‘Fading Times’ Required for Apparently Complete Repair in Irradiated Tissues Assuming the Linear Quadratic Model of Dose Response

Fowler, J. F.

doi:10.1080/09553008614551001

Cited by 12 publications

(3 citation statements)

References 14 publications

(13 reference statements)

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“…Animal studies indicate that the repair half‐time in many tissues is around 1–1.5 hr 18. Clinical results provide confirmatory evidence indicating that intervals below 4 hr may be associated with an unacceptable incidence of delayed toxicity to normal tissue 19, 20. Moreover, Short et al 21 reported that 4 hr are needed between 2 irradiations to allow the HRS to be conserved.…”

Section: Resultsmentioning

confidence: 90%

“…18 Clinical results provide confirmatory evidence indicating that intervals below 4 hr may be associated with an unacceptable incidence of delayed toxicity to normal tissue. 19,20 Moreover, Short et al 21 reported that 4 hr are needed between 2 irradiations to allow the HRS to be conserved. Therefore, we tested an ultrafractionated regimen: 3 fractions of 0.8 Gy spaced by 4 hr compared to the biologically equivalent single dose of 2 Gy on G5, CL35, G152 and MRC5 (we determined that 4.8 Gy for hyperfractionation is roughly biologically equivalent to 4 Gy for conventional fractionation by graphically determining ␣/␤ assuming that the curve did not have a dip at 0.8 Gy, i.e., was following the LQ model).…”

Section: Cumulative Effect Of Low Radiation Doses On Cell Survivalmentioning

confidence: 99%

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Human malignant glioma cell lines are sensitive to low radiation doses

Beauchesne

Bertrand

et al. 2003

Intl Journal of Cancer

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Malignant gliomas display aggressive local behavior and are not cured by existing therapy. Some cell lines that are considered radioresistant respond to low radiation doses (<1 Gy) with increased cell killing (low-dose hypersensitivity). In our study, 4 of 5 human glioma cell lines exhibited significant X-ray sensitivity at doses below 1 Gy. The surviving fractions (SFs) obtained at 0.7 and/or 0.8 Gy were comparable to those at 1.5 Gy. Low-dose hypersensitivity was evident when irradiation was combined with etoposide treatment. Repeated irradiation with low doses was markedly more effective than irradiation with single, biologically equivalent doses in decreasing SFs, inhibiting xenograft tumor growth in mice. All experiments were conducted with an accelerator used in clinics, establishing that low-dose hypersensitivity was present following megavoltage X-irradiation. Malignant glioma is one of the most radioresistant tumor types and accounts for approximately 60% of all primary brain tumors in adults. The prognosis of malignant glioma patients remains dismal. The standard of care has been essentially unchanged for many decades: surgical resection of as much of the tumor as is safe, followed by radiation therapy and chemotherapy. Even under the best of circumstances, in which essentially all of the tumor seen on magnetic resonance imaging scan can be surgically removed and the patients fully treated with radiation and chemotherapy, mean survival is extended only from 2-3 months to 1 year. [1][2][3] Despite the widespread use of radiation therapy for the treatment of malignant glioma, the uniformly poor response of these tumors remains a critical problem in the management of these patients. 3 Disruption of cell-cycle arrest or apoptotic pathways by INK4a loss or by p53 mutations or inactivation (approx. 40 -60% of malignant gliomas have p53 mutations) associated with CDK4 amplification or Rb loss may be significant factors in determining the response of these tumors to irradiation and treatment outcome. 4 -6 The radiation survival response of mammalian cells is more complicated than once believed. A few studies indicate that some human cell lines are sensitive to killing by low radiation doses (Ͻ1 Gy). This has been termed low-dose hyper-radiosensitivity (HRS). [7][8][9][10][11] This may reflect differential triggering or induction of repair mechanisms. Cells may be sensitive to low doses because repair mechanisms are not induced, whereas higher doses may cause enough damage to induce or trigger repair mechanisms and, therefore, exhibit increased radioresistance. 9 We report here that 4 malignant glioma cell lines displayed a significant increase in X-ray radiosensitivity at doses below 1 Gy compared to the prediction extrapolated from a linear-quadratic (LQ) model that fits to the data at higher doses. In addition, this phenomenon was extended to 4 human melanoma cell lines and MRC5 human fibroblasts. Moreover, ultrafractionated irradiation with low doses was markedly more effective than conventional irradiati...

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Section: Resultsmentioning

confidence: 90%

Section: Cumulative Effect Of Low Radiation Doses On Cell Survivalmentioning

confidence: 99%

Human malignant glioma cell lines are sensitive to low radiation doses

Beauchesne

Bertrand

et al. 2003

Intl Journal of Cancer

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“…6 h intervals, between 3F/d (36F/12 d) for bronchial carcinoma (Saunders and Dische 1986) . It is in principle necessary to allow four or five half-lives between doses per fraction (Fowler 1986), and in practice 6 h rather than 4 appears to be necessary (Marcial et al 1987) . For this application the slowest component present is important .…”

Section: Discussionmentioning

confidence: 99%

Repair Kinetics in Mouse Lung after Multiple X-ray Fractions Per Day

Parkins

Whitsed

Fowler

1988

International Journal of Radiation Biology

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The potential advantage for sparing normal tissue damage by hyperfractionation of low-LET radiation may be limited by the repair kinetics of tissues in the irradiated field. Tissues with slow repair kinetics will limit the number of fractions that may be given on the same day. Results are presented for mouse lung treated with a range of doses per fraction using either two or three fractions per day in multiple X-ray fractionation schedules. The results are analysed to determine whether the repair kinetics follow a single exponential function of time. The calculated repair rate (T1/2) was about 1.2 h for two fractions per day of 2 Gy (10F/5d) but slightly less (T1/2 = 0.8 h) for two fractions of 9 Gy (2F/1d). For smaller doses per fraction of 1.1 Gy, given three times per day (39F/13d), the T1/2 was not significantly less (T1/2 = 0.3-0.7 h). For three fractions per day of 1.1 Gy per fraction an unsatisfactory fit is achieved using a single exponential function of time, and a better fit is obtained using two components of repair. The repair kinetics are slow for lung, in comparison to acute reacting tissues (except skin), and may require that 6-8 h (i.e. four or five half-times) should be allowed between fractions on the same day so that more than 95 per cent of the repairable dose is repaired. At present the variation in repair kinetics with doses per fraction between 1.1 and 9 Gy are not significantly different, so no reduction of interfraction interval should be proposed.

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The use of the linear quadratic model in radiotherapy: a review

Jones

Hoban

Metcalfe

2001

Australas. Phys. Eng. Sci. Med.

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To be able to predict the impact of any radiotherapy treatment the physics of radiation interactions and the expected biological effect for any radiotherapy treatment situation (dose, fractionation, modality) must be both understood and modelled. This review considers the current use and accuracy of the linear quadratic model which can be used to consider the variation in tissue response with fraction size. Cell kill following radiation damage results from damage to the DNA which can take a variety of forms. In many cases the linear quadratic model is used to estimate the relative impact for different situations especially clinical studies relating to fraction size. This is mainly undertaken using parameters derived from the linear quadratic model such as biological effective dose and standard effective dose. The model has also been adapted to consider the effect of overall treatment time, repair during treatment (as occurs for brachytherapy treatments) and other situations. There are some concerns over its use, mainly in the small dose ranges (both total low doses and low doses per fraction) where studies have shown its inaccuracy. In other situations however it does appear to provide a reasonable estimate of relative clinical effect. As with all models, however results should never be considered out of clinical context.

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‘Fading Times’ Required for Apparently Complete Repair in Irradiated Tissues Assuming the Linear Quadratic Model of Dose Response

Abstract: The time required between well-separated pairs of doses of X-rays (e.g. 2F/day) for repairable damage to be apparently completed increases with dose per fraction and with the alpha/beta ratio, even when the underlying half-life is invariant.

Cited by 12 publications

References 14 publications

Human malignant glioma cell lines are sensitive to low radiation doses

Human malignant glioma cell lines are sensitive to low radiation doses

Repair Kinetics in Mouse Lung after Multiple X-ray Fractions Per Day

The use of the linear quadratic model in radiotherapy: a review

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