-
肺癌是各种癌症相关死亡的首要原因[1-2]。其中小细胞肺癌(small cell lung cancer, SCLC)恶性程度高,占比10%~15%。该类肿瘤生长快速,早期容易出现远处转移,具有高度侵袭性和致命性,这些特点导致大多数SCLC病人在确诊时已处于疾病晚期阶段,预后极差[3]。近年来,PD-L1抑制剂如Atezolizumab、Durvalumab让广泛期小细胞肺癌(ES-SCLC)的治疗有了一些突破[4-5],但由于该类制剂在中国上市较国外晚,且上市后价格昂贵,导致单纯化疗在一段时间内将仍然是ES-SCLC的主流方案。一线化疗是该类疾病的基石,但有效的疗效预测方法和预后判断生物标志物的缺乏在一定程度上限制了病人的获益。近年来,免疫炎症指标淋巴细胞-单核细胞比值(lymphocyte to monocyte ratio, LMR)协助判断包括SCLC在内的多种恶性肿瘤的疗效和预后的作用被多项研究[6-10]所证实。其中GO等[9]发现,诊断时的LMR可预测在接受一线化疗或放化疗的SCLC病人的疗效和预后,但该研究没有对局限期和广泛期SCLC进行区分。QI等[11]在研究基线LMR对使用免疫联合化疗治疗ES-SCLC病人预后预测价值时发现,LMR并不是其独立预后因素。可见,LMR在ES-SCLC病人中的临床价值值得进一步探索。本研究选择接受一线化疗的ES-SCLC病人,探讨LMR对病人一线化疗疗效及生存的预测价值。
-
纳入ES-SCLC病人共50例,年龄45~88岁,男45例(90%)。基线LMR与病人是否患有低蛋白血症和骨转移有关(P < 0.05);而年龄、性别、吸烟状况、ECOG评分、有无肺部炎症、有无浆膜腔积液、有无脏器、脑以及肝转移均与基线LMR无关(P>0.05)(见表 1)。
变量 n LMR t P 性别 男
女45
53.04±1.15
2.87±1.710.30 >0.05 年龄/岁 ≤60
>6017
333.08±1.21
2.99±1.210.23 >0.05 吸烟 否
是34
163.21±1.19
2.63±1.161.61 >0.05 ECOG评分/分 0~1
232
183.19±1.16
2.72±1.241.37 >0.05 白蛋白/(g/L) < 35.0
≥35.07
432.12±0.77
3.17±1.202.24 < 0.05 肺部炎症 否
是16
342.76±1.07
3.15±1.251.06 >0.05 浆膜腔积液 否
是24
263.33±1.10
2.74±1.241.79 >0.05 脏器转移 否
是15
353.26±1.17
2.92±1.210.91 >0.05 脑转移 否
是39
112.96±1.25
3.26±1.030.73 >0.05 肝转移 否
是28
223.15±1.14
2.86±1.280.84 >0.05 骨转移 否
是28
223.32±1.08
2.64±1.262.05 < 0.05 表 1 ES-SCLC病人基线血清LMR与临床特征的关系(x±s)
-
50例ES-SCLC病人一线化疗后,CR 0例,PR 25例,SD 18例,PD 7例。ORR为50.0%,DCR为86.0%。LMR最佳截断值为3.08,高LMR组22例,化疗疗效评价为CR或PR的病人15例,PD或SD为7例;低LMR组28例,化疗疗效评价为CR或PR的病人10例,PD或SD为18例。分析发现,基线LMR越高,一线化疗疗效越好(χ2=5.20,P < 0.05)(见表 2)。
分组 n PD+SD PR+CR χ2 P 低LMR组 28 18 10 高LMR组 22 7 15 5.20 < 0.05 合计 50 25 25 表 2 ES-SCLC病人基线血清LMR与一线化疗疗效的关系(n)
-
50例病人中位PFS为7.4个月。LMR最佳截断值为3.16,其中高LMR组20例,低LMR组30例,中位PFS分别为9.0个月与5.8个月。生存结果分析提示,PFS在高、低LMR组间差异有统计学意义(χ2=4.50, P < 0.05)(见图 1)。单因素Cox回归分析表明,有无脏器转移和基线LMR与PFS相关(P < 0.05)(见表 3)。将有无脏器转移和基线LMR纳入多因素Cox回归分析,结果显示,有无脏器转移和基线LMR均是ES-SCLC病人PFS的独立预测因素(P < 0.05)(见表 4)。
变量 B SE Waldχ2 P HR(95%CI) 性别 -0.842 0.488 2.98 >0.05 0.431(0.165~1.122) 年龄 -0.214 0.361 0.35 >0.05 0.808(0.398~1.638) 吸烟 0.006 0.342 0.00 >0.05 1.006(0.515~1.966) ECOG评分 0.069 0.338 0.04 >0.05 1.071(0.552~2.077) 白蛋白 -0.846 0.453 3.48 >0.05 0.429(0.177~1.044) 肺部炎症 0.048 0.393 0.02 >0.05 1.049(0.485~2.268) 浆膜腔积液 -0.105 0.323 0.11 >0.05 0.900(0.478~1.697) 脏器转移 0.897 0.412 4.74 < 0.05 2.451(1.093~5.496) 脑转移 0.056 0.402 0.02 >0.05 1.057(0.481~2.327) 肝转移 0.411 0.331 1.54 >0.05 1.508(0.788~2.886) 骨转移 -0.608 0.339 3.21 >0.05 0.545(0.280~1.058) LMR -0.722 0.348 4.30 < 0.05 0.486(0.246~0.961) 表 3 ES-SCLC病人PFS的单因素Cox回归分析
变量 B SE Waldχ2 P HR(95%CI) 脏器转移 0.867 0.408 4.52 < 0.05 2.381(1.070~5.297) LMR -0.698 0.347 4.05 < 0.05 0.498(0.252~0.982) 表 4 ES-SCLC病人PFS的多因素Cox回归分析
-
50例病人中位OS为11.0个月。LMR最佳截断值为3.16,其中高LMR组20例,低LMR组30例,中位OS分别为18.5个月和9.7个月。生存结果分析提示,OS在高、低LMR组间差异有统计学意义(χ2=8.47, P < 0.01)(见图 2)。单因素Cox分析显示,性别、有无脏器转移和基线LMR与OS相关(P < 0.05~P < 0.01)(见表 5)。将性别、有无脏器转移和基线LMR纳入多因素Cox回归分析,结果显示,性别、有无脏器转移和基线LMR均是ES-SCLC病人OS的独立预测因素(P < 0.05~P < 0.01)(见表 6)。
变量 B SE Waldχ2 P HR(95%CI) 性别 -1.54 0.524 8.63 < 0.01 0.214(0.077~0.599) 年龄 -0.127 0.395 0.10 >0.05 0.881(0.406~1.910) 吸烟 -0.069 0.355 0.04 >0.05 0.933(0.466~1.871) ECOG评分 0.096 0.354 0.07 >0.05 1.101(0.550~2.205) 白蛋白 -0.381 0.464 0.67 >0.05 0.683(0.275~1.696) 肺部炎症 -0.122 0.439 0.08 >0.05 0.885(0.374~2.092) 浆膜腔积液 -0.364 0.353 1.06 >0.05 0.695(0.348~1.388) 脏器转移 0.869 0.441 3.88 < 0.05 2.384(1.004~5.663) 脑转移 0.126 0.429 0.09 >0.05 1.135(0.490~2.628) 肝转移 0.495 0.37 1.79 >0.05 1.641(0.794~3.388) 骨转移 0.033 0.353 0.01 >0.05 1.034(0.518~2.063) LMR -1.084 0.387 7.86 < 0.01 0.338(0.158~0.722) 表 5 ES-SCLC病人OS的单因素Cox回归分析
变量 B SE Waldχ2 P HR(95%CI) 性别 -1.253 0.522 5.77 < 0.05 0.286(0.103~0.794) 脏器转移 1.006 0.453 4.94 < 0.05 2.735(1.126~6.644) LMR -1.130 0.406 7.74 < 0.01 0.323(0.146~0.716) 表 6 ES-SCLC病人OS的多因素Cox回归分析
LMR对广泛期小细胞肺癌一线化疗疗效和预后的预测价值
Value of LMR in predicting the efficacy of first-line chemotherapy and prognosis for extensive-stage small cell lung cancer
-
摘要:
目的探讨免疫炎症指标淋巴细胞-单核细胞比值(LMR)预测广泛期小细胞肺癌(ES-SCLC)病人一线化疗疗效和预后的价值。 方法回顾性收集符合本研究纳入标准的ES-SCLC病人临床资料, 计算LMR, 应用ROC曲线选择最佳截断值, 分为高LMR组和低LMR组, 分析2组一线化疗疗效、无进展生存时间(PFS)和总生存时间(OS)的差异。 结果共纳入50名ES-SCLC病人, 临床特征分析提示, 基线LMR与病人是否患有低蛋白血症和骨转移有关(P < 0.05)。高、低LMR组客观缓解率分别为68.2%和35.7%, 疾病控制率分别为90.9%和82.1%;基线LMR越高, 化疗疗效越好(P < 0.05)。高低2组中位PFS分别为9.0个月与5.8个月, 中位OS分别为18.5个月与9.7个月。Cox回归分析提示, 基线LMR是ES-SCLC病人一线治疗PFS和OS的独立预测因素(P < 0.05~P < 0.01)。 结论LMR有望成为评估ES-SCLC病人一线化疗应答和预后的新指标, 低LMR病人的疗效和预后较差。 -
关键词:
- 小细胞肺癌 /
- 广泛期 /
- 淋巴细胞-单核细胞比值 /
- 一线化疗 /
- 预后
Abstract:ObjectiveTo investigate the value of immune-inflammation index lymphocyte to monocyte ratio (LMR) in predicting the efficacy of first-line chemotherapy and also the prognosis in patients with extensive-stage small cell lung cancer (ES-SCLC). MethodsThe clinical data of ES-SCLC patients eligible for the inclusion criteria of this study were retrospectively collected.The LMR value were calculated, and the optimal cut-off value was selected based on receiver operating characteristic (ROC) curve.The patients were then divided into high- and low-LMR groups.The efficacy and progression-free survival (PFS) of first-line chemotherapy, and overall survival (OS) of patients in high- and low-LMR groups were finally analyzed. ResultsA total of 50 patients with ES-SCLC were included and divided into high- and low-LMR groups.Analyses of clinical characteristics showed that baseline LMR was associated with hypoproteinemia and bone metastasis(P < 0.05).The objective response rates were 68.2% and 35.7%, and the disease control rates were 90.9% and 82.1%, in patients in high- and low-LMR groups, respectively.Better efficacy of first-line chemotherapy can be achieved in patients with higher baseline LMR (P < 0.05).The median PFS in the high- and low-LMR groups were 9.0 and 5.8 months, and the median OS were 18.5 and 9.7 months, respectively.The Cox regression analyses results showed that LMR is an independent predictor of both PFS and OS in ES-SCLC patients treated with first-line chemotherapy(P < 0.05 to P < 0.01). ConclusionsLMR has the potential to sever as a new predictor of the treatment response of first-line chemotherapy and prognosis for patients with ES-SCLC, and the population with low LMR value tend to demonstrate poor efficacy and prognosis. -
表 1 ES-SCLC病人基线血清LMR与临床特征的关系(x±s)
变量 n LMR t P 性别 男
女45
53.04±1.15
2.87±1.710.30 >0.05 年龄/岁 ≤60
>6017
333.08±1.21
2.99±1.210.23 >0.05 吸烟 否
是34
163.21±1.19
2.63±1.161.61 >0.05 ECOG评分/分 0~1
232
183.19±1.16
2.72±1.241.37 >0.05 白蛋白/(g/L) < 35.0
≥35.07
432.12±0.77
3.17±1.202.24 < 0.05 肺部炎症 否
是16
342.76±1.07
3.15±1.251.06 >0.05 浆膜腔积液 否
是24
263.33±1.10
2.74±1.241.79 >0.05 脏器转移 否
是15
353.26±1.17
2.92±1.210.91 >0.05 脑转移 否
是39
112.96±1.25
3.26±1.030.73 >0.05 肝转移 否
是28
223.15±1.14
2.86±1.280.84 >0.05 骨转移 否
是28
223.32±1.08
2.64±1.262.05 < 0.05 表 2 ES-SCLC病人基线血清LMR与一线化疗疗效的关系(n)
分组 n PD+SD PR+CR χ2 P 低LMR组 28 18 10 高LMR组 22 7 15 5.20 < 0.05 合计 50 25 25 表 3 ES-SCLC病人PFS的单因素Cox回归分析
变量 B SE Waldχ2 P HR(95%CI) 性别 -0.842 0.488 2.98 >0.05 0.431(0.165~1.122) 年龄 -0.214 0.361 0.35 >0.05 0.808(0.398~1.638) 吸烟 0.006 0.342 0.00 >0.05 1.006(0.515~1.966) ECOG评分 0.069 0.338 0.04 >0.05 1.071(0.552~2.077) 白蛋白 -0.846 0.453 3.48 >0.05 0.429(0.177~1.044) 肺部炎症 0.048 0.393 0.02 >0.05 1.049(0.485~2.268) 浆膜腔积液 -0.105 0.323 0.11 >0.05 0.900(0.478~1.697) 脏器转移 0.897 0.412 4.74 < 0.05 2.451(1.093~5.496) 脑转移 0.056 0.402 0.02 >0.05 1.057(0.481~2.327) 肝转移 0.411 0.331 1.54 >0.05 1.508(0.788~2.886) 骨转移 -0.608 0.339 3.21 >0.05 0.545(0.280~1.058) LMR -0.722 0.348 4.30 < 0.05 0.486(0.246~0.961) 表 4 ES-SCLC病人PFS的多因素Cox回归分析
变量 B SE Waldχ2 P HR(95%CI) 脏器转移 0.867 0.408 4.52 < 0.05 2.381(1.070~5.297) LMR -0.698 0.347 4.05 < 0.05 0.498(0.252~0.982) 表 5 ES-SCLC病人OS的单因素Cox回归分析
变量 B SE Waldχ2 P HR(95%CI) 性别 -1.54 0.524 8.63 < 0.01 0.214(0.077~0.599) 年龄 -0.127 0.395 0.10 >0.05 0.881(0.406~1.910) 吸烟 -0.069 0.355 0.04 >0.05 0.933(0.466~1.871) ECOG评分 0.096 0.354 0.07 >0.05 1.101(0.550~2.205) 白蛋白 -0.381 0.464 0.67 >0.05 0.683(0.275~1.696) 肺部炎症 -0.122 0.439 0.08 >0.05 0.885(0.374~2.092) 浆膜腔积液 -0.364 0.353 1.06 >0.05 0.695(0.348~1.388) 脏器转移 0.869 0.441 3.88 < 0.05 2.384(1.004~5.663) 脑转移 0.126 0.429 0.09 >0.05 1.135(0.490~2.628) 肝转移 0.495 0.37 1.79 >0.05 1.641(0.794~3.388) 骨转移 0.033 0.353 0.01 >0.05 1.034(0.518~2.063) LMR -1.084 0.387 7.86 < 0.01 0.338(0.158~0.722) 表 6 ES-SCLC病人OS的多因素Cox回归分析
变量 B SE Waldχ2 P HR(95%CI) 性别 -1.253 0.522 5.77 < 0.05 0.286(0.103~0.794) 脏器转移 1.006 0.453 4.94 < 0.05 2.735(1.126~6.644) LMR -1.130 0.406 7.74 < 0.01 0.323(0.146~0.716) -
[1] SIEGEL RL, MILLER KD, FUCHS HE, et al. Cancer statistics, 2022[J]. CA Cancer J Clin, 2022, 72(1): 7. doi: 10.3322/caac.21708 [2] XIA C, DONG X, LI H, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants[J]. Chin Med J (Engl), 2022, 135(5): 584. doi: 10.1097/CM9.0000000000002108 [3] BERNHARDT EB, JALAL SI. Small cell lung cancer[J]. Cancer Treat Res, 2016, 170: 301. [4] GOLDMAN JW, DVORKIN M, CHEN Y, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial[J]. Lancet Oncol, 2021, 22(1): 51. doi: 10.1016/S1470-2045(20)30539-8 [5] HORN L, MANSFIELD AS, SZCZESNA A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer[J]. N Engl J Med, 2018, 379(23): 2220. doi: 10.1056/NEJMoa1809064 [6] 柴广金, 李围围, 吕博, 等. PET/CT代谢参数与LMR在评估肺癌放化疗近期疗效的临床研究[J]. 中国CT和MRI杂志, 2021, 19(8): 54. doi: 10.3969/j.issn.1672-5131.2021.08.017 [7] KURAMOCHI H, YAMADA T, YOSHIDA Y, et al. The Pre-treatment lymphocyte-to-monocyte ratio predicts efficacy in metastatic colorectal cancer treated with TAS-102 and bevacizumab[J]. Anticancer Res, 2021, 41(6): 3131. doi: 10.21873/anticanres.15098 [8] MENG X, WANG X, JIANG C, et al. Correlation analysis of lymphocyte-monocyte ratio with pathological complete response and clinical prognosis of neoadjuvant chemotherapy in patients with breast cancer[J]. Transl Oncol, 2022, 18: 101355. doi: 10.1016/j.tranon.2022.101355 [9] GO SI, KIM RB, SONG HN, et al. Prognostic significance of the lymphocyte-to-monocyte ratio in patients with small cell lung cancer[J]. Med Oncol, 2014, 31(12): 323. doi: 10.1007/s12032-014-0323-y [10] 刘建清, 林秀华, 沈志勇. 淋巴细胞与单核细胞比值对晚期肺癌预后预测的价值[J]. 现代肿瘤医学, 2018, 26(11): 1706. doi: 10.3969/j.issn.1672-4992.2018.11.015 [11] QI WX, XIANG Y, ZHAO S, et al. Assessment of systematic inflammatory and nutritional indexes in extensive-stage small-cell lung cancer treated with first-line chemotherapy and atezolizumab[J]. Cancer Immunol Immunother, 2021, 70(11): 3199. doi: 10.1007/s00262-021-02926-3 [12] CHENG Y, FAN Y, LIU X, et al. Randomized controlled trial of lobaplatin plus etoposide vs. cisplatin plus etoposide as first-line therapy in patients with extensive-stage small cell lung cancer[J]. Oncol Lett, 2019, 17(5): 4701. [13] FRIDMAN WH, GALON J, DIEU-NOSJEAN MC, et al. Immune infiltration in human cancer: prognostic significance and disease control[J]. Curr Top Microbiol Immunol, 2011, 344: 1. [14] 麦晓君, 周凤丽. 肺癌微环境细胞分类研究进展[J]. 中国免疫学杂志, 2020, 36(13): 1661. doi: 10.3969/j.issn.1000-484X.2020.13.025 [15] SUZUKI R, LIN SH, WEI X, et al. Prognostic significance of pretreatment total lymphocyte count and neutrophil-to-lymphocyte ratio in extensive-stage small-cell lung cancer[J]. Radiother Oncol, 2018, 126(3): 499. doi: 10.1016/j.radonc.2017.12.030 [16] CAMPIAN JL, YE X, BROCK M, et al. Treatment-related lymphopenia in patients with stage Ⅲ non-small-cell lung cancer[J]. Cancer Invest, 2013, 31(3): 183. doi: 10.3109/07357907.2013.767342 [17] SAITO H, KONO Y, MURAKAMI Y, et al. Prognostic significance of pre- and postoperative lymphocyte counts in patients with gastric cancer[J]. Dig Surg, 2019, 36(2): 137. doi: 10.1159/000486581 [18] TALMOR M, MIRZA A, TURLEY S, et al. Generation or large numbers of immature and mature dendritic cells from rat bone marrow cultures[J]. Eur J Immunol, 1998, 28(3): 811. doi: 10.1002/(SICI)1521-4141(199803)28:03<811::AID-IMMU811>3.0.CO;2-S [19] SCHOPPMANN SF, BIRNER P, STÖCKL J, et al. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis[J]. Am J Pathol, 2002, 161(3): 947. doi: 10.1016/S0002-9440(10)64255-1 [20] 吴婧婧, 孙妩弋, 魏伟. 肝细胞癌中M2巨噬细胞标志物与NF-κB p50相关性研究[J]. 蚌埠医学院学报, 2019, 44(4): 421. [21] COUSSENS LM, WERB Z. Inflammation and cancer[J]. Nature, 2002, 420(6917): 860. doi: 10.1038/nature01322 [22] MINAMI S, OGATA Y, IHARA S, et al. Pretreatment Glasgow prognostic score and prognostic nutritional index predict overall survival of patients with advanced small cell lung cancer[J]. Lung Cancer (Auckl), 2017, 8: 249. [23] 许文娟, 马莹, 王译民, 等. 预后营养指数预测小细胞肺癌预后的临床应用研究[J]. 四川大学学报(医学版), 2020, 51(4): 573. [24] KUWADA K, KAGAWA S, YOSHIDA R, et al. The epithelial-to-mesenchymal transition induced by tumor-associated macrophages confers chemoresistance in peritoneally disseminated pancreatic cancer[J]. J Exp Clin Cancer Res, 2018, 37(1): 307. doi: 10.1186/s13046-018-0981-2 [25] 唐和孝, 白玉泉, 申武林, 等. 白介素6在肺癌中的作用研究进展[J]. 浙江大学学报(医学版), 2018, 47(6): 659. [26] MIYAHARA Y, TAKASHI S, SHIMIZU Y, et al. The prognostic impact of neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) in patients with distal bile duct cancer[J]. World J Surg Oncol, 2020, 18(1): 78. doi: 10.1186/s12957-020-01847-2 [27] MILLER RE, JONES JC, TOMETSKO M, et al. RANKL inhibition blocks osteolytic lesions and reduces skeletal tumor burden in models of non-small-cell lung cancer bone metastases[J]. J Thorac Oncol, 2014, 9(3): 345. doi: 10.1097/JTO.0000000000000070