| BackgroundCancer has become the leading cause and the major threats to Chinese people for its high morbidity and mortality. Lung cancer is the leading cause of cancer-related mortality in China, and has become one of the major threats to people. More than five million of people dead for lung cancer all over the world every year. Over the past 20 years, the incidence of lung cancer in China has increased significantly. The risk factors that can increase lung cancer include smoking, atmospheric pollution and occupational factors.According to the classification by WHO, lung cancer is divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC accounts for 85% of lung cancer cases. The survival of patients with lung cancer has been greatly improved After decades of exploration. However, the data from UICC (Union for International Cancer Control) in 2009 showed that the five year survival rate of lung cancer is still not optimistic at present. Complete resection is the only hope for long-term survival in patients with early and part of late stage of NSCLC.The discovery of driver genes has led to a new era in the treatment of lung cancer:the era of precision medicine. The emergence of targeted therapeutic drugs has greatly extended the survival of patients with lung cancer. The overall survival (OS) of advanced NSCLC was significantly different according to oncogenic drivers and genotape-directed therapy: the median survival was 3.5 years for patients with an oncogenic driver and genotape-directed therapy compared with 2.4 years for patients with oncogenic driver who did not receive genotape-directed therapy. However, the median survival was 2.1 years for patients without oncogenic driver. The prognosis of patients with lung cancer has been significantly improved on the base of molecular marker and targeted drug therapy. In clinical, the driver genes include EGFR (epidermal growth factor receptor), ALK (anaplasticlymphoma kinase) and c-MET and so on. Immune therapy has been getting better and better in recent years.In recent years, many scholars reported indolent tumors. Which refers to the natural course of tumor progression is very slow, with a volume double time more than 600 days. Even if without any systemic antitumor treatment, tumor will not progress or progress slowly, and the patients will achieve a long survival. About indolent tumor, there are many researches of prostate cancer and breast cancer at present, and with high reliability research results. In 2015, value of anticancer therapy by American Society of Clinical Oncology(ASCO) published in Journal of Clinical Oncology(JCO) told us that the success in anticancer therapy was not only the extend of overall survival,another criteria should also be considered. Treatment free interval(TFI) was one of five indicators, which was the time of follow-up without any therapy. The other four indicators were clinical benefit, toxicity, net health benefit and cost. If we could identify slow-growing lung cancer,follow-up would obtain the highest scores.With the progress of the physical examination technology, more and more small nodules were found in the lungs, including a special type of GGO (ground-glass opacity) lesions. The progression of pulmonary GGO was slow,5 years survival rate of lobe/ sublobe resection was close to 100%. Is there slow growing type in advanced NSCLC? In clinical, we also found that the progression of some patients with advanced lung cancer was relatively slow and the prognosis was good. This part of the patients were often with intrathoracic disseminated lesions, and with the characteristics of late appearance of lymph nodes and distant metastasis. The prognosis is still better than expected even without any systemic anti-tumor treatment, but the relevant prognostic factors and the specific mechanism are unknown.This study analysed the clinical, pathological and molecular characteristics of three different processes of intrathoracic disseminated lung cancer, and exploring its prognosis. To discuss the common characteristics of the slow growing intrathoracic disseminated lung cancer and the opportunity to intervene in the treatment, and explore the specific mechanism of good prognosis in patients with advanced lung cancer.Chapter 1 Accidental invisible Intrathoracic Disseminated pT4-Mla:A Distinct Lung Cancer with Favorable PrognosisObjectiveIn the 7th edition of the TNM classification of malignant tumors, the prognosis for pT4-Mla stage IV lung cancer is better than for stage pIIIB. Subgroups of lung cancer patients who underwent incomplete resection (R1/R2) have a favorable prognosis. This study compares the prognosis between cases of invisible local residual disease and intrathoracic disseminated pT4-M1aIV.MethodsPatient characteristics and histological and molecular profiles were retrospectively collected for lung cancer patients who underwent resection intended to be curative but was accidentally incomplete. All patients were divided into either a local residual group or an intrathoracic disseminated pT4Mla group. Progression-free survival (PFS) and overall survival (OS) were evaluated by Kaplan-Meier and Cox regression models.ResultsIn total,2187 consecutive lung cancer patients receiving thoracotomies at Guangdong Lung Cancer Institute were retrospectively analyzed. Seventy-seven patients receiving incomplete resections (R1/R2) were enrolled, including 45 patients with local residual cancer (2.1% of all patients) and 32 patients with disseminated pMla (1.5%). Patient characteristics, and histological and molecular profiles of the two groups were different. Compared to the local residual group, the disseminated pT4-M1a group contained more females (P=0.005), more patients younger than 60 years of age (P=0.013), more non-smokers (P=0.001), more adenocarcinomas (31/32 vs.25/45, P<0.001), higher CEA levels (P=0.020), higher EGFR mutation rates (24/32 vs.8/45, P<0.001), a higher R2/R1 resection ratio (P=0.013), a higher advanced stage Ⅳ/ⅢB ratio (P<0.001), but fewer lymph node metastases (P=0.013). Median PFS for the local residual and disseminated pT4-M1a groups was 9.8 and 21.2 months, respectively (95% CI,8.6-15.0, P=0.012). Median OS was 12.7 and 37.2 months, respectively (95% CI,15.4-37.8, P<0.001). Cox regression analysis revealed that group (local residual vs. disseminated pT4-M1a) was the only independent prognostic factor (P=0.047) for OS.ConclusionAccidental invisible intrathoracic disseminated pT4-Mla may be a distinct lung cancer subtype with a favorable prognosis. The prolonged PFS and OS might reflect the natural history of this distinct subtype, together with a favorable response to EGF receptor tyrosine kinase inhibitors (EGFR-TKI). For asymptomatic and slow-growing accidental pT4-M1a disease, the role of a wait-and-see strategy and the appropriate timing of systemic treatment require further investigation.Chapter 2 The clinical, pathological and molecular characteristics of postoperative recurrent M1a (rMla)ObjectiveTo investigate the clinical, pathological and molecular characteristics and the prognosis of postoperative recurrent M1a (rMla).MethodsPatients of postoperative recurrent M1a (r-M1a) were retrospectively collected. Including general data, pathological subtype, stage, N status, comprehensive treatment and molecular profiles. Progression-free survival (PFS) and overall survival (OS) were evaluated by Kaplan-Meier and Cox regression models. To explore the characteristics and the prognosis of postoperative rMla.ResultsFrom 2005.01 to 2009.12, postoperative recurrent M1a of Guangdong Lung Cancer Institute was 59 (2.4%), postoperative pathological stage of I/II/III was 30/8/21, respectively. The average progress to M1a was 25.0 months. From the progression of M1a, median OS(OS1) was 34.0 months (95%CI,26.4-41.6). And the total OS was 71.0 months (95%CI, 58.8-83.2). OS1 was similar to stage IB (31.0 months) of the 7th edition of the TNM classification of malignant tumors. Postoperative stage NO and N1/2 were 33 and 26, respectively. The average progress to M1a of these two groups was 23.0 VS 27.0 months (P=0.205). From the progression of M1a, median OS of these two groups was 39.0 VS 27.7 months (P=0.060). And the total OS of these two groups was 76.0 VS 61.0 months (P=0.341). Similarly, we collected 81 cases (3.3%) of postoperative recurrent Mlb from 2005.01 to 2009.12, from the progression of M1a or Mlb, the OS of these two groups was 34.6 VS 14.5 months (P<0.001).ConclusionrMla has a relative good prognosis in advanced NSCLC. Maybe a wait and see strategy could be adoptted.Chapter 3 The clinical, pathological and molecular characteristics of clinical diagnosis of Mla(cMla)ObjectiveTo investigate the clinical, pathological and molecular characteristics and the prognosis of clinical diagnosis of M1a (cM1a) with EGFR-TKI treatment.MethodsPatients of clinical diagnosis of M1a (cMla) with EGFR-TKI treatment were retrospectively collected. Including general data, pathological subtype, stage, N status, comprehensive treatment and molecular profiles. Progression-free survival (PFS) and overall survival (OS) were evaluated by Kaplan-Meier and Cox regression models. To explore the characteristics and the prognosis of cMla.ResultsFrom 2007.01 to 2012.12,388 consecutive lung cancer patients receiving TKI at Guangdong Lung Cancer Institute were analyzed. Finally,230 (59.3%) cases were enrolled. Median PFS of receiving TKI was 9.0 months, and median PFS for Iressa group (119) and Erlotinib group (111) was both 9.0 months (P=0.683). Median PFS for 76 cases was longer than 1 year, including 27 cases of M1a (35.5%); Median PFS for 27 cases of M1a and other 49 cases was 18.0 and 19.0 months, while median OS was 36.0 and 26.0 months, respectively (P=0.074). Median PFS for 16 cases was longer than 2 years, including 6 cases of M1a (37.5%).In our Institute, three modes of TKI resistance were found as follows:130 patients with dramatic progression,42 with gradual progression, and 55 with local progression. Median PFS for the dramatic progression, gradual progression, and local progression groups was 9.3, 12.9 and 9.2 months, respectively (P=0.007). Median OS was 17.1,39.4 and 23.1 months, respectively (P<0.001). However, M1a proportion of these three groups was 11/130,13/42 and 3/55 (P<0.001), gradual progression group had the most of M1a patients.ConclusionThe progression of M1a was relatively slow in advanced lung cancer. rM1a, sM1a, and cMla represent three different stages of intrathoracic disseminated lung cancer.Chapter 4 The characteristics and prognosis of slow growing intrathoracic disseminated M1aObjectiveThis study explores the characteristics and prognosis of slow growing intrathoracic disseminated M1a.MethodsPatient characteristics and histological and molecular profiles were retrospectively collected for the patients of intrathoracic disseminated M1a. Progression-free survival (PFS) and overall survival (OS) were evaluated by Kaplan-Meier and Cox regression models. To explore the characteristics and prognosis of slow growing intrathoracic disseminated M1a.ResultsIn total,91 intrathoracic disseminated M1a patients at Guangdong Lung Cancer Institute were retrospectively analyzed. Including 59 patients with rMla and 32 patients with sM1a. Clinical symptom was quantified based on EORTC QLQ-LC13, mainly including five parts:cough, hemoptysis, chest pain, fever and dyspnea. Firstly, Scores≤1 (group of mild symptom) and >1 (group of serious symptom) was quantified based on symptom, no recordance was the unknown group. The OS of mild symptom, unknown and serious symptom group was 39.0,34.9 and 21.8 months, respectively (95% CI,29.721-42.279, P=0.001). Secondly, dividing into small lesion group (thoracic lesions were all less than 1cm) and large lesion group (not all the thoracic lesions were less than 1cm) according to the imaging findings. No imaging recordance was the unknown group. The OS of small lesion, unknown and large lesion group was 39.0,34.9 and 18.2 months, respectively (95% CI,29.721-42.279, P=0.001). Thirdly, according to mild symptom and small lesion, we divided the patients into three groups of meet the two criteria, meet only one of the two criteria and not meet neither of the two criteria. The OS of these three groups was 41.9,32.6 and 21.8 months, respectively (95% CI,30.601-41.399, P<0.001). Cox regression analysis revealed that the size of thoracic lesions was the only independent prognostic factor (P=0.047) for OS.ConclusionThe progress is relatively slow and the prognosis is relatively good in the subgroup of small thoracic lesions and mild symptom of intrathoracic disseminated M1a. The characteristics of intrathoracic disseminated lung cancer in clinical and genetic aspects need further exploration. |
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