( EO 2 ) Effects of track structure in radiation chemistry

Purpose: Lung cancer is the leading cause of cancer death with chance of survival restricted to a subset of NSCLC patients able to undergo surgical resection. However, the recurrence rate of NSCLC after surgery remains high with few prognostic indicators of clinical outcome. Prx1 is shown to be elevated in various cancers and confers an aggressive survival phenotype. We recently cloned the prx1 promoter and found that Nrf2 is a key transcription factor for prx1 up-regulation. Previous studies suggest that Nrf2 may be constitutively activated in NSCLC. Based on the above information, we investigated whether Prx1 and/or Nrf2 levels have prognostic significance in stage I NSCLC. Methods and Results: Immunohistochemical expression of Prx1 and Nrf2 was evaluated in paraffin embedded tissues from 90 patients who underwent a curative surgical resection. Increased expression of cytosolic Prx1 (66.7%) and nuclear Nrf2 (61.8%) was observed in this series. Prx1 elevation, but not Nrf2, correlated with reduced recurrence free survival and overall survival on univariate (P1⁄4 0.01 and P1⁄4 0.03) and multivariate (P1⁄4 0.003 and P1⁄4 0.005) analyses. Conclusion: This is the first study to test the prognostic significance of Prx1 and Nrf2 in human cancers. Our results demonstrate that Prx1 expression status predicts for recurrence and shorter survival in stage I NSCLC after surgery. Considering the possible role of Prx1 and Nrf2 in radio-/chemo-resistance, it warrants future investigation to evaluate whether elevated Prx1 and/ or Nrf2 levels are predictive of treatment response in advanced lung cancer and other malignancies. (PS2036) Hypofractionation results in reduced tumor cell kill compared to conventional fractionation for tumors with regions of hypoxia. David J. Carlson, Paul J. Keall, J. Martin Brown. Stanford University, Stanford, CA, USA. Tumor hypoxia has been observed in many human cancers and has been shown to correlate with treatment failure in radiation therapy. The purpose of this study was to quantify the effect of dose per fraction on tumor cell killing assuming a realistic distribution of tumor oxygenation and full reoxygenation between dose fractions. We assessed the sensitivity of the results to variations in the radiobiologically hypoxic fraction, the dose per fraction, oxygen diffusion model parameters, and intrinsic radiosensitivity parameters. We calculated a probability density function for the partial pressure of oxygen in a tumor cell population as a function of radial distance from the capillary wall. Estimates of the oxygen partial pressures for subpopulations of tumor cells were used to determine the corresponding oxygen enhancement ratios (OERs) for cell killing. The overall surviving fraction of a tumor cell population consisting of maximally resistant cells, cells at intermediate levels of hypoxia, and well-oxygenated cells was calculated as a function of dose per fraction for an equivalent tumor biological effective dose (BED). Our model predicts that increasing hypoxia as a function of distance from blood vessels causes a decrease in tumor cell killing by a factor of 10 over a radial distance of 130 lm (assuming a partial oxygen pressure of 60 mmHg at the capillary wall). For tumor cells with a/b1⁄410 Gy (typical of head and neck cancers), the overall surviving fraction for the tumor over a full treatment course increases by a factor of 10 as the dose per fraction is increased from 2–24 Gy. For tumors cells with a/b 1⁄4 3.0 Gy (typical of prostate cancers), the surviving fraction over a full treatment course increases by a factor of 10 as the dose per fraction is increased from 2–18 Gy. The total dose delivered for each dose per fraction has been calculated to achieve equivalent tumor BED values of 80.5 Gy and 130.0 Gy for reference head and neck (30 fractions of 2.2 Gy) and prostate (39 fractions of 2.0 Gy) treatments, respectively. The modeling studies presented in this work suggest that hypofractionation of a radiotherapy regimen results in a significant decrease in tumor cell killing compared to standard fractionation as a result of tumor hypoxia. (PS2037) The correlation of intrinsic radiosensitivity with bystander response in individual colorectal carcinoma patients undergoing radiotherapy treatment. Orla L. Howe, Jacintha O Sullivan, Blathnaid Nolan, Brenden McClean, Fiona M. Lyng. Dublin Institute of technology, Dublin, Ireland, University College Dublin, Dublin, Ireland, St. Vincents Hospital, Dublin, Ireland, St. Lukes Hospital, Dublin, Ireland. Intrinsic radiosensitivity is an important factor that influences the individual response of tumours to radiotherapy treatment. This P O S T E R S E S S I O N S 107 P o s te r S e s s io n s factor also influences the levels of cell death in bystander cells and thus may enhance or reduce bystander responses. The main objective of this work is to assess intrinsic radiosensitivity and the corresponding bystander responses ‘in vitro’ in individual colorectal carcinoma patient’s cells throughout a course of radiotherapy treatment. These radiobiological endpoints will be compared and contrasted with patient clinical prognosis post radiotherapy