-
目前调强放疗已成为非小细胞肺癌(non-small cell lung cancer,NSCLC)重要的治疗手段之一,该技术可以在保障靶区剂量准确的情况下尽可能降低正常组织的受照剂量[1-2]。但放疗后,部分患者仍然会发生放射性肺损伤这一常见并发症[3],从而延长了患者的康复时间,增加了患者的治疗成本[4],因此,探索发生放射性肺损伤的危险因素具有实际应用价值。本研究对行调强放疗的216例局部晚期NSCLC患者的临床资料进行分析,筛选发生急性放射性肺损伤的危险因素并建立预测发生风险的列线图模型,为局部晚期NSCLC患者调强放疗后发生急性放射性肺损伤的防治提供依据。
-
216例局部晚期NSCLC患者行调强放疗后有65例发生急性放射性肺损伤,其中急性放射性肺损伤2级34例、3级17例、4级11例、5级3例,急性放射性肺损伤的发生率为30.09%。急性放射性肺损伤组和无急性放射性肺损伤组患者的性别、糖尿病、吸烟史、化疗、体重指数、病理学分期、病理学类型、肿瘤位置、射野数、处方剂量、大体肿瘤体积、慢阻肺、间质性肺炎、肺弥散功能和心功能不齐的组间差异均无统计学意义(均P>0.05);而年龄、V5、V20、V30、平均肺剂量、FEV1、放疗剂量分割模式和图像验证的组间差异均有统计学意义(均P<0.05,表1)。
项目 急性放射性
肺损伤组(n=65)无急性放射性
肺损伤组(n=151)χ2值 P值 项目 急性放射性肺
损伤组(n=65)无急性放射性
肺损伤组(n=151)χ2值 P值 年龄 8.737 0.003 V20 9.510 0.002 ≥70岁 22(33.85) 24(15.89) ≥28% 15(23.08) 12(7.95) <70岁 43(66.15) 127(84.11) <28% 50(76.92) 139(92.05) 性别 0.263 0.608 V30 10.014 0.002 男 30(46.15) 64(42.38) ≥18% 18(27.69) 16(10.60) 女 35(53.85) 87(57.62) <18% 47(72.31) 135(89.40) 糖尿病 0.782 0.376 平均肺剂量 9.248 0.002 有 10(15.38) 31(20.53) ≥13 Gy 20(30.77) 20(13.25) 无 55(84.62) 120(79.47) <13 Gy 45(69.23) 131(86.75) 吸烟史 0.048 0.826 FEV1 8.737 0.003 有 12(18.46) 26(17.22) <70% 22(33.85) 24(15.89) 无 53(81.54) 125(82.78) ≥70% 43(66.15) 127(84.11) 化疗 0.095 0.758 大体肿瘤体积 0.481 0.488 是 15(23.08) 32(21.19) ≥160 cm3 18(27.69) 49(32.45) 否 50(76.92) 119(78.81) <160 cm3 47(72.31) 102(67.55) 体重指数 0.035 0.851 放疗剂量分割模式 9.135 0.003 ≥24 kg/m2 8(12.31) 20(13.25) 大分割 24(36.92) 27(17.88) <24 kg/m2 57(87.69) 131(86.75) 常规分割 41(63.08) 124(82.12) 病理学分期 0.056 0.812 图像验证 8.945 0.003 ⅢA 33(50.77) 74(49.01) 是 49(75.38) 137(90.73) ⅢB 32(49.23) 77(50.99) 否 16(24.62) 14(9.27) 病理学类型 0.509 0.476 慢阻肺 0.039 0.843 腺癌 34(52.31) 71(47.02) 有 13(20.00) 32(21.19) 鳞癌 31(47.69) 80(52.98) 无 52(80.00) 119(78.81) 肿瘤位置 0.254 0.615 间质性肺炎 0.110 0.740 周围型 36(55.38) 78(51.66) 有 10(15.38) 26(17.22) 中央型 29(44.62) 73(48.34) 无 55(84.62) 125(82.78) 射野数 0.381 0.537 肺弥散功能 0.832 0.362 ≥6 20(30.77) 53(35.10) <25 mm Hg/min 17(26.15) 31(20.53) <6 45(69.23) 98(64.90) ≥25 mm Hg/min 48(73.85) 120(79.47) 处方剂量 0.505 0.477 心功能不齐 0.716 0.398 ≥60 Gy 27(41.54) 55(36.42) 有 11(16.92) 19(12.58) <60 Gy 38(58.46) 96(63.58) 无 54(83.08) 132(87.42) V5 8.497 0.004 ≥60% 17(26.15) 16(10.60) <60% 48(73.85) 135(89.40) 注:V5、V20、V30分别为 5、20、30 Gy剂量照射的肺体积占全肺总体积的百分比;FEV1为第1秒用力呼气容积 表 1 急性放射性肺损伤组和无急性放射性肺损伤组局部晚期非小细胞肺癌患者一般资料的比较[例(%)]
Table 1. Comparison of the general data of patients with locally advanced non-small cell lung cancer in the acute radiation-induced lung injury group and the non-acute radiation-induced lung injury group (cases (%))
-
对216例局部晚期NSCLC患者的临床资料进行LASSO回归分析,结果显示,年龄、V5、V20、V30、平均肺剂量、FEV1、放疗剂量分割模式和图像验证是非零系数的预测因素(图1)。
-
以LASSO回归分析筛选的预测因素(年龄、V5、V20、V30、平均肺剂量、FEV1、放疗剂量分割模式和图像验证)为自变量,以是否发生急性放射性肺损伤为因变量,进行多因素Logistic回归分析。结果显示,年龄、V5、V20、V30、平均肺剂量、FEV1、放疗剂量分割模式和图像验证是局部晚期NSCLC患者调强放疗后发生急性放射性肺损伤的独立危险因素(均P<0.05,表2)。
因素 回归系数 标准误 Wald值 P值 OR值 95%CI 年龄 1.225 0.431 8.086 0.004 3.404 1.463~7.918 V5 1.144 0.465 6.052 0.014 3.138 1.262~7.805 V20 1.431 0.513 7.791 0.005 4.183 1.531~11.428 V30 1.434 0.461 9.667 0.002 4.197 1.699~10.365 平均肺剂量 1.479 0.438 11.418 0.001 4.388 1.861~10.346 第1秒用力呼气容积 1.081 0.423 6.533 0.011 2.946 1.287~6.748 放疗剂量分割模式 1.158 0.402 8.306 0.004 3.185 1.449~7.002 图像验证 1.545 0.475 10.596 0.001 4.688 1.849~11.886 注:V5、V20、V30分别为5、20、30 Gy剂量照射的肺体积占全肺总体积的百分比;CI为置信区间 表 2 局部晚期非小细胞肺癌患者调强放疗后发生急性放射性肺损伤的多因素Logistic回归分析
Table 2. Multivariate Logistic regression analysis of acute radiation-induced lung injury in patients with locally advanced non-small cell lung cancer after intensity-modulated radiation therapy
-
发生急性放射性肺损伤的风险列线图模型见图2,当年龄≥70岁为79分、V5≥60%为74分、V20≥28%为92.5分、V30≥18%为92.5分、平均肺剂量≥13 Gy为96分、FEV1<70%为70分、大分割放疗为75分、未进行图像验证为100分。总分为50~330分时,对应局部晚期NSCLC患者调强放疗后发生急性放射性肺损伤的概率为10%~90%,其中风险列线图模型的一致性指数为0.819(95%CI:0.789~0.853)。由图3可见,校正曲线与理想曲线接近。由图4可见,ROC曲线的AUC为0.802。由图5可见,决策曲线显示阈值概率在6%~100%时,具有较高的净获益值。以上结果均说明本模型具有良好的预测准确性。
图 2 预测局部晚期非小细胞肺癌患者调强放疗后发生急性放射性肺损伤的风险列线图模型
Figure 2. A nomogram model for predicting the risk of acute radiation-induced lung injury after intensity-modulated radiation therapy in patients with locally advanced non-small cell lung cancer
图 3 预测局部晚期非小细胞肺癌患者调强放疗后发生急性放射性肺损伤的风险列线图模型的校正曲线
Figure 3. Calibration curve of a nomogram model for predicting the risk of acute radiation-induced lung injury after intensity-modulated radiotherapy in patients with locally advanced non-small cell lung cancer
局部晚期非小细胞肺癌患者调强放疗后发生急性放射性肺损伤的影响因素及风险预测模型研究
Influencing factors and risk prediction model of acute radiation-induced lung injury in patients with locally advanced non-small cell lung cancer after intensity-modulated radiotherapy
-
摘要:
目的 探讨局部晚期非小细胞肺癌(NSCLC)患者调强放疗后发生急性放射性肺损伤的危险因素,并建立预测风险的列线图模型。 方法 回顾性分析2017年5月至2019年11月于南京医科大学附属脑科医院行调强放疗的216例局部晚期NSCLC患者的临床资料,其中男性94例、女性122例,年龄37~83(61.5±9.6)岁。根据急性放射性肺损伤的发生情况将患者分为急性放射性肺损伤组和无急性放射性肺损伤组。计数资料的比较采用χ2检验,采用LASSO分析和Logistic回归分析筛选局部晚期NSCLC患者调强放疗后发生急性放射性肺损伤的独立危险因素,采用R软件包建立预测局部晚期NSCLC患者调强放疗后发生急性放射性肺损伤的风险列线图模型,计算一致性指数,绘制校正曲线、受试者工作特征(ROC)曲线和决策曲线。 结果 216例局部晚期NSCLC患者调强放疗后有65例患者发生急性放射性肺损伤,发生率为30.09%。LASSO分析和Logistic回归分析结果显示,年龄、V5、V20、V30、平均肺剂量、第1秒用力呼气容积(FEV1)、放疗剂量分割模式及图像验证是局部晚期NSCLC患者调强放疗后发生急性放射性肺损伤的独立危险因素(OR=2.946~4.688,均P<0.05)。建立预测局部晚期NSCLC患者调强放疗后发生急性放射性肺损伤的风险列线图模型的一致性指数为0.819(95%CI:0.789~0.853),校正曲线与理想曲线相接近,ROC曲线下面积为0.802,决策曲线显示阈值概率在6%~100%时,具有较高的净获益值。 结论 基于年龄、V5、V20、V30、平均肺剂量、FEV1、放疗剂量分割模式及图像验证建立的列线图对局部晚期NSCLC患者调强放疗后急性放射性肺损伤发生风险的预测具有较高的准确率。 Abstract:Objective To investigate the risk factors of acute radiation-induced lung injury in patients with locally advanced non-small cell lung cancer (NSCLC) after intensity-modulated radio therapy (IMRT) and establish a nomogram model to predict the corresponding risk. Methods The clinical data of 216 patients with locally advanced NSCLC who were treated with IMRT in the Brain Hospital Affiliated to Nanjing Medical University from May 2017 to November 2019 were retrospectively analyzed, including 94 males and 122 females, with an average age of 37–83(61.5±9.6) years old. Based on the occurrence of acute radiation-induced lung injury, the selected patients with locally advanced NSCLC were divided into the acute radiation-induced lung injury group and the non-acute radiation-induced lung injury group. Herein, count data were compared using the χ2 test, LASSO analysis, and Logistic regression analysis used to screen independent risk factors of acute radiation-induced lung injury in patients with locally advanced NSCLC after IMRT. In addition, the R software was used to predict the occurrence of acute radiation in patients with locally advanced NSCLC after IMRT. Risk nomogram model of lung injury, plotting calibration curve, receiver operating characteristic (ROC) curve, and decision curve. Results Among 216 patients with locally advanced NSCLC, acute radiation-induced lung injury occurred in 65 patients after IMRT, with an incidence rate of 30.09%. Logistic regression analysis showed that age, V5, V20, V30, mean lung dose, forced expiratory volume in the first second (FEV1), hypofractionated radiotherapy, and image verification are independent risk factors for acute radiation-induced lung injury in patients with locally advanced NSCLC after IMRT (OR=2.946–4.688, all P<0.05). The consistency index of the nomogram model for predicting the risk of acute radiation-induced lung injury in patients with locally advanced NSCLC after IMRT was 0.819(95%CI: 0.789–0.853), the calibration curve was close to the ideal curve, and the area under the ROC curve was 0.802, the decision curve shows that when the threshold probability is between 6% and 100%, hence, there is a higher net benefit value. Conclusions The nomogram established based on age, V5, V20, V30, mean lung dose, FEV1, hypofractionated radiotherapy, and image verification has high accuracy in predicting the risk of acute radiation-induced lung injury in patients with locally advanced NSCLC after IMRT. -
表 1 急性放射性肺损伤组和无急性放射性肺损伤组局部晚期非小细胞肺癌患者一般资料的比较[例(%)]
Table 1. Comparison of the general data of patients with locally advanced non-small cell lung cancer in the acute radiation-induced lung injury group and the non-acute radiation-induced lung injury group (cases (%))
项目 急性放射性
肺损伤组(n=65)无急性放射性
肺损伤组(n=151)χ2值 P值 项目 急性放射性肺
损伤组(n=65)无急性放射性
肺损伤组(n=151)χ2值 P值 年龄 8.737 0.003 V20 9.510 0.002 ≥70岁 22(33.85) 24(15.89) ≥28% 15(23.08) 12(7.95) <70岁 43(66.15) 127(84.11) <28% 50(76.92) 139(92.05) 性别 0.263 0.608 V30 10.014 0.002 男 30(46.15) 64(42.38) ≥18% 18(27.69) 16(10.60) 女 35(53.85) 87(57.62) <18% 47(72.31) 135(89.40) 糖尿病 0.782 0.376 平均肺剂量 9.248 0.002 有 10(15.38) 31(20.53) ≥13 Gy 20(30.77) 20(13.25) 无 55(84.62) 120(79.47) <13 Gy 45(69.23) 131(86.75) 吸烟史 0.048 0.826 FEV1 8.737 0.003 有 12(18.46) 26(17.22) <70% 22(33.85) 24(15.89) 无 53(81.54) 125(82.78) ≥70% 43(66.15) 127(84.11) 化疗 0.095 0.758 大体肿瘤体积 0.481 0.488 是 15(23.08) 32(21.19) ≥160 cm3 18(27.69) 49(32.45) 否 50(76.92) 119(78.81) <160 cm3 47(72.31) 102(67.55) 体重指数 0.035 0.851 放疗剂量分割模式 9.135 0.003 ≥24 kg/m2 8(12.31) 20(13.25) 大分割 24(36.92) 27(17.88) <24 kg/m2 57(87.69) 131(86.75) 常规分割 41(63.08) 124(82.12) 病理学分期 0.056 0.812 图像验证 8.945 0.003 ⅢA 33(50.77) 74(49.01) 是 49(75.38) 137(90.73) ⅢB 32(49.23) 77(50.99) 否 16(24.62) 14(9.27) 病理学类型 0.509 0.476 慢阻肺 0.039 0.843 腺癌 34(52.31) 71(47.02) 有 13(20.00) 32(21.19) 鳞癌 31(47.69) 80(52.98) 无 52(80.00) 119(78.81) 肿瘤位置 0.254 0.615 间质性肺炎 0.110 0.740 周围型 36(55.38) 78(51.66) 有 10(15.38) 26(17.22) 中央型 29(44.62) 73(48.34) 无 55(84.62) 125(82.78) 射野数 0.381 0.537 肺弥散功能 0.832 0.362 ≥6 20(30.77) 53(35.10) <25 mm Hg/min 17(26.15) 31(20.53) <6 45(69.23) 98(64.90) ≥25 mm Hg/min 48(73.85) 120(79.47) 处方剂量 0.505 0.477 心功能不齐 0.716 0.398 ≥60 Gy 27(41.54) 55(36.42) 有 11(16.92) 19(12.58) <60 Gy 38(58.46) 96(63.58) 无 54(83.08) 132(87.42) V5 8.497 0.004 ≥60% 17(26.15) 16(10.60) <60% 48(73.85) 135(89.40) 注:V5、V20、V30分别为 5、20、30 Gy剂量照射的肺体积占全肺总体积的百分比;FEV1为第1秒用力呼气容积 表 2 局部晚期非小细胞肺癌患者调强放疗后发生急性放射性肺损伤的多因素Logistic回归分析
Table 2. Multivariate Logistic regression analysis of acute radiation-induced lung injury in patients with locally advanced non-small cell lung cancer after intensity-modulated radiation therapy
因素 回归系数 标准误 Wald值 P值 OR值 95%CI 年龄 1.225 0.431 8.086 0.004 3.404 1.463~7.918 V5 1.144 0.465 6.052 0.014 3.138 1.262~7.805 V20 1.431 0.513 7.791 0.005 4.183 1.531~11.428 V30 1.434 0.461 9.667 0.002 4.197 1.699~10.365 平均肺剂量 1.479 0.438 11.418 0.001 4.388 1.861~10.346 第1秒用力呼气容积 1.081 0.423 6.533 0.011 2.946 1.287~6.748 放疗剂量分割模式 1.158 0.402 8.306 0.004 3.185 1.449~7.002 图像验证 1.545 0.475 10.596 0.001 4.688 1.849~11.886 注:V5、V20、V30分别为5、20、30 Gy剂量照射的肺体积占全肺总体积的百分比;CI为置信区间 -
[1] 尤静, 杨丹, 李东明, 等. 同步推量调强放疗在局部晚期非小细胞肺癌中的应用[J]. 中国肺癌杂志, 2019, 22(11): 696−701. DOI: 10.3779/j.issn.1009-3419.2019.11.03.
You J, Yang D, Li DM, et al. Application of simultaneous integrated boost intensity modulated radiotherapy in locally advanced non-small cell lung cancer[J]. Chin J Lung Cancer, 2019, 22(11): 696−701. DOI: 10.3779/j.issn.1009-3419.2019.11.03.[2] 郑连喜, 邓超, 何平, 等. 重组人血管内皮抑制素注射液联合EP化疗[J]. 蚌埠医学院学报, 2020, 45(8): 1013−1016, 1019. DOI: 10.13898/j.cnki.issn.1000-2200.2020.08.006.
Zheng LX, Deng C, He P, et al. Effect of the recombinant human endostatin injection combined with EP chemotherapy and intensity-modulated radiotherapy in patients with advanced non-small cell lung cancer[J]. J Bengbu Med Coll, 2020, 45(8): 1013−1016, 1019. DOI: 10.13898/j.cnki.issn.1000-2200.2020.08.006.[3] 张凌云, 田飞, 龚正, 等. 尼达尼布治疗放射性肺损伤一例并文献复习[J]. 中国呼吸与危重监护杂志, 2021, 20(8): 584−587. DOI: 10.7507/1671-6205.202008044.
Zhang LY, Tian F, Gong Z, et al. Nintedanib in the treatment of a case of radiation-induced lung injury and literature review[J]. Chin J Respir Crit Care Med, 2021, 20(8): 584−587. DOI: 10.7507/1671-6205.202008044.[4] 唐正中, 胡宗涛, 王崇, 等. 局部晚期非小细胞肺癌三维适形放射治疗致放射性肺损伤相关因素探讨[J]. 安徽医药, 2018, 22(6): 1116−1119. DOI: 10.3969/j.issn.1009-6469.2018.06.029.
Tang ZZ, Hu ZT, Wang C, et al. The related factors of radiation-induced lung injury caused by 3DCRT for locally advanced non-small cell lung cancer[J]. Anhui Med Pharm J, 2018, 22(6): 1116−1119. DOI: 10.3969/j.issn.1009-6469.2018.06.029.[5] 中华医学会重症医学分会. 急性肺损伤/急性呼吸窘迫综合征诊断与治疗指南(2006)[J]. 中华内科杂志, 2007, 46(5): 430−435. DOI: 10.3760/j.issn:0578-1426.2007.05.037.
Severe Medicine Branch of Chinese Medical Association. Guidelines for diagnosis and treatment of acute lung injury/acute respiratory distress syndrome (2006)[J]. Chin J Intern Med, 2007, 46(5): 430−435. DOI: 10.3760/j.issn:0578-1426.2007.05.037.[6] Cox JD, Stetz JA, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC)[J]. Int J Radiat Oncol Biol Phys, 1995, 31(5): 1341−1346. DOI: 10.1016/0360-3016(95)00060-C. [7] 陈斌, 石翔翔, 唐涛. 局部晚期周围型非小细胞肺癌调强放疗中大体肿瘤靶区体积变化及肺受量预测研究[J]. 中华肿瘤防治杂志, 2020, 27(14): 1166−1170. DOI: 10.16073/j.cnki.cjcpt.2020.14.10.
Chen B, Shi XX, Tang T. Changes of gross tumor target volume and prediction of lung dose in locally advanced peripheral non-small cell lung cancer treated with intensity-modulated radiotherapy[J]. Chin J Cancer Prev Treat, 2020, 27(14): 1166−1170. DOI: 10.16073/j.cnki.cjcpt.2020.14.10.[8] 朱成斌, 古丽娜尔·吐尔地, 赵辉. 新疆少数民族地区IMRT治疗肺癌诱发的急性放射性肺损伤的危险因素研究[J]. 医学研究杂志, 2019, 48(12): 124−127.
Zhu CB, Tuurdi GL, Zhao H. Risk factors of acute radiation-induced lung injury induced by IMRT in the treatment of lung cancer in ethnic minority areas in Xinjiang[J]. J Med Res, 2019, 48(12): 124−127.[9] 刘青峰, 王葳, 王亿龙. 局部Ⅲ期NSCLC患者调强适形放疗后重度急性放射性肺损伤的危险因素分析[J]. 中国临床研究, 2018, 31(1): 28−31. DOI: 10.13429/j.cnki.cjcr.2018.01.007.
Liu QF, Wang W, Wang YL. Risk factors analysis of severe acute radiation pneumonitis injury following intensity-modulated conformal radiotherapy in local stage Ⅲ non-small cell lung cancer[J]. Chin J Clin Res, 2018, 31(1): 28−31. DOI: 10.13429/j.cnki.cjcr.2018.01.007.[10] Tang X, Li YY, Tian X, et al. Predicting severe acute radiation pneumonitis in patients with non-small cell lung cancer receiving postoperative radiotherapy: development and internal validation of a nomogram based on the clinical and dose–volume histogram parameters[J]. Radiother Oncol, 2019, 132: 197−203. DOI: 10.1016/j.radonc.2018.10.016. [11] 王佩, 岳成山, 王会霞, 等. 食管癌调强放射治疗的初期疗效及急性放射性肺损伤的影响因素分析[J]. 现代生物医学进展, 2020, 20(22): 4373−4377. DOI: 10.13241/j.cnki.pmb.2020.22.039.
Wang P, Yue CS, Wang HX, et al. Analysis of the initial efficacy of intensity modulated radiotherapy for esophageal cancer and the influencing factors of acute radiation-induced lung injury[J]. Prog Mod Biomed, 2020, 20(22): 4373−4377. DOI: 10.13241/j.cnki.pmb.2020.22.039.[12] Zhou ZR, Han Q, Liang SX, et al. Dosimetric factors and Lyman normal-tissue complication modelling analysis for predicting radiation-induced lung injury in postoperative breast cancer radiotherapy: a prospective study[J/OL]. Oncotarget, 2017, 8(20): 33855−33863[2021-12-19]. https://www.oncotarget.com/article/12979/text/. DOI: 10.18632/oncotarget.12979. [13] 许群英, 蒙以良, 黄升武. Ⅲ/Ⅳ期非手术非小细胞肺癌患者行高剂量大分割放疗临床疗效与剂量学参数及放射性肺损伤的关系分析[J]. 癌症进展, 2019, 17(21): 2520−2523.
Xu QY, Meng YL, Huang SW. Analysis of the relationship among clinical efficacy, dosimetric parameters and radiation-induced lung injury in patients with stage Ⅲ/Ⅳ non-small cell lung cancer treated with hypofractionated radiotherapy without surgical management[J]. Oncol Prog, 2019, 17(21): 2520−2523.[14] Pan WY, Bian C, Zou GL, et al. Combing NLR, V20 and mean lung dose to predict radiation induced lung injury in patients with lung cancer treated with intensity modulated radiation therapy and chemotherapy[J/OL]. Oncotarget, 2017, 8(46): 81387−81393[2021-12-19]. https://www.oncotarget.com/article/19032/text/. DOI: 10.18632/oncotarget.19032.