Harney, J.A.; (2005) An investigation of low dose hyper-radiosensitivity - Does it have a role clinically? Doctoral thesis , University of London.

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Abstract

Laboratory studies have demonstrated that some radioresistant tumours are hypersensitive to low doses of radiotherapy (<1Gy) and characteristically display features of radioresistance at more conventional radiation doses (2Gy per fraction), i.e. there is excess cell kill at doses <1Gy relative to that predicted by the linear quadratic (LQ) model. This phenomenon is called "low dose hyper-radiosensitivity" (LDHRS). The aim of this thesis was to investigate if LDHRS could be demonstrated in tumours and in normal tissues and to assess whether there was a difference between them that could be exploited clinically. The epidermal basal cell layer of human skin was chosen as a model of normal tissue. 8 patients with metastatic tumour nodules to skin were recruited. The nodules were measured, their volume calculated and randomised to receive conventionally fractionated radiotherapy (1.5Gy/day) or ultrafractionated radiotherapy (0.5Gy TDS with a 4hr inter-fraction gap). Both groups were treated for 12 days. Measurements were taken on days 0, 5,8,12 & 26 and monthly until regrowth occurred. Time to regrowth to original volume was calculated and compared between groups using the Wilcoxon Signed Rank test. In addition skin biopsies were performed on days 0, 5, 8, 12 and 26 changes in BCD were compared using non-linear regression analysis. Proliferation was assessed using the proliferation markers Ki67 and Cyclin A. Analysis of all re-growth data demonstrates greater tumour growth delay in the nodules treated with the "ultrafractionated" regime. This was most marked in tumours generally accepted as being radioresistant and known to show LDHRS in vitro, 2-tailed p-value 0.009. Analysis of the surrounding normal skin does not demonstrate any evidence of LDHRS The proliferative response was similar in both treatment groups. In-vitro experiments carried out in parallel failed to demonstrate LDHRS following multiple low doses of radiation in Hs633T - a sarcoma cell line that has demonstrated LDHRS to single low doses. It was concluded that there was a potential therapeutic window that could be exploited by using "ultrafractionated" radiotherapy for the treatment of "radioresistant" tumours". A feasibility study of "ultrafractionated" radiation in high-grade glioma (HGG) was initiated, with the ultimate aim of a larger phase II study. To date 2 patients have been recruited to the feasibility study.

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