- Email: [email protected]
Lateral Dose-volume Effects in Single-fraction Radiosurgery of the Cervical Spinal Cord: A Swine Model
Proceedings of the 53rd Annual ASTRO Meeting presentation, affected portion of the bladder and fistula by cystoscopy were investigated. These findings were evaluated in relation to the dose received by the bladder calculated at the reference point (PRB) and according to the ICRU bladder dose points in JD and JE which is a model suggested by Pinezi (2005). The fifty brachytherapy planning was recalculated using the two point model and the bladder absorbed dose were compared with the incidence of late effects. The association between p53, ATM e MDM2 gene’s single nucleotide polymorphisms and radiosensitivity will be performed. Results: The average age of these patients was 59.8 ± 10.6 years. All of these cervical cancer patients had undergone to radiotherapy from 1999 to 2005. Of these, 14% were diabetic, 48.0% have hypertension, 36% were smokers, 2% were and 20% said rheumatic disease. The average follow-up was 7.4 ± 0.9 years. Unexpectedly, association with these factors was the biological effective dose (BED) of teletherapy, with both the a/b of 3 as well as the a/b of 5 (p\0.05). This suggests that the bladder undergoes major consequences to the dose received throughout its volume. None of the other factors analyzed showed statistical association with the occurrence of urinary late effects. Conclusions: It was demonstrated that the dose received by the bladder points JD and JE is statistically higher than the dose calculated at the reference point recommended by the ICRU bladder. None of the other factors analyzed showed statistical association with the occurrence of urinary late effects. It is undergoing the evaluation of TP53, ATM and MDM2 genes single nucleotide polymorphisms of cervical cancer patients with late side effects to brachytherapy. These genes are involved in DNA repair pathways, whose are capable of modifying the responses of normal tissues to radiation. Author Disclosure: J.C. Pinezi: None. H.S. Cintra: None. D.A.C. Passos: None. T.R. Costa: None. P.A. Simon: None. M.T. Senna: None. G.D.P. Machado: None. R.B.A. Soares: None. H.A. Carvalho: None.
3064
The Protective Effect of Novel Small Molecule Inhibitor (SKI2162) of Transforming Growth Factor-b Receptor against Radiation-induced Fibrosis
J. Park1, S. Lee1, S. Ryu1, K. Ryu2, S. Kang2, E. Park2, H. Lee2, J. Lee2, H. Jung2, D. Shin2 1
Asan Medical Center, Seoul, Korea, Republic of Korea, 2SK Chemicals, Seongnam, Korea, Republic of Korea
Purpose/Objective(s): Although radiation-induced fibrosis (RIF) is one of common sequelae after irradiation, a protective method was not well investigated. SKI2162 is a novel small molecule inhibitor of TGF-b1 receptor developed for the prevention of RIF. The present study was done to assess the protective effect of SK2162 against RIF in mouse model. Materials/Methods: BALB/c male mice were irradiated 8 weeks after birth. Selective irradiation of the hind limb of mice was done by linear accelerator and specially designed shielding. A single radiation dose of 35 Gy was done for molecular study, and two radiation doses of 22 Gy, once in a week, for assay of radiation-induced leg contracture. For molecular study, change in levels of collagen IA2 mRNA was examined in mouse skin by quantitative real time polymerase chain reaction after 14-day topical application of SKI2162 (1.0%) or vehicle. For the assay of leg contracture, 40 mice were randomly divided into two groups of 20 mice each. Each group was treated with once daily intraperitoneal injections of saline (group 1) or SKI2162 (group 2, 10 mg/Kg/ day) for 16 weeks. Leg contraction test was done by specially designed Lucite jig under anesthesia every 2 weeks after irradiation. The length of the irradiated leg was compared with the contralateral unirradiated leg. Early and late skin reactions were scored by grading system. Results: In molecular study, collagen IA2 mRNA levels in the vehicle treated mouse were increased by 3.0 fold, compared to sham-operated animals. SKI2162 treatment completely inhibited the induction of COL-IA2 mRNA, and the difference in collagen IA2 mRNA expression between SKI2162-treated and vehicle-treated mouse was statistically significant (p \ 0.05). In the assay of radiation-induced contracture, SKI2162 was well tolerated, and no toxic effects were observed. The acute skin reaction was almost identical between the two groups. The leg contraction test showed significant protective effect in group 2. The average length of the irradiated leg (percent of the contralateral leg) was significantly lower in group 1, and the differences between the two groups tended to increase with time; 92% vs. 96% in 6-week (p \ 0.01), 93% vs. 96% in 8-week (p \ 0.01), 88% vs. 93% in 10-week (p \ 0.01), 83% vs. 92% in 12-week (p \ 0.01), 77% vs. 88% in 14-week (p \ 0.01), and 74% vs. 83% in 16-week (p \ 0.01). Also, late skin reactions were more adverse in control group; the average score of late skin reaction was 3.14 vs. 2.73 (p = 0.03). Conclusions: The current study showed that inhibition of TGF-b signaling by SKI2162 had a protective effect on RIF in mouse model. Also, there was no significant toxicity related to the drug administration. This newly developed drug could be considered as a novel agent for protection of RIF. Author Disclosure: J. Park: None. S. Lee: None. S. Ryu: None. K. Ryu: A. Employment; SK Chemicals. S. Kang: A. Employment; SK Chemicals. E. Park: A. Employment; SK Chemicals. H. Lee: A. Employment; SK Chemicals. J. Lee: A. Employment; SK Chemicals. H. Jung: A. Employment; SK Chemicals. D. Shin: A. Employment; SK Chemicals.
3065
Lateral Dose-volume Effects in Single-fraction Radiosurgery of the Cervical Spinal Cord: A Swine Model
P. M. Medin1, R. D. Foster1, A. van der Kogel2, J. Sayre3, T. D. Solberg1 1 University of Texas Southwestern Medical Center, Dallas, TX, 2Radboud University, Nijmegen, Netherlands, 3University of California Los Angeles, Los Angeles, CA
Purpose/Objective(s): This study was performed to test the hypothesis that the dose-related incidence of motor neurologic deficits following spinal radiosurgery is significantly increased by the use of uniform versus laterally non-uniform dose distributions. Materials/Methods: A uniform dose distribution was delivered to a 4.5 - 7.0cm length of cervical spinal cord in 22 mature Yucatan minipigs for comparison with a companion study in which a laterally non-uniform dose was given(reported previously). Pigs were stratified into four dose levels with mean maximum spinal cord doses of 17.5 ± 0.1 Gy(n = 7), 19.5 ± 0.2 Gy(n = 6), 22.0 ± 0.1 Gy(n = 5), and 24.1 ± 0.2 Gy(n = 4). The mean 10Gy and 14Gy volumes were very similar for all dose groups ranging from
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3.74cc to 4.33cc. The study endpoint was motor neurologic deficit determined by a change in gait during a one year follow-up period. Results: Dose-response curves for uniform versus non-uniform spinal cord irradiation were nearly identical with ED50’s (95% confidence interval) of 20.2 Gy(19.1 - 25.8) and 20.0 Gy(18.3 - 21.7), respectively. No neurologic change was observed for either dose distribution when the maximum spinal cord dose was less than or equal to 17.8 Gy while all animals experienced deficits at doses greater than or equal to 21.8Gy. Responders that received uniform irradiation had bilateral deficits while non-uniform irradiation resulted in deficits on the irradiated side only. All animals with motor deficits showed some degree of demyelination and focal white matter necrosis with relative sparing of the gray matter. This histologic damage was randomly distributed in the white matter of the uniformly irradiated cords, while limited to the ipsilateral white matter of the non-uniformly irradiated animals. Conclusions: No dose-volume effect is observed in pigs for the dose distributions studied and the endpoint of motor neurologic deficit; however, partial spinal cord irradiation results in less debilitating neurologic and histopathologic morbidity. Author Disclosure: P.M. Medin: D. Speakers Bureau/Honoraria; BrainLAB AG. R.D. Foster: None. A. van der Kogel: None. J. Sayre: None. T.D. Solberg: D. Speakers Bureau/Honoraria; BrainLAB AG.
3066
Glycyrrhetinic Acid Protects Lungs from Radiation-Induced Toxicity
1
C. Chen , S. Yang1, M. Zhang1, Y. Guo2, S. B. Zhang1, X. Wang1, L. Yin1, S. G. Swarts1, P. Okunieff1, L. Zhang1 1
UF Shands Cancer Center, Gainesville, FL, 2Fujian Medical University, Fujian, China
Purpose/Objective(s): Radiation-induced pneumonitis and lung fibrosis are major dose-limiting effects of ionizing radiation (IR) therapy of lung cancer. Currently, no drug can effectively mitigate against these toxicities. Thus, our purpose was to explore glycyrrhetinic acid (GA) as a potential non-toxic agent to prevent IR-induced lung fibrosis without concomitant protection against tumors. Materials/Methods: Two murine models were used to test the effectiveness of GA. A) IR-induced lung fibrosis murine model. C57BL/6 mice were irradiated with 15 Gy to the chest. Twenty-four hours after IR, 30 mg/kg of GA was delivered orally; thereafter, this dosage was repeated every other day for 3 months. At the end of the experiment, enzyme-linked immunosorbent assay (ELISA) for plasma surfactant protein-D (SP-D) and other inflammatory molecules (IM), cone-beam computed tomography (CBCT), respiratory rate and lung compliance, collagen deposition, and hydroxyproline assays were performed. B) Experimental lung metastasis murine model. B16 murine melanoma cells were intravenously injected into C57BL/6 mice. They were then treated with GA as in the IR-induced lung fibrosis murine model. At the end of the experiments, the ratio of lung weight to body weight was measured. Results: GA has the following effects: 1) reduces IR-induced IM (i.e. interleukin 1a) in the acute, sub-acute, and late phases after lung irradiation; 2) reduces plasma SP-D, a surrogate marker for the GA effect; 3) ameliorates IR-induced changes in lung function (respiratory rate and lung compliance); 4) pathologically and biochemically reverses IR-induced changes, preserving the lung structure by reducing inflammation, infiltration, and collagen deposition as demonstrated in CBCT, H&E/Trichrome blue staining, and hydroxyproline content measurements; 5) exhibits no side effects after long-term use; 6) slightly reduces the growth of experimental lung metastases, as evidenced by the smaller ratio of lung weight to body weight than that of the controls. Conclusions: GA is a safe and effective agent for IR-induced lung damage without concomitant benefit to lung tumors. Author Disclosure: C. Chen: None. S. Yang: None. M. Zhang: None. Y. Guo: None. S.B. Zhang: None. X. Wang: None. L. Yin: None. S.G. Swarts: None. P. Okunieff: None. L. Zhang: None.
3067
Evaluation of the Radiation Safety of using 131Cs Seeds for Permanent Breast Seed Implantation
A. Ravi, B. M. Keller, J. Pignol Sunnybrook Odette Cancer Centre, Toronto, ON, Canada Purpose/Objective(s): Permanent breast seed implantation (PBSI) is an accelerated partial breast irradiation technique, implanting 103Pd brachytherapy sources (average energy of 21 keV, 17 day half-life) directly into the target volume within the breast. In 2004, 131Cs became clinically available as an alternative brachytherapy source. Cs-131 has a higher energy (average energy of 30 keV) and a shorter half-life (9.7 days) than 103Pd. The purpose of this study was to determine whether or not 131Cs is safe to use in terms of radiation exposure to a patient’s spouse or primary care giver for PBSI. Materials/Methods: The annual effective doses of the 103Pd and 131Cs implants were compared to determine which radionuclide was more favorable in terms of radiation safety. The NCRP recommend doses to care givers not exceed 5 mSv over the course of the therapy. The effective doses were calculated using a generalized mathematical expression which considered the total exposure to a spouse for different target volumes at different depths for a given prescription dose and for a given length of time that the spouse would spend in the vicinity of the patient. The configurations ranged from a 2 cm diameter target 0.7 cm deep to the skin surface, to a 6 cm diameter target 4 cm deep. Exposure rate versus depth in tissue-equivalent material were measured for both 103Pd and 131Cs and used in the calculation of effective dose. An ion chamber survey meter, that was calibrated for the 103 Pd and 131Cs photon energies, was used for the measurements. The calibration of the meter was done in-house by positioning the meter at a known distance from NIST traceable calibrated 103Pd and 131Cs brachytherapy sources and then correlating the reading on the survey meter with the expected exposure rate at that distance. Results: The effective doses to a spouse for the Cs-131 implants ranged from 3.6 - 24.1 mSv while for the Pd-103 implants the doses ranged from 0.2 - 2.9 mSv, a difference of 10 times higher for the 131Cs implants. Pd-103 is currently the only seed that can be used practically for PBSI, limiting the effective dose to a patient’s spouse to \ 5 mSv/yr. An interesting finding of this study was the fact that published energy response from survey meter manufacturers are not reliable reflections of their true performance.
3064
The Protective Effect of Novel Small Molecule Inhibitor (SKI2162) of Transforming Growth Factor-b Receptor against Radiation-induced Fibrosis
J. Park1, S. Lee1, S. Ryu1, K. Ryu2, S. Kang2, E. Park2, H. Lee2, J. Lee2, H. Jung2, D. Shin2 1
Asan Medical Center, Seoul, Korea, Republic of Korea, 2SK Chemicals, Seongnam, Korea, Republic of Korea
Purpose/Objective(s): Although radiation-induced fibrosis (RIF) is one of common sequelae after irradiation, a protective method was not well investigated. SKI2162 is a novel small molecule inhibitor of TGF-b1 receptor developed for the prevention of RIF. The present study was done to assess the protective effect of SK2162 against RIF in mouse model. Materials/Methods: BALB/c male mice were irradiated 8 weeks after birth. Selective irradiation of the hind limb of mice was done by linear accelerator and specially designed shielding. A single radiation dose of 35 Gy was done for molecular study, and two radiation doses of 22 Gy, once in a week, for assay of radiation-induced leg contracture. For molecular study, change in levels of collagen IA2 mRNA was examined in mouse skin by quantitative real time polymerase chain reaction after 14-day topical application of SKI2162 (1.0%) or vehicle. For the assay of leg contracture, 40 mice were randomly divided into two groups of 20 mice each. Each group was treated with once daily intraperitoneal injections of saline (group 1) or SKI2162 (group 2, 10 mg/Kg/ day) for 16 weeks. Leg contraction test was done by specially designed Lucite jig under anesthesia every 2 weeks after irradiation. The length of the irradiated leg was compared with the contralateral unirradiated leg. Early and late skin reactions were scored by grading system. Results: In molecular study, collagen IA2 mRNA levels in the vehicle treated mouse were increased by 3.0 fold, compared to sham-operated animals. SKI2162 treatment completely inhibited the induction of COL-IA2 mRNA, and the difference in collagen IA2 mRNA expression between SKI2162-treated and vehicle-treated mouse was statistically significant (p \ 0.05). In the assay of radiation-induced contracture, SKI2162 was well tolerated, and no toxic effects were observed. The acute skin reaction was almost identical between the two groups. The leg contraction test showed significant protective effect in group 2. The average length of the irradiated leg (percent of the contralateral leg) was significantly lower in group 1, and the differences between the two groups tended to increase with time; 92% vs. 96% in 6-week (p \ 0.01), 93% vs. 96% in 8-week (p \ 0.01), 88% vs. 93% in 10-week (p \ 0.01), 83% vs. 92% in 12-week (p \ 0.01), 77% vs. 88% in 14-week (p \ 0.01), and 74% vs. 83% in 16-week (p \ 0.01). Also, late skin reactions were more adverse in control group; the average score of late skin reaction was 3.14 vs. 2.73 (p = 0.03). Conclusions: The current study showed that inhibition of TGF-b signaling by SKI2162 had a protective effect on RIF in mouse model. Also, there was no significant toxicity related to the drug administration. This newly developed drug could be considered as a novel agent for protection of RIF. Author Disclosure: J. Park: None. S. Lee: None. S. Ryu: None. K. Ryu: A. Employment; SK Chemicals. S. Kang: A. Employment; SK Chemicals. E. Park: A. Employment; SK Chemicals. H. Lee: A. Employment; SK Chemicals. J. Lee: A. Employment; SK Chemicals. H. Jung: A. Employment; SK Chemicals. D. Shin: A. Employment; SK Chemicals.
3065
Lateral Dose-volume Effects in Single-fraction Radiosurgery of the Cervical Spinal Cord: A Swine Model
P. M. Medin1, R. D. Foster1, A. van der Kogel2, J. Sayre3, T. D. Solberg1 1 University of Texas Southwestern Medical Center, Dallas, TX, 2Radboud University, Nijmegen, Netherlands, 3University of California Los Angeles, Los Angeles, CA
Purpose/Objective(s): This study was performed to test the hypothesis that the dose-related incidence of motor neurologic deficits following spinal radiosurgery is significantly increased by the use of uniform versus laterally non-uniform dose distributions. Materials/Methods: A uniform dose distribution was delivered to a 4.5 - 7.0cm length of cervical spinal cord in 22 mature Yucatan minipigs for comparison with a companion study in which a laterally non-uniform dose was given(reported previously). Pigs were stratified into four dose levels with mean maximum spinal cord doses of 17.5 ± 0.1 Gy(n = 7), 19.5 ± 0.2 Gy(n = 6), 22.0 ± 0.1 Gy(n = 5), and 24.1 ± 0.2 Gy(n = 4). The mean 10Gy and 14Gy volumes were very similar for all dose groups ranging from
S719
I. J. Radiation Oncology d Biology d Physics
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Volume 81, Number 2, Supplement, 2011
3.74cc to 4.33cc. The study endpoint was motor neurologic deficit determined by a change in gait during a one year follow-up period. Results: Dose-response curves for uniform versus non-uniform spinal cord irradiation were nearly identical with ED50’s (95% confidence interval) of 20.2 Gy(19.1 - 25.8) and 20.0 Gy(18.3 - 21.7), respectively. No neurologic change was observed for either dose distribution when the maximum spinal cord dose was less than or equal to 17.8 Gy while all animals experienced deficits at doses greater than or equal to 21.8Gy. Responders that received uniform irradiation had bilateral deficits while non-uniform irradiation resulted in deficits on the irradiated side only. All animals with motor deficits showed some degree of demyelination and focal white matter necrosis with relative sparing of the gray matter. This histologic damage was randomly distributed in the white matter of the uniformly irradiated cords, while limited to the ipsilateral white matter of the non-uniformly irradiated animals. Conclusions: No dose-volume effect is observed in pigs for the dose distributions studied and the endpoint of motor neurologic deficit; however, partial spinal cord irradiation results in less debilitating neurologic and histopathologic morbidity. Author Disclosure: P.M. Medin: D. Speakers Bureau/Honoraria; BrainLAB AG. R.D. Foster: None. A. van der Kogel: None. J. Sayre: None. T.D. Solberg: D. Speakers Bureau/Honoraria; BrainLAB AG.
3066
Glycyrrhetinic Acid Protects Lungs from Radiation-Induced Toxicity
1
C. Chen , S. Yang1, M. Zhang1, Y. Guo2, S. B. Zhang1, X. Wang1, L. Yin1, S. G. Swarts1, P. Okunieff1, L. Zhang1 1
UF Shands Cancer Center, Gainesville, FL, 2Fujian Medical University, Fujian, China
Purpose/Objective(s): Radiation-induced pneumonitis and lung fibrosis are major dose-limiting effects of ionizing radiation (IR) therapy of lung cancer. Currently, no drug can effectively mitigate against these toxicities. Thus, our purpose was to explore glycyrrhetinic acid (GA) as a potential non-toxic agent to prevent IR-induced lung fibrosis without concomitant protection against tumors. Materials/Methods: Two murine models were used to test the effectiveness of GA. A) IR-induced lung fibrosis murine model. C57BL/6 mice were irradiated with 15 Gy to the chest. Twenty-four hours after IR, 30 mg/kg of GA was delivered orally; thereafter, this dosage was repeated every other day for 3 months. At the end of the experiment, enzyme-linked immunosorbent assay (ELISA) for plasma surfactant protein-D (SP-D) and other inflammatory molecules (IM), cone-beam computed tomography (CBCT), respiratory rate and lung compliance, collagen deposition, and hydroxyproline assays were performed. B) Experimental lung metastasis murine model. B16 murine melanoma cells were intravenously injected into C57BL/6 mice. They were then treated with GA as in the IR-induced lung fibrosis murine model. At the end of the experiments, the ratio of lung weight to body weight was measured. Results: GA has the following effects: 1) reduces IR-induced IM (i.e. interleukin 1a) in the acute, sub-acute, and late phases after lung irradiation; 2) reduces plasma SP-D, a surrogate marker for the GA effect; 3) ameliorates IR-induced changes in lung function (respiratory rate and lung compliance); 4) pathologically and biochemically reverses IR-induced changes, preserving the lung structure by reducing inflammation, infiltration, and collagen deposition as demonstrated in CBCT, H&E/Trichrome blue staining, and hydroxyproline content measurements; 5) exhibits no side effects after long-term use; 6) slightly reduces the growth of experimental lung metastases, as evidenced by the smaller ratio of lung weight to body weight than that of the controls. Conclusions: GA is a safe and effective agent for IR-induced lung damage without concomitant benefit to lung tumors. Author Disclosure: C. Chen: None. S. Yang: None. M. Zhang: None. Y. Guo: None. S.B. Zhang: None. X. Wang: None. L. Yin: None. S.G. Swarts: None. P. Okunieff: None. L. Zhang: None.
3067
Evaluation of the Radiation Safety of using 131Cs Seeds for Permanent Breast Seed Implantation
A. Ravi, B. M. Keller, J. Pignol Sunnybrook Odette Cancer Centre, Toronto, ON, Canada Purpose/Objective(s): Permanent breast seed implantation (PBSI) is an accelerated partial breast irradiation technique, implanting 103Pd brachytherapy sources (average energy of 21 keV, 17 day half-life) directly into the target volume within the breast. In 2004, 131Cs became clinically available as an alternative brachytherapy source. Cs-131 has a higher energy (average energy of 30 keV) and a shorter half-life (9.7 days) than 103Pd. The purpose of this study was to determine whether or not 131Cs is safe to use in terms of radiation exposure to a patient’s spouse or primary care giver for PBSI. Materials/Methods: The annual effective doses of the 103Pd and 131Cs implants were compared to determine which radionuclide was more favorable in terms of radiation safety. The NCRP recommend doses to care givers not exceed 5 mSv over the course of the therapy. The effective doses were calculated using a generalized mathematical expression which considered the total exposure to a spouse for different target volumes at different depths for a given prescription dose and for a given length of time that the spouse would spend in the vicinity of the patient. The configurations ranged from a 2 cm diameter target 0.7 cm deep to the skin surface, to a 6 cm diameter target 4 cm deep. Exposure rate versus depth in tissue-equivalent material were measured for both 103Pd and 131Cs and used in the calculation of effective dose. An ion chamber survey meter, that was calibrated for the 103 Pd and 131Cs photon energies, was used for the measurements. The calibration of the meter was done in-house by positioning the meter at a known distance from NIST traceable calibrated 103Pd and 131Cs brachytherapy sources and then correlating the reading on the survey meter with the expected exposure rate at that distance. Results: The effective doses to a spouse for the Cs-131 implants ranged from 3.6 - 24.1 mSv while for the Pd-103 implants the doses ranged from 0.2 - 2.9 mSv, a difference of 10 times higher for the 131Cs implants. Pd-103 is currently the only seed that can be used practically for PBSI, limiting the effective dose to a patient’s spouse to \ 5 mSv/yr. An interesting finding of this study was the fact that published energy response from survey meter manufacturers are not reliable reflections of their true performance.