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非小细胞肺癌(non-small-cell lung cancer,NSCLC)占全部肺癌的80%,通过手术、放疗和药物的综合治疗,患者生存已得到明显改善[1]。对于行根治性切除术后病理分期为ⅢA-N2(pⅢA-N2)的NSCLC患者,术后辅助化疗可显著提高生存期[2-3],但局部区域复发率仍高达20%~40%[4-5]。在多种实体瘤的治疗中,术后放疗均可有效地杀灭潜在的亚临床病灶,提高局部控制率进而进一步改善生存[6-7]。对于pⅢA-N2 NSCLC患者,相关研究结果显示术后放疗(postoperative radiotherapy, PORT)虽能明显降低局部区域复发率,但对生存的影响仍不确定[8-13]。其原因可能是胸部放疗相关的心肺毒性降低了生存获益,这些不良反应可通过放疗技术的进步逐渐改善。此外,pⅢA-N2 NSCLC患者的异质性很大,可通过亚组分析确定能从PORT获益的亚组人群,达到精准治疗的目的,同时避免无生存获益的患者接受过度治疗。笔者回顾性分析804例ⅢA-N2 NSCLC患者的临床资料,依据简单的术前临床资料,筛选能从PORT获益的亚组人群。
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PORT组和单纯化疗组患者的中位年龄分别为54.5岁和57.0岁,PORT组 < 60岁的患者更多(χ2=15.48,P < 0.001);化疗周期数为3~4个的患者亦更多(χ2=18.42,P<0.001),差异均有统计学意义。其余一般临床资料两组间差异无统计学意义(χ2=0.48~4.28,均P>0.05)。两组患者的一般临床资料见表 1。
临床因素 总例数(%) 单纯化疗组(%) PORT组(%) χ2值 P值 性别 男性 475(59.1) 300(56.8) 175(63.4) 2.99 0.084 女性 329(40.9) 228(43.2) 101(36.6) 年龄/岁 <60 519(64.6) 315(59.7) 204(73.9) 15.48 <0.001 ≥60 285(35.4) 213(40.3) 72(26.1) 吸烟 否 394(49.0) 269(50.9) 125(45.3) 2.10 0.147 是 410(51.0) 259(49.1) 151(54.7) 术前T分期 T1 257(32.0) 167(31.6) 90(32.6) 4.28 0.369 T2 431(53.5) 288(54.5) 143(51.9) T3 74(9.2) 51(9.7) 23(8.3) T4 7(0.9) 3(0.6) 4(1.4) Tx 35(4.4) 19(3.6) 16(5.8) 术前N分期 N0 340(42.3) 221(41.9) 119(43.1) 0.48 0.924 N1 73(9.1) 49(9.3) 24(8.7) N2 379(47.1) 251(47.5) 128(46.4) Nx 12(1.5) 7(1.3) 5(1.8) 病理类型 鳞癌 197(24.5) 129(24.4) 68(24.6) 1.36 0.508 腺癌 554(68.9) 368(69.7) 186(67.4) 其他 53(6.6) 31(5.9) 22(8.0) 化疗周期数 1~2 64(8.0) 56(10.6) 8(2.9) 18.42 <0.001 3~4 658(81.8) 412(78.0) 246(89.1) ≥5 40(5.0) 30(5.7) 10(3.6) 不详 42(5.2) 30(5.7) 12(4.3) 注:表中,PORT:术后放疗;NSCLC:非小细胞肺癌。 表 1 PORT组和单纯化疗组804例NSCLC患者的一般临床资料比较
Table 1. Comparison of general clinical data between non-postoperative radiotherapy group and postoperative radiotherapy group of 804 non-small-cell lung cancer patients
全组患者化疗周期数中位数为4周期。化疗开始日期距离手术日期的中位值为1.1个月,放疗开始日期距化疗开始日期的中位值为3.5个月。计划靶体积的处方剂量中位值为50 Gy(30~64 Gy),单次剂量中位值为2 Gy/次(1.8~2.2 Gy/次)。
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截至2017年6月30日,全组患者中位随访时间为32.07个月(2.50~133.98个月),中位生存时间为68.67个月,2年、5年总生存(overall survival,OS)分别为82.1%、54.5%,中位无病生存(disease-free survival, DFS)为19.84个月,中位无局部区域复发生存(locoregional recurrence-free survival, LRFS)为120.31个月,中位无远处转移生存(distant metastasis-free survival, DMFS)为30.52个月。
对与OS相关的多项临床因素(包括性别、年龄、吸烟状态、术前T分期、术前N分期、病理类型、化疗周期数、是否PORT)进行单因素分析,结果显示男性、年龄≥60岁、术前T分期增加、术前N分期为N1~N2、病理类型为非鳞癌非腺癌、化疗周期数为1~2、未行PORT是显著影响OS的不良预后因素(表 2)。
临床因素 例数(%) 中位生存
时间/月5年
OS/%χ2值 P值 性别 男性 475(59.1) 64.10 50.6 7.238 0.007 女性 329(40.9) 74.35 60.0 年龄/岁 <60 519(64.6) 85.29 58.7 9.131 0.003 ≥60 285(35.4) 55.29 46.7 吸烟 否 394(49.0) 68.67 55.9 2.720 0.099 是 410(51.0) 65.71 52.8 术前T分期 T1 257(32.0) 92.09 61.7 23.323 < 0.001 T2 431(53.6) 65.68 53.0 T3 74(9.2) 34.14 36.4 T4 7(0.9) - - Tx 35(4.4) 72.64 55.1 术前N分期 N0 340(42.3) 97.31 61.9 21.039 < 0.001 N1 73(9.1) 47.54 39.9 N2 379(47.1) 60.03 50.3 Nx 12(1.5) 68.67 58.3 病理类型 鳞癌 197(24.5) 91.14 55.7 18.024 < 0.001 腺癌 554(68.9) 68.67 54.9 其他 53(6.6) 34.04 38.0 化疗周期数 1~2 64(8.0) 33.68 33.4 21.134 < 0.001 3~4 658(81.8) 70.77 55.2 ≥5 40(5.0) - 63.9 不详 42(5.2) - 64.5 PORT 否 528(65.7) 64.10 50.8 5.253 0.022 是 276(34.3) 97.31 60.6 注:表中,pⅢA-N2:病理分期为ⅢA-N2;NSCLC:非小细胞肺癌;OS:总生存;PORT:术后放疗;“-”:无相关统计结果。 表 2 804例pⅢA-N2 NSCLC患者单因素预后分析结果
Table 2. Univariate analysis for overall survival of 804 pⅢA-N2 non-small-cell lung cancer patients
多因素分析结果显示性别、年龄、术前N分期、病理类型、是否PORT为OS相关的独立预后因素(表 3)。
影响因素 偏回归系数 偏回归系数标准误 Wald P值 OR值 OR值95%CI 性别 -0.418 0.183 5.196 0.023 0.658 0.460~0.943 年龄 -0.312 0.123 6.423 0.011 1.367 1.073~1.740 吸烟 -0.061 0.180 0.114 0.735 0.941 0.661~1.339 术前T分期 -0.114 0.059 3.719 0.054 1.121 0.998~1.259 术前N分期 -0.141 0.059 5.789 0.016 1.151 1.026~1.292 病理类型 -0.288 0.120 5.774 0.016 1.333 1.054~1.686 化疗周期数 -0.191 0.098 3.816 0.051 0.826 0.681~1.001 PORT -0.283 0.130 4.694 0.030 0.754 0.584~0.973 注:表中,pⅢA-N2:病理分期为ⅢA-N2;NSCLC:非小细胞肺癌;PORT:术后放疗。 表 3 804例pⅢA-N2 NSCLC患者Cox模型多因素预后分析结果
Table 3. Multivariate analysis for overall survival of 804 pⅢA-N2 non-small-cell lung cancer patients
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PORT组和单纯化疗组的中位OS、中位DFS、中位LRFS、中位DMFS分别为97.31和64.10个月(χ2=5.253,P=0.022)、25.76和17.97个月(χ2=18.397, P < 0.001)、120.31和101.03个月(χ2=15.358, P < 0.001)、36.83和28.49个月(χ2=6.434, P=0.011),PORT组的各生存参数均显著优于单纯化疗组,且差异有统计学意义(表 4)。
组别 OS DFS LRFS DMFS 中位值/月 2年/% 5年/% 中位值/月 2年/% 5年/% 中位值/月 2年/% 5年/% 中位值/月 2年/% 5年/% 非PORT组 64.10 80.0 50.8 17.97 42.1 21.5 101.03 71.9 59.0 28.49 54.3 30.6 PORT组 97.31 86.1 60.6 25.76 53.1 36.7 120.31 83.2 73.6 36.83 60.1 42.8 χ2值 5.253 18.397 15.358 6.434 P值 0.022 < 0.001 < 0.001 0.011 注:表中,pⅢA-N2:病理分期为ⅢA-N2;NSCLC:非小细胞肺癌;PORT:术后放疗;OS:总生存;DFS:无病生存;LRFS:无局部区域复发生存;DMFS:无远处转移生存。 表 4 804例pⅢA-N2 NSCLC患者PORT与生存相关性的单因素分析结果
Table 4. Stratified analysis for survive of 804 pⅢA-N2 non-small-cell lung cancer patients according to postoperative radiotherapy
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根据以下术前临床因素(包括性别、年龄、吸烟状态、肿瘤位置、术前T分期、术前N分期、术前分期、病理类型)进行预后因素的亚组分析,结果显示以下亚组行PORT能有OS获益(图 1),分别是:男性患者(HR:0.697,95%CI:0.513~0.947,P=0.021)(图 2),吸烟的患者(HR:0.648,95%CI:0.464~0.905,P=0.011)(图 3),术前N分期为N1~N2的患者(HR:0.640,95%CI:0.465~0.881,P=0.006)(图 4),术前分期为Ⅲ期的患者(HR:0.688,95%CI:0.484~0.980,P=0.038),以及病理类型为腺癌的患者(HR:0.726,95%CI:0.527~0.999,P=0.049)。
图 1 804例pⅢA-N2非小细胞肺癌患者PORT与生存相关性:术前临床因素亚组分析 图中,pⅢA-N2:病理分期为ⅢA-N2;PORT:术后放疗。
Figure 1. Correlation between postoperative radiotherapy and survival in 804 pⅢA-N2 NSCLC patients—subgroup analysis of preoperative clinical factors
图 2 PORT组和单纯化疗组pⅢA-N2非小细胞肺癌患者的OS曲线:不同性别的亚组分析 图中,OS:总生存;PORT:术后放疗;pⅢA-N2:病理分期为ⅢA-N2。
Figure 2. Overall survival curve for the postoperative radiothrapy and non-postoperative radiothrapy: subgroup analysis of different gender
术前临床因素预测pⅢA-N2非小细胞肺癌术后放疗获益人群的研究
Preoperative clinical risk factors in selecting patients with pathological ⅢA-N2 non-small-cell lung cancer benefiting from postoperative radiotherapy
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摘要:
目的分析病理分期为ⅢA-N2(pⅢA-N2)的非小细胞肺癌(NSCLC)患者行手术+辅助化疗后,加或不加术后放疗(PORT)的疗效,从术前临床因素中筛选能从PORT中获益的亚组人群。 方法回顾性分析2006年1月至2015年12月行根治性手术的pⅢA-N2 NSCLC患者804例。其中,PORT组患者276例,单纯化疗组528例。通过增强CT或者PET/CT获取准确的临床淋巴结分期。CT上淋巴结短径≥10 mm或者PET/CT上淋巴结SUV>2.5定义为转移淋巴结。PORT使用三维适形或调强放疗技术,计划靶体积的设计处方剂量为50~60 Gy,剂量分割为1.8~2.2 Gy/次。采用Log Rank法进行单因素预后分析,Cox回归进行多因素预后分析及亚组分析,通过Kaplan-Meier法和Log Rank检验评估PORT对总生存(OS)、无病生存(DFS)、无局部区域复发生存(LRFS)和无远处转移生存(DMFS)的影响,并进行亚组分析。 结果全组患者的中位随访时间为32.07个月。2年、5年OS分别为82.1%、54.5%,中位DFS为19.84个月,中位LRFS为120.31个月,中位DMFS为30.52个月。行PORT显著改善了OS(χ2=5.253,P=0.022)、DFS(χ2=18.397,P < 0.001)、LRFS(χ2=15.358,P < 0.001)和DMFS(χ2=6.434,P=0.011),且差异均有统计学意义。单因素分析结果显示,男性、年龄≥60岁、术前T分期增加、术前N分期为N1~N2、病理类型为非鳞癌非腺癌、化疗周期为1~2、未行PORT是显著影响OS的不良预后因素。多因素分析结果显示性别、年龄、术前N分期、病理类型、是否PORT为OS相关的独立预后因素;行PORT有OS获益的亚组分别为男性(HR:0.697,95% CI:0.513~0.947,P=0.021)、吸烟(HR:0.648,95% CI:0.464~0.905,P=0.011)、术前N分期为N1~N2(HR:0.640,95% CI:0.465~0.881,P=0.006)、临床分期为Ⅲ期(HR:0.688,95% CI:0.484~0.980,P=0.038)以及病理类型为腺癌(HR:0.726,95% CI:0.527~0.999,P=0.049)的患者。 结论PORT能改善全组患者的OS、DFS、LRFS和DMFS。部分术前临床因素具有预测PORT后有OS获益的亚组人群的价值,包括男性、吸烟、术前N分期为N1~N2、临床分期为Ⅲ期以及病理类型为腺癌的患者。 Abstract:ObjectivePathological ⅢA-N2 non-small-cell lung cancer (pⅢA-N2 NSCLC) is a heterogeneous population, and the role of postoperative radiotherapy(PORT) after the adjuvant chemotherapy (ACT) in pⅢA-N2 NSCLC remains ambiguous. Not all pⅢA-N2 patients can benefit from PORT. This study was performed to identify the subgroup that can benefit from PORT after ACT. MethodsThis study included 804 pⅢA-N2 NSCLC patients completing radical resection and ACT from January 2006 to December 2015. The patients were divided into two groups:PORT group, patients who underwent PORT after radical resection and ACT; and NON-PORT group, control group of patients who only underwent radical resection and ACT. The PORT and NON-PORT groups consisted of 276 and 528 patients, respectively. Accurate clinical lymph node staging was obtained through contrast-enhanced CT and/or PET/CT. Lymph nodes measured in the short axis ≥ 10 mm on CT or SUV>2.5 on PET/CT were considered as metastases. Using 3-dimensional conformal radiation therapy or intensity modulated radiation therapy techniques, PORT was administered at 1.8-2.2 Gy per fraction to a prescription dose to the planning target volume of 50-60 Gy. Outcome measures included overall survival(OS), disease-free survival(DFS), locoregional recurrence-free survival(LRFS), and distant metastasis-free survival(DMFS). Kaplan-Meier, Log Rank test, and Cox regression were used to analyze survival data and identify prognostic factors. Statistically significant difference was set to P < 0.05. ResultsMedian follow-up time was 32.07 months. The 2-year and 5-year OS of the patients in the entire cohort were 82.1% and 54.5%, respectively. The median values of the DFS, LRFS, and DMFS were 19.84, 120.31, and 30.52 months, respectively. In the overall study cohort, the median values of the OS(97.31 months vs. 64.10 months, χ2=5.253, P=0.022), DFS (25.76 months vs. 17.97 months, χ2=18.397, P < 0.001), LRFS(120.31 months vs. 101.03 months, χ2=15.358, P < 0.001) and DMFS(36.83 months vs. 28.49 months, χ2=6.434, P=0.011) were significantly higher in the PORT group than in the NON-PORT group. Univariate analysis showed that the adverse prognostic factors which significantly affected OS were:male, age ≥ 60 years, advanced preoperative T staging, preoperative N1-N2, non-squamous carcinoma and non-adenocarcinoma, 1-2 chemotherapy cycles and NON-PORT. Multivariate Cox analyses revealed that factors independently associated with longer OS were PORT(HR=0.754, 95%CI=0.584-0.973, P=0.03), female, age < 60 years, preoperative clinical N0, clinic stage Ⅰ-Ⅱ, adenocarcinoma, or squamous carcinoma. Subgroup analysis indicated that several preoperative clinical factors could predict the population that would benefit from PORT after ACT. These factors included male(HR=0.697, 95%CI=0.513-0.947, P=0.021), smoking patient(HR=0.648, 95%CI=0.464-0.905, P=0.011), preoperative clinical N1-N2(HR=0.640, 95%CI=0.465-0.881, P=0.006), clinic stage Ⅲ(HR=0.688, 95%CI=0.484-0.980, P=0.038), and adenocarcinoma(HR=0.726, 95%CI=0.527-0.999, P=0.049). ConclusionsPORT after ACT could significantly improve the 5-year OS, DFS, LRFS, and DMFS in pⅢA-N2 NSCLC patients. Moreover, PORT could improve the 5-year OS of the subgroups with the following characteristics:male, smoking patient, preoperative clinical N1-N2, clinic stage Ⅲ, and adenocarcinoma. -
Key words:
- Carcinoma, non-small-cell lung /
- Radiotherapy /
- Chemotherapy /
- Therapeutic evaluation
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表 1 PORT组和单纯化疗组804例NSCLC患者的一般临床资料比较
Table 1. Comparison of general clinical data between non-postoperative radiotherapy group and postoperative radiotherapy group of 804 non-small-cell lung cancer patients
临床因素 总例数(%) 单纯化疗组(%) PORT组(%) χ2值 P值 性别 男性 475(59.1) 300(56.8) 175(63.4) 2.99 0.084 女性 329(40.9) 228(43.2) 101(36.6) 年龄/岁 <60 519(64.6) 315(59.7) 204(73.9) 15.48 <0.001 ≥60 285(35.4) 213(40.3) 72(26.1) 吸烟 否 394(49.0) 269(50.9) 125(45.3) 2.10 0.147 是 410(51.0) 259(49.1) 151(54.7) 术前T分期 T1 257(32.0) 167(31.6) 90(32.6) 4.28 0.369 T2 431(53.5) 288(54.5) 143(51.9) T3 74(9.2) 51(9.7) 23(8.3) T4 7(0.9) 3(0.6) 4(1.4) Tx 35(4.4) 19(3.6) 16(5.8) 术前N分期 N0 340(42.3) 221(41.9) 119(43.1) 0.48 0.924 N1 73(9.1) 49(9.3) 24(8.7) N2 379(47.1) 251(47.5) 128(46.4) Nx 12(1.5) 7(1.3) 5(1.8) 病理类型 鳞癌 197(24.5) 129(24.4) 68(24.6) 1.36 0.508 腺癌 554(68.9) 368(69.7) 186(67.4) 其他 53(6.6) 31(5.9) 22(8.0) 化疗周期数 1~2 64(8.0) 56(10.6) 8(2.9) 18.42 <0.001 3~4 658(81.8) 412(78.0) 246(89.1) ≥5 40(5.0) 30(5.7) 10(3.6) 不详 42(5.2) 30(5.7) 12(4.3) 注:表中,PORT:术后放疗;NSCLC:非小细胞肺癌。 表 2 804例pⅢA-N2 NSCLC患者单因素预后分析结果
Table 2. Univariate analysis for overall survival of 804 pⅢA-N2 non-small-cell lung cancer patients
临床因素 例数(%) 中位生存
时间/月5年
OS/%χ2值 P值 性别 男性 475(59.1) 64.10 50.6 7.238 0.007 女性 329(40.9) 74.35 60.0 年龄/岁 <60 519(64.6) 85.29 58.7 9.131 0.003 ≥60 285(35.4) 55.29 46.7 吸烟 否 394(49.0) 68.67 55.9 2.720 0.099 是 410(51.0) 65.71 52.8 术前T分期 T1 257(32.0) 92.09 61.7 23.323 < 0.001 T2 431(53.6) 65.68 53.0 T3 74(9.2) 34.14 36.4 T4 7(0.9) - - Tx 35(4.4) 72.64 55.1 术前N分期 N0 340(42.3) 97.31 61.9 21.039 < 0.001 N1 73(9.1) 47.54 39.9 N2 379(47.1) 60.03 50.3 Nx 12(1.5) 68.67 58.3 病理类型 鳞癌 197(24.5) 91.14 55.7 18.024 < 0.001 腺癌 554(68.9) 68.67 54.9 其他 53(6.6) 34.04 38.0 化疗周期数 1~2 64(8.0) 33.68 33.4 21.134 < 0.001 3~4 658(81.8) 70.77 55.2 ≥5 40(5.0) - 63.9 不详 42(5.2) - 64.5 PORT 否 528(65.7) 64.10 50.8 5.253 0.022 是 276(34.3) 97.31 60.6 注:表中,pⅢA-N2:病理分期为ⅢA-N2;NSCLC:非小细胞肺癌;OS:总生存;PORT:术后放疗;“-”:无相关统计结果。 表 3 804例pⅢA-N2 NSCLC患者Cox模型多因素预后分析结果
Table 3. Multivariate analysis for overall survival of 804 pⅢA-N2 non-small-cell lung cancer patients
影响因素 偏回归系数 偏回归系数标准误 Wald P值 OR值 OR值95%CI 性别 -0.418 0.183 5.196 0.023 0.658 0.460~0.943 年龄 -0.312 0.123 6.423 0.011 1.367 1.073~1.740 吸烟 -0.061 0.180 0.114 0.735 0.941 0.661~1.339 术前T分期 -0.114 0.059 3.719 0.054 1.121 0.998~1.259 术前N分期 -0.141 0.059 5.789 0.016 1.151 1.026~1.292 病理类型 -0.288 0.120 5.774 0.016 1.333 1.054~1.686 化疗周期数 -0.191 0.098 3.816 0.051 0.826 0.681~1.001 PORT -0.283 0.130 4.694 0.030 0.754 0.584~0.973 注:表中,pⅢA-N2:病理分期为ⅢA-N2;NSCLC:非小细胞肺癌;PORT:术后放疗。 表 4 804例pⅢA-N2 NSCLC患者PORT与生存相关性的单因素分析结果
Table 4. Stratified analysis for survive of 804 pⅢA-N2 non-small-cell lung cancer patients according to postoperative radiotherapy
组别 OS DFS LRFS DMFS 中位值/月 2年/% 5年/% 中位值/月 2年/% 5年/% 中位值/月 2年/% 5年/% 中位值/月 2年/% 5年/% 非PORT组 64.10 80.0 50.8 17.97 42.1 21.5 101.03 71.9 59.0 28.49 54.3 30.6 PORT组 97.31 86.1 60.6 25.76 53.1 36.7 120.31 83.2 73.6 36.83 60.1 42.8 χ2值 5.253 18.397 15.358 6.434 P值 0.022 < 0.001 < 0.001 0.011 注:表中,pⅢA-N2:病理分期为ⅢA-N2;NSCLC:非小细胞肺癌;PORT:术后放疗;OS:总生存;DFS:无病生存;LRFS:无局部区域复发生存;DMFS:无远处转移生存。 -
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