, Department of Physics.
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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.

Place, publisher, year, edition, pages
2014. Vol. 55, no 5, 902-911 p.
Keyword [en]
hypoxia, OER, TCP, RCR, carbon ion, fractionation, LOC
National Category
Cancer and Oncology
Research subject
Medical Radiation Physics; Radiation Physics; Oncology
Identifiers
URN: urn:nbn:se:su:diva-101434DOI: 10.1093/jrr/rru020ISI: 000342223100008OAI: oai:DiVA.org:su-101434DiVA: diva2:703715
Available from: 2014-03-08 Created: 2014-03-08 Last updated: 2017-10-11Bibliographically approved
In thesis
1. Radiobiological end-points for the theoretical evaluation of the effectiveness of carbon ions and photons in treating tumours with dynamic hypoxia
Open this publication in new window or tab >>Radiobiological end-points for the theoretical evaluation of the effectiveness of carbon ions and photons in treating tumours with dynamic hypoxia
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
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:nbn:se:su:diva-102731 (URN)978-91-7447-835-8 (ISBN)
Public defence
2014-05-27, CCK Lecture Hall, R8:00, Karolinska Sjukhuset, Solna, 13:00 (English)
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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
2. Searching for the optimal radiotherapy treatment time, dose and fractionation - the role of hypoxia and reoxygenation: A modelling study
Open this publication in new window or tab >>Searching for the optimal radiotherapy treatment time, dose and fractionation - the role of hypoxia and reoxygenation: A modelling study
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
Hypoxia, Reoxygenation, SBRT, Fractionation
National Category
Other Physics Topics
Research subject
Medical Radiation Physics
Identifiers
urn:nbn:se:su:diva-109348 (URN)
Presentation
2014-12-10, CCK Lecture Hall, Karolinska Universitetssjukhuset Solna, hus R8, Stockholm, 10:00 (English)
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Available from: 2014-12-01 Created: 2014-11-18 Last updated: 2017-10-20Bibliographically approved

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