Abstract
背景与目的
急性炎症反应包括白细胞及急性期炎症蛋白的变化被较多研究证实是各种肿瘤包括非小细胞肺癌(non-small cell lung cancer), NSCLC的预后因素之一。本研究旨在观察Ⅰ期NSCLC患者术前C反应蛋白(C-reactive protein, CRP)水平与临床特征之间的关系及其预后意义。
方法
应用胶乳免疫透射比浊法计算血清CRP含量回顾性收集2000年1月-2004年1月间上海市长宁区中心医院及上海市胸科医院共96例完整手术切除的Ⅰ期NSCLC患者资料, 采用ANOVA检验分析不同临床特征的患者中CRP水平是否存在差异。采用Kaplan-Meier曲线及Logrank检验进行生存分析和比较, 并采用COX多因素回归分析与生存相关的因素。
结果
96例患者中CRP≤5 mg/L者66例。鳞癌(P < 0.001)、肿瘤直径 > 3 cm(P < 0.001)的患者CRP水平较高。多元线性回归分析提示肿瘤最大径与血清CRP水平相关(β=0.322, P=0.039)。CRP > 5 mg/L组患者的5年生存率低于CRP≤5 mg/L组(54.1% vs 78.2%, P=0.021)。COX分析表明CRP水平是影响Ⅰ期NSCLC患者总生存期的独立预后因素(P=0.023)。
结论
Ⅰ期NSCLC患者术前CRP水平与肿瘤最大径呈正相关CRP > 5 mg/L组患者的总生存期低于CRP≤5 mg/L组可能是影响患者预后的不良因素。
Keywords: 肺肿瘤, Ⅰ期, C反应蛋白, 手术, 预后
Abstract
Background and objective
The acute inflammatory, as manifest by alterations in white cell count and circulating concentrations of acute-phase proteins, C-reactive protein (CRP), and albumin, has been shown to be an independent prognostic factor in various cancers including non-small cell lung cancer (NSCLC). The aim of this study is to observe the relation between CRP level before operation and clinical characteristics of NSCLC stage Ⅰ, and its prognostic value.
Methods
Data of ninety-six NSCLC stage Ⅰ cases under total operational excision from Jan 2000 to Jan 2004 were reviewed. The difference of CRP level in different characteristics was analyzed by ANOVA. Distributions and comparisons of survival according to CRP level were analyzed by Kaplan-Meier and Log-rank test. COX regression model was used to analyze prognostic factors of NSCLC.
Results
Sixty-six cases had a CRP level of ≤5 mg/L. The level of CRP in patient with squamous cell carcinoma was remarkably higher than that with nonsquamous cell carcinoma (P < 0.001). The CRP level in tumor diameter > 3 cm was significantly higher than that in tumor diameter < 3 cm (P < 0.001). Multiple linear regression analysis suggested the maximum diameter of tumor was closely related to the level of serum CRP. The 5-year survival rate was lower in CRP > 5 mg/L group than that in CRP≤5 mg/L group (54.1% vs 78.2%, P=0.021). COX model found CRP level was an independent prognostic factor of stage Ⅰ NSCLC.
Conclusion
The pre-operational CRP level of stage Ⅰ NSCLC is positively related to the maximum diameter of tumor. CRP level is probably a poor prognostic factor for stage Ⅰ NSCLC.
Keywords: Lung neoplasms, Stage Ⅰ, C-reactive protein, Operation, Prognosis
血清C反应蛋白（C-reactive protein, CRP）是一种炎症急性时相的反应蛋白，主要在白介素-6（interleukin-6, IL-6）的介导下由肝脏产生[1]。近年来有大量的研究表明CRP在结直肠癌[2]、食管癌[3]等人类肿瘤中可作为发病风险和影响预后的指标。最近又有研究[4]表明在晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）中CRP水平也可作为患者的独立预后因素，但是否对早期手术的患者预后产生影响分析甚少。我们通过回顾性分析2000年1月-2004年1月上海市长宁区中心医院及上海市胸科医院接受手术治疗的Ⅰ期NSCLC患者的临床资料，旨在了解Ⅰ期NSCLC患者术前CRP水平与临床特征之间的关系以及对预后的影响。
1. 资料与方法
1.1. 临床资料
回顾性分析2000年1月-2004年1月上海市长宁区中心医院及上海市胸科医院接受手术治疗的共96例Ⅰ期NSCLC患者，平均年龄65岁（表 1）。术前分期工作包括：血液生化检查、胸部CT扫描、上腹部B超和CT、骨同位素扫描、纤维支气管镜检查、头颅CT或MRI检查。怀疑有远道转移的患者均排除在分析之外。所有患者均接受完整手术切除，支气管切断均为阴性。所有分期标准按照UICC第七版标准。
1.
纳入本研究患者的一般特征
General characteristics of patients included in this study
| Characteristic | n |
| Sex | |
| Male | 44 |
| Female | 52 |
| Pathological type | |
| Squamous cell carcinoma | 37 |
| Non-squamous cell carcinoma | 59 |
| Smoking | |
| Non-smoker | 55 |
| Smoker | 41 |
| Level of C-reactive protein (CRP) | |
| CRP ≤ 5 mg/L | 66 |
| CRP > 5 mg/L | 30 |
1.2. CRP水平检测
术前采外周静脉血5 mL，分离血清。采用胶乳免疫透射比浊法计算出CRP的含量。检测仪器为雅培公司生产的C8000型全自动生化分析仪。CRP正常范围：CRP≤5 mg/L。
1.3. 统计学处理
患者的数据以SPSS 13.0统计软件进行统计处理，用Kaplan-Meier进行生存分析，Log-rank检验分析生存差异，建立COX回归分析了解患者的预后相关因素。P < 0.05为差异有统计学意义。
2. 结果
2.1. 临床特征与CRP水平的相关性
96例患者中CRP≤5 mg/L者66例。鳞癌（P < 0.001）、肿瘤直径 > 3 cm（P < 0.001）的患者CRP水平较高（表 2）。将年龄、性别、吸烟史、病理类型、肿瘤最大径与CRP水平进行多元线性回归分析，结果提示肿瘤最大径与血清CRP水平相关（P=0.039）。
2.
不同临床特征血清CRP水平
Comparison of the level of serum CRP with different clinical characteristics
| Characteristic | CRP ≤ 5 mg/L (n=66) | CRP > 5 mg/L (n=30) | P |
| Age (year) | 0.642 | ||
| ≤ 65 | 35 | 16 | |
| > 65 | 31 | 14 | |
| Sex | 0.564 | ||
| Female | 31 | 19 | |
| Male | 35 | 11 | |
| Smoking | 0.264 | ||
| Smoker | 30 | 18 | |
| Non-smoker | 36 | 12 | |
| Pathological type | < 0.001 | ||
| Squamous cell carcinoma | 12 | 26 | |
| Non-squamous cell carcinoma | 54 | 4 | |
| Tumor max diameter (cm) | < 0.001 | ||
| ≤ 3 | 42 | 5 | |
| > 3 | 24 | 25 |
2.2. 生存分析
96例患者中CRP≤5 mg/L组66例，CRP > 5 mg/L组30例。随访终止时，死亡27人，其中CRP≤5 mg/L组9例，CRP > 5 mg/L组18例。两组总生存曲线见图 1，提示CRP > 5 mg/L组5年生存率明显低于CRP≤5 mg/L组（54.1% vs 78.2%, P=0.021）。COX多因素分析结果见表 3，提示CRP水平是影响总生存期的独立因素（P=0.023）。
1.
CRP > 5 mg/L组与CRP≤5 mg/L组患者的总生存期比较
Kaplan-Meier survival curve between CRP > 5 mg/L group and CRP≤5 mg/L group
3.
影响患者生存状况的多因素分析
Analysis survival condition affected by mutiple factors
| HR (95%CI) | P | |
| Age (year) | 0.220 | |
| ≤ 65 | ||
| > 65 | 2.207 (1.391-3.256) | |
| Sex | 0.230 | |
| Female | ||
| Male | 0.568 (0.354-1.107) | |
| Pathological type | 0.055 | |
| Squamous cell carcinoma | ||
| Non-squamous cell carcinoma | 0.568 (0.354-1.107) | |
| Smoking | 0.290 | |
| Non-smoker | ||
| Smoker | 1.468 (0.677-2.358) | |
| Tumor max diameter (cm) | 0.078 | |
| ≤ 3 | ||
| > 3 | 1.428 (0.987-2.549) | |
| Level of CRP | 0.023 | |
| CRP≤5 mg/L | ||
| CRP>5 mg/L | 2.428 (0.746-2.221) |
3. 讨论
参考文献CRP检测是一项有效的辅助检查指标，可用于感染的早期诊断和抗生素疗效的监测，被誉为炎症标志物而为人们所熟知。近年来研究[5]发现，血清中的CRP水平会随着炎症、损伤或肿瘤等各类疾病的变化而迅速增加或减少，因此可用于预测疾病的危险程度、跟踪病程、判断治疗效果和预后。研究[6]结果显示肺癌患者血清CRP水平的增高主要集中在有吸烟史的鳞癌患者。本研究发现男性、有吸烟史、鳞癌患者的CRP水平较高。考虑其原因是由于吸烟史的男性患者多为鳞癌，而鳞癌组织易坏死变性，且易出现阻塞性炎症，从而导致CRP水平的增高。
2009年出版的UICC第六版国际肺癌新分期标准中，肿瘤组织最大径成为影响患者分期以及预后的重要因素。而本研究结果发现CRP水平与肿瘤最大径正相关。这也预示着CRP水平对患者的预后也存在影响。通过对96例患者进行单因素分析，发现CRP > 5 mg/L组的患者其5年生存率明显低于CRP≤5 mg/L组（54.1% vs 78.2%, P=0.021）。有文献[7]指出肿瘤的进展以及预后与肿瘤以及自身的炎症反应有密切关系。有研究[8]表明大多数的实体上皮恶性肿瘤患者的体内存在炎症，有近半数的患者在诊断时可能存在有急性相反应，另外可能由于恶性肿瘤周边区巨噬细胞胞质或瘤细胞蛋白酶的释放，造成CRP合成的增加，最高可达300 mg/L。现研究[9]认为CRP的升高独立于肿瘤的分期之外可以作为许多类型的恶性肿瘤的预后因子。Kato等[10]研究发现治疗前浓度正常的CRP与增高的CRP患者的中位生存期存在明显差异(24. 9个月vs 3.7个月，P < 0.01)，提示CRP是晚期NSCLC生存预后的独立因素。国内学者潘建平等[11]对NSCLC患者的血清CRP水平与化疗疗效的相关性进行统计，其研究显示治疗有效组化疗后2周血清CRP浓度平均值下降了77.9%，而治疗无效组化疗前后血清CRP浓度平均值无明显变化。
本研究结果表明，肿瘤最大径是引起Ⅰ期NSCLC患者术前CRP水平增高的独立危险因素，CRP增高者5年生存率降低。提示对于接受手术治疗的Ⅰ期NSCLC患者，可以考虑通过术前血清CRP水平预测患者的临床特征并评价其预后，这无疑给临床提供了一个简便而又具有可重复性的方法。但本研究样本量较少，尚待前瞻性深入研究籍以进一步验证该指标的潜在价值。
References
- 1.Allin KH, Bojesen SE, Nordestgaard BG. Baseline C-reactive protein is associated with incident cancer and survival in patients with cancer. Clin Oncol. 2009;27(13):2217–2224. doi: 10.1200/JCO.2008.19.8440. [DOI] [PubMed] [Google Scholar]
- 2.Nozoe T, Matsumata T, Kitamura M, et al. Significance of preoperative elevation of serum C-reactive protein as an indicator for prognosis in colorectal cancer. Am J Surg. 1998;176(4):335–338. doi: 10.1016/S0002-9610(98)00204-9. [DOI] [PubMed] [Google Scholar]
- 3.Gockel I, Dirksen K, Messow CM, et al. Significance of preoperative C-reactive protein as a parameter of the perioperative course and longterm prognosis in squamous cell carcinoma and adenocarcinoma of the oesophagus. World J Gastroenterol. 2006;12(23):3746–3750. doi: 10.3748/wjg.v12.i23.3746. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Koch A, Fohlin H, Sorenson S, et al. Prognostic significance of C-reactive protein and smoking in patients with advanced non-small cell lung cancer treated with first-line palliative chemotherapy. J Thorac Oncol. 2009;4(3):326–332. doi: 10.1097/JTO.0b013e31819578c8. [DOI] [PubMed] [Google Scholar]
- 5.Forrest LM, McMillan DC, McArdle CS, et al. Evaluation of cumulative prognostic scores based on the systemic inflammatory response in patients with inoperable non-small-cell lung cancer. Br J Cancer. 2003;89(6):1028–1030. doi: 10.1038/sj.bjc.6601242. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Siemes C, Visser LE, Coebergh JW, et al. C-reactive protein levels, variation in the C-reactive protein gene, and cancer risk: The Rotterdam Study. Clin Oncol. 2006;24(33):5216–5222. doi: 10.1200/JCO.2006.07.1381. [DOI] [PubMed] [Google Scholar]
- 7.Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–867. doi: 10.1038/nature01322. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Kasprzyk M, Dyszkiewicz W, Zwarun D, et al. Assessment of acute phase proteins as prognostic factors in patients surgically treated for non-small cell lung cancer. http://pubmed.cn/26005016. Pneumonol Alergol Pol. 2008;76(5):321–326. [PubMed] [Google Scholar]
- 9.Caspers RJ, Pidcock NB, Cooper EH, et al. The prognostic significance of acute phase proteins in patients with inoperable squamous cell carcinoma of the bronchus. Radiother Oncol. 1984;2(2):107–113. doi: 10.1016/S0167-8140(84)80046-8. [DOI] [PubMed] [Google Scholar]
- 10.Kato K, Hitsuda Y, Kawasaki Y, et al. The value of serum C-reactive protein as a survival determinant in patients with advanced non-small-cell lung cancer. http://www.ncbi.nlm.nih.gov/pubmed/25450276. Nihon Kokyuki Gakkai Zasshi. 2000;38(8):575–580. [PubMed] [Google Scholar]
- 11.Pan JP, Zhai YC, Zhu WJ, et al. The study of the relationship with serum concentration of sICAM-1 and CRP on lung cancer. http://www.cnki.com.cn/Article/CJFDTOTAL-ZJYE200112006.htm Acta Zhejiang Univ (Med) 2000;29(4):149–150. [Google Scholar]; 潘 建平, 瞿 幼存, 祝 文炯, et al. 肺癌患者血清可溶性细胞间粘附分子21与C2反应蛋白浓度相关性研究. http://www.cnki.com.cn/Article/CJFDTOTAL-ZJYE200112006.htm 浙江大学学报(医学版) 2000;29(4):149–150. [Google Scholar]