Clinical And Laboratory Study On Risk Factors Predicting Radiation Pneumonitis

PartⅠ:Combination of Serum Cytokine with lung DVH for Prediction Radiation PneumonitisPurpose:To study the relationship between level of plasma transform growth factor bata(TGF-beta),interleukin(IL-6),angiotensin-converting enzyme(ACE),vascular endothelial growth factor(VEGF),dose volume histogram(DVH) and radiation pneumonitis(RP).Materials and Methods:The records of all patients with lung cancer treated with radiotherapy(RT) with curative intent from February 2004 to April 2007.A total of 131 patients were identified.Blood samples were collected and measured with enzyme-linked immunosorbent assay(ELISA).TGF-beta,IL-6, VEGF and ACE measurements obtained before RT(Pre-RT) and when RT dose reached 40-50Gy(during-RT).The endpoint of the study was the development of=grade 2 RP(National Cancer Institute common toxicity criteria 3.0).Results:The Median follow-up time for the alive patients is 24.7 months.The incidence of=grade 2 RP was 17.6%.Between the RP and non-RP group, there was no difference in Pre- or during- RT level of VEGF,IL-6.In those patient whose TGF-βlevel during- RT was higher than the pre- RT baseline, RP occurred more frequently than in patients whose TGF-βlevel during- RT was less than the baseline value(39.4%vs 14.3%,P=0.017).We observed TGF-βlevel was higher and ACE level was lower in RP group than in the non-RP group,during-RT respectively(4.52ng/ml vs 3.29ng/ml,P=0.027 and 384.72ng/ml vs 479.72ng/ml,P=0.043).In RP group,patients are received higher contra-lateral lung MLD,contra-lateral lung V10,contra-lateral lung V15, contra-lateral lung V20(1576cGy vs1028 cGy,43%vs 33%,34%vs 21%,27%vs 15%,P＜0.05).On multivariate analysis,a persistent elevation of plasma TGF-βabove the baseline concentration during- RT was an independent risk factor for the occurrence of RP(P=0.005).Total 124 patients of the stageⅢ～Ⅳentered the survival analysis;median follow time was 24.1 months.The 1-y,2-y,3-y overall survival was 70.0%,40.0%,30.8%.1-y,2-y, 3-y progress free survival time was 52.8%,38.7%,32.7%.The median survival time was 17.7 months and the median progress free time was 14.3 months.On univariate analysis,KPS less than 80,weight loss more than 5%,radiation dose less than 60Gy,elevated plasma TGF-βlevel during- RT were risk factors for overall survival time and progress free survival time.On COX multivariate analysis,weight loss,radiation dose and the elevated TGF-βlevel were independent risk factors for overall survival.KPS less than 80,weight loss more than 5%and the elevated TGF-βlevel were independent risk factors for progress free survival.Conclusions:(1) The DVH parameter contra-lateral lung MLD,contra-lateral lung V10, contra-lateral lung V15,contra-lateral lung V20 are important risk factors in NSCLC patients who received 3DCRT.The ACE level lower than 347 ng/ml, an elevated plasma TGF-βlevel during- RT are independent risk factor for RP.(2) Pre- RT KPS less than 80,weight loss more than 5%,radiation dose less than 60Gy,elevated plasma TGF-βlevel during- RT are important risk factors for overall survival of the NSCLC patients.An elevated plasma TGF-βlevel during- RT are independent risk factor for overall survival and progress free survival. PartⅡ:Prognosis and RP Risk Factors for NSCLC who received Post-Operative 3-Dimensional Conformal RadiothrapyPurpose:The purpose of this study is to evaluate the prognosis and relationship between lung dosimetric parameters and the risk of symptomatic radiation pneumonitis(RP) in patients with non-small cell lung cancer(NSCLC) who received postoperative radiotherapy.Materials and Methods:From November 2002 November to March 2006 March,ninety patients with NSCLC who received postoperative 3-dimentinal conformal radiotherapy were included in this study.Seventy(78%) of them underwent lobectomy,and 20(22%) underwent pneumonectomy.Eighty-four received adjuvant radiotherapy according to the pathological status.X-ray with energy of 6MV was used for all patients.The median radiation dose was 60Gy with fraction size of 2Gy.Thirty-eight patients(42.2%) received median 3 cycles adjuvant chemotherapy.The percentage of the whole lung volume (Vp-dose) and the ipsilateral absolute lung volume(Vipsi-dose) which received more than a specific dose of irradiation were generated for every patient.The endpoint was grade 2 and above radiation pneumonitis based on CTC AE 3.0. The relation between the dosimetric factors and RP was also analyzed with receiver operating characteristic(ROC) curves.Results:Eighty-four patients who received adjuvant post-operative radiotherapy were analyzed for overall survival and treatment failure mode. Median follow-up was 37.7 months for survivors.The overall median survival time was 48 months.The overall 1-,2-,3- 4-year survival rate was 90.3%, 72.6%,58.6%and 43.9%respectively.The 3-,4-year overall survival rate of the forty-eight patients who received completely resection was 65.2%and 46.6%respectively.Eight-one patients had the data of the failure mode,53.1% (43/81) who had treated failure,the recurrence the in-thoracic and superclavicular was far less than the distant metastasis.On univariate analysis for all patients,sex,age,weight loss,tumor size,pathology and stage were not prognostic.R1/R2 resection was associated with significantly worse survival. The 3-year overall survival rate of the R0 and R1+R2 dissection was 64.3% and 35.7%respectively(P=0.047).Ninety patients were analyzed for radiation pneumonitis.Nine patients(10%) developed RP(grade 2 in 7 cases,and grade 3 in 2 cases),and all of them were in the lobectomy group.No RP was observed in patients who received pneumonectomy.The sex,age,tumor location,pathological type,T or N stage,Pulmonary function test were not the risk factors for RP.Adjuvant chemotherapy had a trend to increase the RP rate. The total dose and the field size had no different in the two groups.The all lung MLD,all lung V5-V25,contra-lateral MLD,contra-lateral V5-V40,ipsi-lateral MLD,ipsi-lateral V5-V35 were much higher with RP group than in those without RP.The area under curve in receiver operating characteristic curves based on the relationship between incidence of RP and the value of Vipsi-dose was 0.757(P=0.020).Using Vipsi-30 of 340cm~3 as a cut-off to predict RP,the sensitivity and the specificity were 88%and 70%,respectivly.The incidence of RP was 2.5%in patients with Vipsi-30＜340cm3 compared with 29.2%in patients with a Vipsi-30＞340cm3(P=0.003).Conclusions:It was safe for patients with NSCLC to receive postoperative 3DCRT if irradiation dose to lung tissue was well defined.The absolute volume of ipsilateral lung received more than 30 Gy after lobectomy was significantly correlated with the risk of RP.The volume should be less than 340cm~3. Patients with pneumonectomy received modern 3DCRT are safe when the whole lung V20 less than 10%. PartⅢ:Effects of pirfenidone on prevention of radiation-induced lung toxicity-Results of animal experimentPurpose:Pirfenidone(5-methyl-1-phenyl-2-(1H)-pyridone),is a novel experimental drug used as anti-fibrotic agent.This study was undertaken to investigate the effect of pirfenidone on prevention of radiation-induced lung toxicity.Materials and Methods:Male BALB/C mice were randomized into 4 groups: Control(group C);Radiation alone(group R);Pirfenidone alone(group P); Radiation+Pirfenidone(group R+P).Either sham irradiation(groups C and P)or single fraction of 12Gy to whole thorax(groups R and R+P) were given to the animals.The animals were fed with control diet or same diet plus 0.5% Pirfenidone from 3 days prior to irradiation to 12 weeks after irradiation.The animals(6-8 mice per group) were sacrificed 1,2,3,4,5,6 months after irradiation.Bronchoalveolar lavage fluid(BALF) from the right lungs was collected for detection of cell counting,and the left lungs were collected for hydroxyproline measurement or fixed for Masson trichrome staining.The plasm transforming growth factorβ(TGF-β) was measured with ELISA method. T test and Chi square were used for statistical analysis.Results:Macrophages in BALF were dramatically increased in the R and R+P groups at 4,5,and 6 months after irradiaiton,but the number of macrophages were lower in group R than in group R+P(18.51×10~4/ml vs 4.50×10~4/ml P= 0.005;60.61×10~4/ml vs 23.05×10~4/ml P=0.046;46.24×10~4/ml vs 35.00×10~4/ml P=0.305).Plasma TGF-βlevel in group R+P was lower comparing to that in group R at 3,4 and 5 months after irradiation,but not statistically significant (3.48 pg/ml vs 5.03 pg/ml P=0.223;3.82pg/ml vs 5.31 pg/ml P=0.666; 3.31pg/ml vs 4.27pg/ml P=0.310).Total lung hydroxyproline content,an index of fibrosis,was gradually increased with time in both group R and group R+P. But the level in R+P group were 21%,24%lower comparing to group R at 4 and 5 months(86.1μg/lung vs 67.7μg/lung P=0.007;104.1μg/lung vs 79.2μg/lung P=0.001).Based on Masson trichrome staining,we found that pirfenidone can ameliorate the severity of lung fibrosis at 4,5 and 6 months after irradiation,the mean fibrosis score was higher in group R than in group R+P(47.50 vs 20.30 P=0.003;47.91 vs 29.15 P=0.039;42.50 vs 19.46 P= 0.000).Conclusions:Pirfenidone has a protective effect on radiation-induced lung toxicity in mice.