Biology of high single doses of IORT: RBE, 5 R's, and other biological aspects

Abstract

Intraoperative radiotherapy differs from conventional, fractionated radiotherapy in several aspects that may influence its biological effect. The radiation quality influences the relative biologic effectiveness (RBE), and the role of the five R's of radiotherapy (reassortment, repair, reoxygenation, repopulation, radiosensitivity) is different. Furthermore, putative special biological effects and the small volume receiving a high single dose may be important. The present review focuses on RBE, repair, and repopulation, and gives an overview of the other factors that potentially contribute to the efficacy. The increased RBE should be taken into account for low-energy X-rays while evidence of RBE < 1 for high-energy electrons at higher doses is presented. Various evidence supports a hypothesis that saturation of the primary DNA double-strand break (DSB) repair mechanisms leads to increasing use of an error-prone backup repair system leading to genomic instability that may contribute to inactivate tumour cells at high single doses. Furthermore, the elimination of repopulation of residual tumour cells in the tumour bed implies that some patients are likely to have very few residual tumour cells which may be cured even by low doses to the tumour bed. The highly localised dose distribution of IORT has the potential to inactivate tumour cells while sparing normal tissue by minimising the volume exposed to high doses. Whether special effects of high single doses also contribute to the efficacy will require further experimental and clinical studies.

Fig. 1

Survival curves for irradiation of cells in vitro with 10 MeV electrons (20 mm water-equivalent depth) or 6 MV X-rays. The RBE of electrons was not significantly different from 1 (RBE = 0.98 ± 0.01; P = 0.10, n = 3) for MCF7 cells (a) while RBE was significantly reduced (RBE = 0.91 ± 0.02, P = 0.015, n = 3) after irradiation of HUVEC with higher doses (b). These experiments corroborated trends observed in independent experiments at lower doses (Additional file 2: Figures S1B, C)

Fig. 2

Sublinear dose response for the mean number of γH2AX foci per cell (V79) at maximum induction and after 4 h repair (30 min and 240 min post-irradiation, respectively) (a). Reduced colony size of V79 cells irradiated 14.3 Gy but not 5.7 Gy (10 MeV electrons, 20 mm water-equivalent depth) (b)

Fig. 3

Proposed schematic model of increasing use of alternative end joining (alt-EJ) leading to increased chromosomal instability at higher doses. HR: homologous recombination. NHEJ: non-homologous end joining. Modified after Shibata and Jeggo [30]

Fig. 4

Schematic overview of biological effects contributing to the efficacy of IORT with high single doses. RBE: relative biologic effectiveness; S.o.E.: Sphere of Equivalence; NT: normal tissue