Determination of the optimum dose per fraction in fractionated radiotherapy when there is delayed onset of tumour repopulation during treatment

Armpilia, Christina; Dale, Roger G.; Jones, Bleddyn

doi:10.1259/bjr/47388747

Cited by 28 publications

(34 citation statements)

References 8 publications

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“…An AR boost factor value of 10 results in an extra dose between 0.5 and 0.8 Gy per fraction, which is consistent with clinical trial reports [8, 63, 64]. An AR boost factor less than 10 increases the dose per fraction by 0.3 Gy or less, while an AR boost factor more than 10 results in an extra dose per fraction above 1.0 Gy.…”

Section: Resultssupporting

confidence: 88%

The HYP-RT Hypoxic Tumour Radiotherapy Algorithm and Accelerated Repopulation Dose per Fraction Study

Harriss-Phillips

Bezak

Yeoh

2012

Computational and Mathematical Methods in Medicine

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The HYP-RT model simulates hypoxic tumour growth for head and neck cancer as well as radiotherapy and the effects of accelerated repopulation and reoxygenation. This report outlines algorithm design, parameterisation and the impact of accelerated repopulation on the increase in dose/fraction needed to control the extra cell propagation during accelerated repopulation. Cell kill probabilities are based on Linear Quadratic theory, with oxygenation levels and proliferative capacity influencing cell death. Hypoxia is modelled through oxygen level allocation based on pO2 histograms. Accelerated repopulation is modelled by increasing the stem cell symmetrical division probability, while the process of reoxygenation utilises randomised pO2 increments to the cell population after each treatment fraction. Propagation of 108 tumour cells requires 5–30 minutes. Controlling the extra cell growth induced by accelerated repopulation requires a dose/fraction increase of 0.5–1.0 Gy, in agreement with published reports. The average reoxygenation pO2 increment of 3 mmHg per fraction results in full tumour reoxygenation after shrinkage to approximately 1 mm. HYP-RT is a computationally efficient model simulating tumour growth and radiotherapy, incorporating accelerated repopulation and reoxygenation. It may be used to explore cell kill outcomes during radiotherapy while varying key radiobiological and tumour specific parameters, such as the degree of hypoxia.

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Section: Resultssupporting

confidence: 88%

The HYP-RT Hypoxic Tumour Radiotherapy Algorithm and Accelerated Repopulation Dose per Fraction Study

Harriss-Phillips

Bezak

Yeoh

2012

Computational and Mathematical Methods in Medicine

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“…This result is in accordance with a previous sensitivity study that aimed to validate the AR boost factor through calculations of the extra dose per fraction required to account for AR. In this conventional fraction study an AR boost factor of 10 resulted in average equivalent doses per fraction of 2.6 Gy, which was in agreement with literature values ranging from 2.5-3.0 Gy per fraction [10,29,39,40,42,61]. Note that some radiotherapy plus concomitant chemotherapy schedules may have the effect of delaying tumour AR; however, this mechanism has not been considered for this report.…”

Section: Oxic Tumour Radiotherapy and Accelerated Repopulationsupporting

confidence: 89%

“…for random seed 333: from 35 to 65 days before the boost decreased to 1 to 5 days after the boost, depending on oxygenation status) and an analysis of the extra dose per fraction required to kill the extra cells that had propagated as a result of AR (published data reporting values between 0.5-1.0 Gy per fraction [10,[39][40][41][42]). The comparison of the doses per fraction have not been disclosed here and will form part of a separate report.…”

Section: Hypoxic Tumour Growth and Radiotherapy In The Modelmentioning

confidence: 99%

Monte Carlo radiotherapy simulations of accelerated repopulation and reoxygenation for hypoxic head and neck cancer

Harriss-Phillips

Bezak²,

Yeoh³

2011

BJR

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Objective: A temporal Monte Carlo tumour growth and radiotherapy effect model (HYP-RT) simulating hypoxia in head and neck cancer has been developed and used to analyse parameters influencing cell kill during conventionally fractionated radiotherapy. The model was designed to simulate individual cell division up to 10 8 cells, while incorporating radiobiological effects, including accelerated repopulation and reoxygenation during treatment. Method: Reoxygenation of hypoxic tumours has been modelled using randomised increments of oxygen to tumour cells after each treatment fraction. The process of accelerated repopulation has been modelled by increasing the symmetrical stem cell division probability. Both phenomena were onset immediately or after a number of weeks of simulated treatment. Results: The extra dose required to control (total cell kill) hypoxic vs oxic tumours was 15-25% (8-20 Gy for 562 Gy per week) depending on the timing of accelerated repopulation onset. Reoxygenation of hypoxic tumours resulted in resensitisation and reduction in total dose required by approximately 10%, depending on the time of onset. When modelled simultaneously, accelerated repopulation and reoxygenation affected cell kill in hypoxic tumours in a similar manner to when the phenomena were modelled individually; however, the degree was altered, with non-additive results. Simulation results were in good agreement with standard linear quadratic theory; however, differed for more complex comparisons where hypoxia, reoxygenation as well as accelerated repopulation effects were considered. Conclusion: Simulations have quantitatively confirmed the need for patient individualisation in radiotherapy for hypoxic head and neck tumours, and have shown the benefits of modelling complex and dynamic processes using Monte Carlo methods.

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“…Such cancers respond to RT with an increase in tumor doubling times and hence accelerated proliferation during extended treatment times, therefore decreasing the TCP. Radiobiological modeling suggests that any strategy that delays the onset and/or decreases the rate of tumor repopulation could increase TCP at a given NTCP or decrease the late responding NTCP through the application of smaller doses in the presence of a larger number of fractions without impairing TCP [64]. Figure 3 demonstrates this effect qualitatively if one assumes the solid blue curve to be the TCP with accelerated repopulation starting within the treatment period.…”

Section: How Calorie and Carbohydrate Restriction May Influence The Rmentioning

confidence: 99%

Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R’s through dietary manipulation

Klement

Champ

2014

Cancer Metastasis Rev

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Aggressive tumors typically demonstrate a high glycolytic rate, which results in resistance to radiation therapy and cancer progression via several molecular and physiologic mechanisms. Intriguingly, many of these mechanisms utilize the same molecular pathways that are altered through calorie and/or carbohydrate restriction. Furthermore, poorer prognosis in cancer patients who display a glycolytic phenotype characterized by metabolic alterations, such as obesity and diabetes, is now well established, providing another link between metabolic pathways and cancer progression. We review the possible roles for calorie restriction (CR) and very low carbohydrate ketogenic diets (KDs) in modulating the five R’s of radiotherapy to improve the therapeutic window between tumor control and normal tissue complication probability. Important mechanisms we discuss include (1) improved DNA repair in normal, but not tumor cells; (2) inhibition of tumor cell repopulation through modulation of the PI3K–Akt–mTORC1 pathway downstream of insulin and IGF1; (3) redistribution of normal cells into more radioresistant phases of the cell cycle; (4) normalization of the tumor vasculature by targeting hypoxia-inducible factor-1α downstream of the PI3K–Akt–mTOR pathway; (5) increasing the intrinsic radioresistance of normal cells through ketone bodies but decreasing that of tumor cells by targeting glycolysis. These mechanisms are discussed in the framework of animal and human studies, taking into account the commonalities and differences between CR and KDs. We conclude that CR and KDs may act synergistically with radiation therapy for the treatment of cancer patients and provide some guidelines for implementing these dietary interventions into clinical practice.

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Determination of the optimum dose per fraction in fractionated radiotherapy when there is delayed onset of tumour repopulation during treatment

Cited by 28 publications

References 8 publications

The HYP-RT Hypoxic Tumour Radiotherapy Algorithm and Accelerated Repopulation Dose per Fraction Study

The HYP-RT Hypoxic Tumour Radiotherapy Algorithm and Accelerated Repopulation Dose per Fraction Study

Monte Carlo radiotherapy simulations of accelerated repopulation and reoxygenation for hypoxic head and neck cancer

Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R’s through dietary manipulation

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