- Email: [email protected]
2653
Proceedings of the 48th Annual ASTRO Meeting
Results: The morphing procedure ran within 5 CPU mins. Cross validation indicates less than 0.1% error, illustrating reliability. Dose escalation was performed with PTV dose prescribed at 144Gy using 125I seeds, and 75.6Gy for IMRT. An escalated dose of ⬎⫽ 120% was placed on MRS-identified tumor pockets. Several sites of dose escalation are tested. Even when a tumor pocket is near the urethra, low urethral dose can be maintained while achieving good tumor dose escalation. Based on a biological model, TCP improves from 65% to 95%. Conclusions: With advances in biological and functional imaging, there is an urgent need to incorporate radiobiological parameters within the planning process. The voxel transformation algorithm allows for biologically-enhanced treatment, which facilitates targeted delivery of escalated dose and the potential to improve overall clinical outcome. Expected improvements in tumor control, and organs-at-risk dose reduction can be significant. Clinical studies are needed to validate its importance, and to measure potential gain in clinical outcome. The morphing algorithm has been adapted for 4D IMRT planning in which organ motion and tumor shrinkage information is incorporated. Author Disclosure: E.K. Lee, None; M. Zaider, None.
2653
Tumor Cell Radiosensitivity is the Primary Determinant of Tumor Response to Radiation
L. E. Gerweck1, S. Vijayappa1, A. Kurimasa2, K. Ogawa1, D. J. Chen3 1 Massachusetts General Hospital, Boston, MA, 2Tottori University, Tottori, Japan, 3University of Texas Southwestern Medical Center, Dallas, TX Purpose/Objective(s): To assess the role of tumor cell intrinsic radiosensitivity as a determinant of tumor response to radiation. Materials/Methods: A cloned tumor cell line from DNA-PK-/- SCID mice was bulk transfected with human DNA-PK⫹/⫹. Seventy-five clones were examined for changes in their intrinsic radiosensitivity. Four clones exhibited increased radioresistance and the presence of human DNA-PK⫹/⫹ was confirmed by genomic and RT-PCR. Clone T53 exhibited a 1.5-fold increased in vitro radioresistance compared to its DNA-PK-/- parental clone. The isogenic cell lines were used to initiate tumors in NCR (nu/nu) mice. Upon reaching a diameter of 6.5–7.5 mm, the mice were randomly assigned to receive 0 Gy; 15 Gy tumor irradiation under normal blood flow or clamp hypoxia; 30 Gy and 4 X 5 Gy fractionated dose irradiation. Results: As pertained to their similar in-vitro plating efficiencies and doubling times, the control and irradiated isogenic tumors grew and re-grew at similar rates following the initial period of radiation induced growth delay. The approximately 1.5-fold difference in tumor cell radiosensitivity resulted in a 1.5 fold difference in growth delay between the tumors over the dose range of 4 X 5 Gy per fraction to a single dose of 30 Gy. Conclusions: Isogenic tumors implanted in the same strain of mice and exposed to the same dose of radiation may be expected to exhibit a similar response to radiation if tumor stroma including vascular endothelium is the determinant of response. This was not observed. Tumor cell radiosensitivity is the primary determinant of tumor response to radiation in repair proficient mice NCR(nu/nu) mice. Author Disclosure: L.E. Gerweck, None; S. Vijayappa, None; A. Kurimasa, None; K. Ogawa, None; D.J. Chen, None.
2654
Dietary Selenium Supplementation Prolongs Survival Following Thoracic Irradiation in Mice by Protecting From Radiation-Induced Pulmonary Fibrosis and Stimulating Selenoenzyme Production
K. A. Cengel1, J. Lee1, A. Workman1, E. Arguiri1, C. C. Solomides2, K. Hill3, M. Christofidou Solomidou1 1 University of Pennsylvania Medical Ctr., Philadelphia, PA, 2Temple University, Philadelphia, PA, 3Vanderbilt University, Nashville, TN Purpose/Objective(s): Radiation-induced pulmonary fibrosis can be a devastating side effect of radiation therapy for intra-thoracic malignancies; however there is, as of yet, no effective pharmacologic agent for its prevention. Since oxidative stress has been implicated in the pathogenesis of radiation-induced lung fibrosis we hypothesized that augmenting the lung antioxidant defense by increasing dietary selenium intake prior to and following thoracic radiation in mice would ameliorate fibrosis. Selenium (Se) is a micronutrient, present in protective antioxidant selenoenzymes such as glutathione peroxidase (GPx). Materials/Methods: We evaluated groups of mice (n⫽15) that were fed for 4 weeks prior to irradiation and 16 weeks (or the remainder of the experiment) following irradiation on isocaloric diets containing different levels of Se supplementation: One group was fed a diet containing no Se (Se-0x, 0.00 ppm Se), one group was fed a diet containing sub-saturated (adequate) Se (Se-1x, 0.18 ppm Se), and one group was fed a diet containing super-saturated (exceeding maximum GI absorbable levels) Se (Se-10x, 1.8 ppm). Fibrosis was evaluated by lung hydroxyproline (OH-Pro) and histology. Results: Overall, the diets were well tolerated and there was no significant difference in mean mouse weight between the treatment groups prior to irradiation. Following irradiation, none of the mice in Se-0x group were alive at 4 months. However, the survival at 4 months following irradiation was significantly higher in the Se-1x (66.7%) and the Se-10x (80%) groups. The increased survival promoted by Se-supplemented diet correlated with a decrease in radiation induced fibrosis at 4 months (or at time of death, if before 4 months) as measured by OH-Pro content and trichrome staining. In these experiments, total lung OH-Pro content (g/g lung) was significantly lower in the 10x-Se group (89⫾2) and the 1x group(113⫾4) as compared to the 0x group(171⫾12). This decrease in radiation induced fibrosis was also confirmed using Trichrome (Mason’s Blue) staining of histologic sections from irradiated lung tissues. Finally, samples of liver and lung were evaluated for total GPx content from mice in each dietary Se group after 4 weeks of dietary supplementation. These experiments showed that the increased survival and decreased fibrosis following irradiation correlated with increased liver and lung GPx content at time of irradiation. Conclusions: Taken together, these studies indicate that Se-enriched diets increase the overall survival following irradiation and protect against the development of radiation fibrosis and suggest that the mechanism for this effect may stem from increased tissue levels of antioxidant selenoenzymes such as GPx. Funded by AICR and U. Penn Research Foundation (MCS).
S573
Results: The morphing procedure ran within 5 CPU mins. Cross validation indicates less than 0.1% error, illustrating reliability. Dose escalation was performed with PTV dose prescribed at 144Gy using 125I seeds, and 75.6Gy for IMRT. An escalated dose of ⬎⫽ 120% was placed on MRS-identified tumor pockets. Several sites of dose escalation are tested. Even when a tumor pocket is near the urethra, low urethral dose can be maintained while achieving good tumor dose escalation. Based on a biological model, TCP improves from 65% to 95%. Conclusions: With advances in biological and functional imaging, there is an urgent need to incorporate radiobiological parameters within the planning process. The voxel transformation algorithm allows for biologically-enhanced treatment, which facilitates targeted delivery of escalated dose and the potential to improve overall clinical outcome. Expected improvements in tumor control, and organs-at-risk dose reduction can be significant. Clinical studies are needed to validate its importance, and to measure potential gain in clinical outcome. The morphing algorithm has been adapted for 4D IMRT planning in which organ motion and tumor shrinkage information is incorporated. Author Disclosure: E.K. Lee, None; M. Zaider, None.
2653
Tumor Cell Radiosensitivity is the Primary Determinant of Tumor Response to Radiation
L. E. Gerweck1, S. Vijayappa1, A. Kurimasa2, K. Ogawa1, D. J. Chen3 1 Massachusetts General Hospital, Boston, MA, 2Tottori University, Tottori, Japan, 3University of Texas Southwestern Medical Center, Dallas, TX Purpose/Objective(s): To assess the role of tumor cell intrinsic radiosensitivity as a determinant of tumor response to radiation. Materials/Methods: A cloned tumor cell line from DNA-PK-/- SCID mice was bulk transfected with human DNA-PK⫹/⫹. Seventy-five clones were examined for changes in their intrinsic radiosensitivity. Four clones exhibited increased radioresistance and the presence of human DNA-PK⫹/⫹ was confirmed by genomic and RT-PCR. Clone T53 exhibited a 1.5-fold increased in vitro radioresistance compared to its DNA-PK-/- parental clone. The isogenic cell lines were used to initiate tumors in NCR (nu/nu) mice. Upon reaching a diameter of 6.5–7.5 mm, the mice were randomly assigned to receive 0 Gy; 15 Gy tumor irradiation under normal blood flow or clamp hypoxia; 30 Gy and 4 X 5 Gy fractionated dose irradiation. Results: As pertained to their similar in-vitro plating efficiencies and doubling times, the control and irradiated isogenic tumors grew and re-grew at similar rates following the initial period of radiation induced growth delay. The approximately 1.5-fold difference in tumor cell radiosensitivity resulted in a 1.5 fold difference in growth delay between the tumors over the dose range of 4 X 5 Gy per fraction to a single dose of 30 Gy. Conclusions: Isogenic tumors implanted in the same strain of mice and exposed to the same dose of radiation may be expected to exhibit a similar response to radiation if tumor stroma including vascular endothelium is the determinant of response. This was not observed. Tumor cell radiosensitivity is the primary determinant of tumor response to radiation in repair proficient mice NCR(nu/nu) mice. Author Disclosure: L.E. Gerweck, None; S. Vijayappa, None; A. Kurimasa, None; K. Ogawa, None; D.J. Chen, None.
2654
Dietary Selenium Supplementation Prolongs Survival Following Thoracic Irradiation in Mice by Protecting From Radiation-Induced Pulmonary Fibrosis and Stimulating Selenoenzyme Production
K. A. Cengel1, J. Lee1, A. Workman1, E. Arguiri1, C. C. Solomides2, K. Hill3, M. Christofidou Solomidou1 1 University of Pennsylvania Medical Ctr., Philadelphia, PA, 2Temple University, Philadelphia, PA, 3Vanderbilt University, Nashville, TN Purpose/Objective(s): Radiation-induced pulmonary fibrosis can be a devastating side effect of radiation therapy for intra-thoracic malignancies; however there is, as of yet, no effective pharmacologic agent for its prevention. Since oxidative stress has been implicated in the pathogenesis of radiation-induced lung fibrosis we hypothesized that augmenting the lung antioxidant defense by increasing dietary selenium intake prior to and following thoracic radiation in mice would ameliorate fibrosis. Selenium (Se) is a micronutrient, present in protective antioxidant selenoenzymes such as glutathione peroxidase (GPx). Materials/Methods: We evaluated groups of mice (n⫽15) that were fed for 4 weeks prior to irradiation and 16 weeks (or the remainder of the experiment) following irradiation on isocaloric diets containing different levels of Se supplementation: One group was fed a diet containing no Se (Se-0x, 0.00 ppm Se), one group was fed a diet containing sub-saturated (adequate) Se (Se-1x, 0.18 ppm Se), and one group was fed a diet containing super-saturated (exceeding maximum GI absorbable levels) Se (Se-10x, 1.8 ppm). Fibrosis was evaluated by lung hydroxyproline (OH-Pro) and histology. Results: Overall, the diets were well tolerated and there was no significant difference in mean mouse weight between the treatment groups prior to irradiation. Following irradiation, none of the mice in Se-0x group were alive at 4 months. However, the survival at 4 months following irradiation was significantly higher in the Se-1x (66.7%) and the Se-10x (80%) groups. The increased survival promoted by Se-supplemented diet correlated with a decrease in radiation induced fibrosis at 4 months (or at time of death, if before 4 months) as measured by OH-Pro content and trichrome staining. In these experiments, total lung OH-Pro content (g/g lung) was significantly lower in the 10x-Se group (89⫾2) and the 1x group(113⫾4) as compared to the 0x group(171⫾12). This decrease in radiation induced fibrosis was also confirmed using Trichrome (Mason’s Blue) staining of histologic sections from irradiated lung tissues. Finally, samples of liver and lung were evaluated for total GPx content from mice in each dietary Se group after 4 weeks of dietary supplementation. These experiments showed that the increased survival and decreased fibrosis following irradiation correlated with increased liver and lung GPx content at time of irradiation. Conclusions: Taken together, these studies indicate that Se-enriched diets increase the overall survival following irradiation and protect against the development of radiation fibrosis and suggest that the mechanism for this effect may stem from increased tissue levels of antioxidant selenoenzymes such as GPx. Funded by AICR and U. Penn Research Foundation (MCS).
S573