A Nonparametric Method for the Derivation of α/β Ratios from the Effect of Fractionated Irradiations

Multifractionation isoeffect data are commonly analysed under the assumption that cell survival determines the observed tissue or tumour response, and that it follows a linear-quadratic dose dependence. The analysis is employed to derive the α/β ratios of the linear-quadratic dose dependence, and different methods have been developed for this purpose. A common method uses the so-called Fe plot. A more complex but also more rigorous method has been introduced by Lam et al. (1979). Their method, which is based on numerical optimization procedures, is generalized and somewhat simplified in the present study. Tumour-regrowth data are used to explain the nonparametric procedure which provides α/β ratios without the need to postulate analytical expressions for the relationship between cell survival and regrowth delay

Fractionation Response and Repair Kinetics of Radiation-induced Heart Failure in the Rat.

 Local heart irradiation with single or fractionated doses leads to heart failure after dose-dependent latency times. Clinical symptoms of heart failure are dyspnoea at rest, apathy and subcutaneous oedema. Animals autopsied when they presented with these symptoms, have a congested liver and occasional pleural effusions. The left ventricle is dilated, showing a reduction in wall thickness by 15-17% of control values. Histological examination reveals a focal degeneration and necrosis of about 23% of the total myocardial volume. Loss of alkaline phosphatase activity from myocardial capillaries, which is known to precede myocardial degeneration, involves 77% of the myocardium. These findings at the time of manifest heart failure are constant, independent on whether injury to the heart was inflicted by single-dose or fractionated irradiation or whether heart failure developed within a relatively short time after high total doses or within many months after low total doses. The latent time of heart failure therefore can be considered an appropriate endpoint for comparison of treatment groups. From experiments giving 1, 2, 4 or 10 dose fractions, a low alpha/beta-ratio of 3.7 Gy (95% confidence interval 1.8-5.6 Gy) can be calculated. When the time interval between dose fractions is varied in a split-dose experiment, time intervals of up to 3 h do not increase the survival time significantly. This appears to indicate very slow repair of sublethal damage. On the other hand, it cannot be excluded that pathogenic mechanisms independent of cell death in the renewing cell population contribute to this effect, making an interpretation of the alpha/beta-ratio in terms of cell survival parameters of a defined target cell population difficult

Decreased repopulation as well as increased reoxygenation contribute to the improvement in local control after targeting of the EGFR by C225 during fractionated irradiation.

Item does not contain fulltextBACKGROUND AND PURPOSE: Inhibition of repopulation and enhanced reoxygenation has been suggested to contribute to improvement of local tumour control after fractionated irradiation combined with inhibitors of the epidermal growth factor receptor (EGFR). The present study addresses this hypothesis in FaDu human squamous cell carcinoma. For this tumour model marked repopulation and incomplete reoxygenation during fractionated irradiation has previously been demonstrated. Furthermore, the anti-EGFR monoclonal antibody C225 has been shown to significantly improve the results of fractionated irradiation in this tumour. MATERIALS AND METHODS: FaDu tumours in nude mice were irradiated with 18 fractions in 18 days (18f/18d) or 18 fractions in 36 days (18f/36d). Three Gy fractions were given either under ambient or under clamp hypoxic conditions. C225 or carrier was applied four times during the course of treatment. Fractionated irradiations were followed by graded top-up doses to obtain complete dose-response curves for local tumour control. Tumour control dose 50% (TCD50) was determined at day 120 after end of treatment. RESULTS: Significant repopulation and reoxygenation occurred during fractionated irradiation of FaDu tumours (P-values between 0.028 and <0.001). Application of C225 significantly decreased TCD50 for 18f/36d under ambient conditions (P=0.04). Bootstrap analysis revealed decreased repopulation and increased reoxygenation after application of C225 (P=0.06 for the combined effect). This was further corroborated by a significant effect of C225 on the 'repopulated' dose under ambient conditions which is influenced by both, reoxygenation and repopulation (P=0.012). CONCLUSIONS: Our study provides evidence that both decreased repopulation as well as increased reoxygenation contribute to the improvement of local control after targeting of EGFR by C225 during fractionated irradiation of FaDu tumours