Clinical And Laboratory Study On Factors Affecting Radiation-induced-Lung-Injury

English Abstract: Clinical and Laboratory Study on Factors Affecting Radiation-induced-Lung-Injury.PartⅠ: Gefitinib does not enhance radiation caused lung injury: Animal experimentPurpose: To evaluate whether the combination of gefitinib and thoracic radiation will exacerbate the lung injury of mouse. Methods andmaterials: One hundred and sixty BalB/C mice were divided into five groups: control(C) group; radiation(R) group; gefitinib(G) group; gefitinib followed by radiation(G+R) group; radiation followed by gefitinib(R+G) group. Gefitinib was fed 200 mg/kg/d, once daily for 21 days; Whole thorax radiation was delivered with a single ventral-dorsal field with 6 MV X-ray with dose of 12Gy. Group C received 21 days of 0.5 ml saline(equal volume with gefitinib) feeding; group R received whole thorax radiation, followed with 21 days of 0.5 ml saline. Mice were sacrificed on 1, 2, 4 or 6 months after radiation. Macrophage cell count of lung lavage fluid and hydroxyproline content were assessed, and the lung fibrosis were scored according to the Ashcroft's criteria. The plasma transforming growth factor (TGF-β1) concentration were assayed with ELISA method. The One-way ANOVA was used to test the significance of any differences between groups at each time point. A p-value＜0.05 was considered statistically significant. Results: The macrophage cell number of lung lavage increased significantly in group R, R+G and G+R than group C (p＜0.05) on time points of 4 and 6 months, and there was no significant difference between the former three groups. No significant difference of the macrophage cell number of lung lavage was found between group G and group C. The hydroxyproline content and the fibrosis score of group G, R, R+G and G+R were significantly higher than group C on all the time-points (p＜0.05), but no significant difference was found between these four groups. The TGF-β1 concentration of group R, G+R, R+G at all time points and TGF-β1 concentration of group G at 1^st and 2^nd months were significantly higher than control group. Conclusion: Both oral gefitinib and whole thoracic radiation could cause lung fibrosis in BalB/C mouse. The combination of oral gefitinib and whole thorax radiation did not significantly exacerbate lung injury caused by gefitinib or radiation alone. The mechanism of lung injury caused by gefitinib might be different from that by radiation and needs further research. PartⅡ: Preventive effect of Chinese traditional medicine-QingXue granula on mouse lung injury caused by radiationPurpose: To evaluate whether oral administration of Chinese tradiational medicine-QingXue granula can prevent the mouse lung injury caused by thoracic radiation. Methods and materials: One hundred and twenty-eight BalB/C mice were divided into 4 groups: control(C) group; radiation(R) group; radiation plus high dose (H) QingXue granula group and radiation plus median dose (M) QingXue granula group. The H and M groups were fed 0.64g/day and 0.32g/day of QingXue granula once daily for two months, respectively; corresponding to 4 and 2 times of human dosage, respectively. Whole thorax radiation was delivered with a single ventral-dorsal field with 6 MV X-ray with dose of 12Gy. Group C and group R received 21 days of 0.5 ml saline (equal volume with Qing-Xue granula) feeding. Mice were sacrificed at 1, 2, 4 or 6 months after radiation. Macrophage cell count of lung lavage fluid and hydroxyproline content of whole lung were assayed, and the lung fibrosis were scorred according to the Ashcroft's criteria. The plasma interleukin-6(IL-6), transforming growth factor-β1 (TGFβ1) and vascular endothelial growth factor (VEGF) concentration were assayed with ELISA method. The One-way ANOVA was used to test the significance of any differences between groups at each time point. A p-value＜0.05 was considered statistically significant. Results: The macrophage cell number of lung lavage was significantly lower on 1^st months in group M than in group R (p＜0.05), but no significant difference between group M and C. The hydroxyproline content of group H were significantly lower than group R on 1^st and 6^th months (p＜0.05), but still higher than group C(p＜0.05). The fibrosis score of group H were significantly lower than group R on 2^nd, 4^th and 6^th months (p＜0.05). The IL-6 concentration of group QX was significantly lower than group R on 1^st months, and not significantly higher than group C. The VEGF concentration were significantly higher in group R than group C since the 2^nd months (p＜0.05), The VEGF concentration were significantly higher in group H than group R on 2^nd and 6^th months (p＜0.05). Conclusion: Oral Chinese traditional medicine QingXue granula could prevent the lung fibrosis, especially when use the high dose. The degree of elevation of VEGF in plasma was not equal with the degree of lung fibrosis in mouse. PartⅢ: PhaseⅡTrial of Simmutaneous Paclitaxel/Carboplatin And Radiation For StageⅢNon-small Cell Lung CancerObjective To determine the toxicity and efficacy of paclitaxel or combined with carboplatin plus concurrent radiotherapy for stageⅢnon-small cell lung cancer(NSCLC). Methods All 41 cases pathologically diagnosed as NSCLC(Ⅲa: 17 cases,Ⅲb: 24 cases) received 60-70Gy conventional fractionated external beam radiotherapy, and simultaneously chemotherapy with paclitaxel (45mg/m2, n=13) or combined with carboplatin (AUC=2, n=28), once weekly. Results Thirty-seven cases received total dose of 60-72Gy, two received 54Gy and two received 56Gy. Thirty-eight cases received 4-6 weeks of chemotherapy, three cases received only 2 weeks of chemotherapy. 4.9%of the patients(2/41) experienced gradeⅢandⅣneutropenia; 9.8% of the patients(4/41) experienced gradeⅢradiation esophagitis; 14.7%(6/41) experienced≥gradeⅡradiation pneumonitis; and 2.4%(1/41) had gradeⅢmucositis. The total response rate(CR+PR) was 78%. With the median follow-up time of 17.2 months, the median survival time was 16.5 months (20.0 m for stageⅢa, 15.8 m forⅢb, ) , with 1, 2 and 3 year overall survival of 68.8%, 33.5% and 33.5%, 0respectively.The median and 1 year, 2year progression free survival (PFS) was 57.8 months, 85.3% and 85.3%, respectively. The patterns of failure were 4 intra-field recurrence, 1 local and extra-field regional recurrence, 1 extra-field regional recurrence, 2 carcinomatous pleural effusion and 12 distant metastasis. Conclusion Concurrent chemoradiotherapy with paclitaxel and/or carboplatin can be well tolerated, with relatively good near and future effectiveness. Major pattern of failure was distant metastasis. High radiation dose (no less than 66Gy) provided a more powerful effectiveness.