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  • Title: [Long-term survival of personalized surgical treatment of locally advanced non-small cell lung cancer based on molecular staging].
    Author: Zhou Q, Shi Y, Chen J, Liu B, Wang Y, Zhu D, Zhang HT, Xu P, Gong Y, Chen G, Wei S, Qiu X, Niu Z, Chen X, Lei Z, Duan L, Wu Z.
    Journal: Zhongguo Fei Ai Za Zhi; 2011 Feb; 14(2):86-106. PubMed ID: 21342639.
    Abstract:
    BACKGROUND AND OBJECTIVE: Approximately 35%-40% of patients with newly diagnosed non-small cell Lung cancer have locally advanced disease. The average survival time of these patients only have 6-8 months with chemotherapy. The aim of this study is to explore and summarize the probability of detection of micrometastasis in peripheral blood for molecular staging, and for selection of indication of surgical treatment, and beneficiary of neoadjuvant chemotherapy and postoperative adjuvant therapy in locally advanced lung cancer; to summarize the long-time survival result of personalized surgical treatment of 516 patients with locally advanced non-small cell lung cancer based on molecular staging methods. METHODS: CK19 mRNA expression of peripheral blood samples was detected in 516 lung cancer patients by RT-PCR before operation for molecular diagnosis of micrometastasis, personalized molecular staging, and for selection of indication of surgical treatment and the beneficiary of neoadjuvant chemotherapy and postoperative adjuvant therapy in patients with locally advanced nonsmall cell lung cancer invaded heart, great vessels or both. The long-term survival result of personalized surgical treatment was retrospectively analyzed in 516 patients with locally advanced non-small cell lung cancer based on molecular staging methods. RESULTS: There were 322 patients with squamous cell carcinoma and 194 cases with adenocarcinoma in the series of 516 patients with locally advanced lung cancer involved heart, great vessels or both. There were 112 patients with IIIA disease and 404 cases with IIIB disease according to P-TNM staging. There were 97 patients with M-IIIA disease, 278 cases with M-IIIB disease and 141 cases with III disease according to our personalized molecular staging. Of the 516 patients, bronchoplastic procedures and pulmonary artery reconstruction was carried out in 256 cases; lobectomy combined with resection and reconstruction of partial left atrium was performed in 41 cases; Double sleeve lobectomy combined with resection and reconstruction of super vena cava was carried out in 90 cases; Lobectomy combined with resection and reconstruction of diaphragm was performed in 3 cases; Double sleeve lobectomy combined with resection and reconstruction of partial left atrium was performed in 30 cases; Bronchoplastic procedures and pulmonary artery reconstruction combined with reconstruction of aorta sheath was carried out in 10 cases; Right pneumonectomy combined with resection and reconstruction partial left atrium, total right diaphragm with Dacron, and post cava and right liver vein was performed in one case; Lobectomy combined with resection and reconstruction of carina was carried out in 10 cases; Bronchoplastic procedures and pulmonary artery reconstruction combined with resection and reconstruction of carina and superior vane cava, or combined with superior vena cava and left atrium, or with carina and left atrium was performed in 55 cases in this series. Five patients died of operative complications and the operative mortality was 0.97%. CK19 mRNA expression was found in 141 patients. The positive rate of CK19 mRNA expression was 27.3% in peripheral blood samples in the 516 cases. The positive rates of micrometastasis in peripheral blood was significantly related to histological classification, P-TNM staging and N staging of the cancer (P < 0.05), but not to age, sex, smoking status of the patients, and size of primary tumor, and locations of the tumor (P > 0.05). The median survival time was 43.74 months. The 1, 3, 5 and 10 year survival rates of the 516 cases was 89.1%, 39.3%, 19.8% and 10.4%, respectively. The postoperative survival rate was remarkably correlated with micrometastasis in peripheral blood, histological classification of the tumor, size of primary cancer and lymph mode involvement (P < 0.05). The results of multivariable Cox model analysis showed that "personalized molecular P-TNM staging", micrometastasis in peripheral blood, pathological types of the tumor and mediastinal lymph node metastasis of the cancer were the most significant factors for predicting prognosis in the patients with locally advanced nonsmall lung cancer. CONCLUSIONS: (1) Micrometastasis was existed in peripheral blood of patients with lung cancer, which can not be detected with conventional methods. (2) Detecting of CK19 mRNA expression in peripheral blood in lung cancer patients can be used for diagnosis of micrometastasis of lung cancer and "molecular staging" and "molecular P-TNM staging" for lung cancer patients. It will be helpful for selection of surgical treatment indication, the beneficiary of neoadjuvant chemotherapy and postoperative adjuvant therapy in the patients with locally advanced non-small cell lung cancer. (3) Personalized surgical treatment can significantly improve prognosis and increase curative rate and long-term survival rate of locally advanced nonsmall cell lung cancer based on personalized molecular staging. 背景与目的: 局部晚期肺癌约占肺癌的35%-40%，其内科治疗平均生存6-8个月。本研究的目的是探讨和总结检测肺癌病人外周血"微转移"，对局部晚期肺癌病人进行"分子分期"，指导选择局部晚期肺癌手术适应症、术前新辅助化疗和术后辅助治疗的受益者，以及对局部晚期肺癌进行"个体化外科治疗"的可行性及其对长期生存的影响。 方法: 应用RT-PCR检测516例局部晚期肺癌病人手术前外周血CK19 mRNA表达（其中115例行术前新辅助化疗者在新辅助化疗前后分别检测病人外周血"微转移"），对肺癌"微转移"进行"分子诊断"，对肺癌病人进行"个体化分子分期"，指导临床选择外科手术适应症、术前新辅助化疗和术后辅助治疗的获益者。回顾分析516例局部晚期肺癌基于"分子分期"的"个体化外科治疗"的长期生存结果。 结果: 516例病人中鳞癌322例，非鳞癌194例；P-TNM分期：ⅢA期112例，ⅢB期404例；"个体化分子P-TNM分期"：M-ⅢA期：97例，M-ⅢB期：278例，M-Ⅳ期：141例。本组病例行支气管肺动脉袖状成形肺叶切除256例；肺叶切除联合部分左心房切除重建41例；支气管肺动脉袖状成形联合上腔静脉切除重建90例；肺切除联合部分膈肌切除重建3例；支气管肺动脉袖状成形肺叶切除联合部分左心房切除重建30例；支气管肺动脉袖状成形联合主动脉鞘膜切除10例；右全肺切除联合左心房、右侧全部膈肌、下腔静脉和肝右静脉切除重建1例；肺切除联合气管隆突切除重建10例；支气管肺动脉袖状成形联合气管隆突切除重建和上腔静脉切除重建，或联合上腔静脉和左心房、或联合气管隆突和左心房切除重建55例。手术死亡5例，死亡率为0.97%。516例肺癌病人中141例外周血检测到CK19 mRNA表达，阳性率为27.3%。肺癌病人外周血微转移阳性率与肺癌组织学类型、P-TNM分期、N分期等均有密切关系（P < 0.05），但与患者年龄、性别、是否吸烟、原发肿瘤大小、肿瘤部位等均无明显关系（P > 0.05）。本组肺癌病人术后中位生存时间为43.74±7.21个月，1年生存率为89.1%，3年生存率为39.3%，5年生存率为19.8%，10年生存率为10.4%。术后生存率与外周血"微转移"、肺癌组织学类型、原发肿瘤大小和淋巴结转移有密切关系（P < 0.05）。Cox比例风险模型显示"个体化"分子P-TNM分期、外周血"微转移"、病理类型和N分期是预测局部肺癌预后的独立因素。 结论: （1）肺癌病人外周血中存在用常规方法不能检测得到的"微转移"；（2）检测肺癌病人外周血中CK19 mRNA表达应用于肺癌微转移的"分子诊断"和"分子分期，有助于指导选择外科手术适应症、术前新辅助化疗和术后辅助治疗的受益者；（3）基于"分子分期"的局部晚期肺癌的"个体化外科治疗"能明显改善病人的预后，提高治愈率和长期生存率。
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