Correlation between DNA damage responses of skin to a test dose of radiation and late adverse effects of earlier breast radiotherapy.

AIM: To correlate residual double strand breaks (DSB) 24h after 4Gy test doses to skin in vivo and to lymphocytes in vitro with adverse effects of earlier breast radiotherapy (RT). PATIENTS AND METHODS: Patients given whole breast RT ⩾5years earlier were identified on the basis of moderate/marked or minimal/no adverse effects despite the absence ('RT-Sensitive', RT-S) or presence ('RT-Resistant', RT-R) of variables predisposing to late adverse effects. Residual DSB were quantified in skin 24h after a 4Gy test dose in 20 RT-S and 15 RT-R patients. Residual DSB were quantified in lymphocytes irradiated with 4Gy in vitro in 30/35 patients. RESULTS: Mean foci per dermal fibroblast were 3.29 (RT-S) vs 2.80 (RT-R) (p=0.137); 3.28 (RT-S) vs 2.60 (RT-R) in endothelium (p=0.158); 2.50 (RT-S) vs 2.41 (RT-R) in suprabasal keratinocytes (p=0.633); 2.70 (RT-S) vs 2.35 (RT-R) in basal epidermis (p=0.419); 12.1 (RT-S) vs 10.3 (RT-R) in lymphocytes (p=0.0052). CONCLUSIONS: Residual DSB in skin following a 4Gy dose were not significantly associated with risk of late adverse effects of breast radiotherapy, although exploratory analyses suggested an association in severely affected individuals. By contrast, a significant association was detected based on the in vitro response of lymphocytes.

Inter-individual and inter-cell type variation in residual DNA damage after in vivo irradiation of human skin.

PURPOSE: The aim of this study was to compare inter-individual and inter-cell type variation in DNA double-strand break (DSB) repair following in vivo irradiation of human skin. MATERIALS AND METHODS: Duplicate 4mm core biopsies of irradiated and unirradiated skin were collected from 35 patients 24h after 4Gy exposure using 6MeV electrons. Residual DSB were quantified by scoring 53BP1 foci in dermal fibroblasts, endothelial cells, superficial keratinocytes and basal epidermal cells. RESULTS: Coefficients of inter-individual variation for levels of residual foci 24h after in vivo irradiation of skin were 39.9% in dermal fibroblasts, 44.3% in endothelial cells, 32.9% in superficial keratinocytes and 46.4% in basal epidermal cells (p<0.001, ANOVA). In contrast, the coefficient of inter-cell type variation for residual foci levels was only 11.3% in human skin between the different epidermal and dermal cells (p=0.034, ANOVA). Foci levels between the different skin cell types were correlated (Pearson's R=0.855-0.955, p<0.001). CONCLUSIONS: Patient-specific factors appear to be more important than cell type-specific factors in determining residual foci levels following in vivo irradiation of human skin.

A randomised trial of supine versus prone breast radiotherapy (SuPr study): comparing set-up errors and respiratory motion.

PURPOSE: To test a prone position against the international-standard supine position in women undergoing whole-breast-radiotherapy (WBRT) after wide-local-excision (WLE) of early breast cancer (BC) in terms of feasibility, set-up errors, and respiratory motion. METHODS: Following WLE of BC with insertion of tumour-bed clips, patients underwent 4D-CT for WBRT-planning in supine and prone positions (the latter using an in-house-designed platform). Patients were randomised to undergo WBRT fractions 1-7 in one position, switching to the alternate position for fractions 8-15 (40Gy/15-fractions total). Cone-beam CT-images (CBCT) were acquired prior to fractions 1, 4, 7, 8, 11 and 14. CBCT data were matched to planning-CT data using (i) chest-wall and (ii) clips. Systematic and random errors were calculated. Maximal displacement of chest-wall and clips with respiration was measured on 4D-CT. Clinical- to planning-target-volume (CTV-PTV) margins were calculated. Patient-comfort-scores and treatment-times were evaluated. RESULTS: Twenty-five patients were randomized. 192/192 (100%) planned supine fractions and 173/192 (90%) prone fractions were completed. 3D population systematic errors were 1.3-1.9mm (supine) and 3.1-4.3mm (prone) (p=0.02) and random errors 2.6-3.2mm (supine) and 3.8-5.4mm (prone) (p=0.02). Prone positioning reduced chest-wall and clip motion (0.5±0.2mm (prone) versus 2.7±0.5mm (supine) (p<0.001)) with respiration. Calculated CTV-PTV margins were greater for prone (12-16mm) than for supine treatment (10mm). Patient-comfort-scores and treatment times were comparable (p=0.06). CONCLUSIONS: Set-up errors were greater using our prone technique than for our standard supine technique, resulting in the need for larger CTV-PTV margins in the prone position. Further work is required to optimize the prone treatment-platform and technique before it can become a standard treatment option at our institution.