Determinants Of Long-term Survival After Radical Surgery For Non-small Cell Lung Cancer

Introduction:Lung cancer represents the leading cause of cancer mortality worldwide. Despite improvements in preoperative staging, surgical techniques, neoadjuvant/adjuvant options and postoperative care, there are still major difficulties in significantly improving survival, especially in locally advanced non-small cell lung cancer (NSCLC).Prognostic factor information is important for the stratification of patients in clinical trial protocols and for the individualization of a patient care plan. Previous research identified several elements, including, performance status (PS), clinical signs and symptoms (eg, related to anorexia, weight loss, dyspnea, and dysphagia), and biological factors (eg, leukocytosis, lymphocytopenia, and C-reactive protein), which are associated with differential treatment response and/or outcomes in NSCLC.Complete surgical and loco-regional lymph-nodes represents the standard of care for the NSCLC patients. After surgical resection, defining the stage of a malignant disease is key for planning therapy, estimating prognosis and for comparison of studies. The extent of lymph node involvement in patients with NSCLC is the most important prognostic factor and influences therapeutic strategies.Age was also an important consideration when selecting therapy. Comorbid illness and adverse medical conditions due to aging is a significant concern to treat elderly patients with lung cancer. Lobectomy remains the standard of care for optimal oncologic resection for early-stage NSCLC despite advances in chemotherapy and radiation therapy. However, a number of current investigations have found sublobectomy may achieve equivalent recurrence and survival compared with lobectomy for patients with stage IA NSCLC, furthermore, controversy remains as to whether sublobar resections are adequate oncologic procedures for patients with severely impaired pulmonary function who could not withstand lobectomy, especially for elderly patients.In addition, sex was also one of the most consistently explored factors in studies assessing prognostic or predictive factors. Women were more likely to develop lung cancer when consuming the same amount of cigarettes compared to men and women non-smokers are at a 2.5-fold greater risk than male non-smokers for developing lung adenocarcinoma (AC). Estrogen has been proposed to be responsible for such gender difference. Although lung was not the main target organ of estrogen, there were increasing reports suggesting that estrogen involved in the development of normal lung tissue as well as lung cancer.. In the present study, we’ll analysis the effort of lymph node ratio and surgery types for the long-term survival in non-small cell lung cancer, explore the ERa36 expression and prognostic value of ERa36 NSCLC. This information can be used to inform planning therapy and estimating prognosis for NSCLC.CHAPTER I The prognostic value of ratio based lymph node staging in resected non-small cell lung cancerBackground:Assessment of lymph node status is a critical issue in the surgical management of non-small cell lung cancer (NSCLC). In the latest TNM classification, the nodal system in lung cancer is still based on the anatomical location of involved LNs. However, there is also growing evidence establishing the prognostic role of the number of metastatic lymph node and LNR in NSCLC. In this retrospective study, we aimed to further evaluate the importance of LNR as a prognostic factor on the survival of patients with resectable NSCLC, and to compare its prognostic power against other methods, such as the traditional pN staging and the number of metastatic lymph nodes resected.Methods:We abstracted data from 480 consecutive patients undergoing radical surgery for non-small cell lung cancer between 2006 and 2008 in our institution. For the metastatic lymph node (MLN) and LNR, the’optimal’ cutoff values were determined using x2 scores, which were calculated using the Cox proportional hazards regression model. Kaplan-Meier estimated the survival function using the number of MLN and LNR as categorized variables. The prognostic value of age, sex, smoking status, location of tumor, histology, pathology T stage, pathology N stage, surgical procedure, chemotherapy, MLN and LNR were assessed using a multivariate Gox proportional hazards model for overall survival(OS) and disease-free survival(DFS). ROC curves and the areas under the curves (AUC) were calculated for the three staging systems (LNR staging, MLN staging and pN staging) to assess the accuracy of their predictive ability.Results:1、Based on the maximal x2 score, the’optimal’ cutoff value was three nodes for the number of metastatic lymph nodes and 35% for LNR. Both the MLN and LNR were placed into one of three categories in subsequent analyses (0,1 to 3, or≥4 and 0%,0 to 35%, or>35%, respectively).2、The median number of metastatic lymph nodes was 5 (range 1-51), of the 480 assessable patients,254 (52%) were N0,115(24%) were N1, and111(23%) were N2. The Kaplan-Meier survival curves showed that patients with more metastatic lymph node(s) removed and more advanced pN staging have worse OS and DFS (P<.0001).3、Survival analysis indicated that a higher LNR group was associated with worse overall survival (P<.0001) (Fig.4A) and disease-free survival (P<.0001), in subgroup analysis, there was no significant difference in the OS and DFS of those patients classified as pN2 as a function of LNR, while the survival of patients classified as pNl, OS and DFS was significantly worse in patients with higher LNR (P<0.0001).4、Multivariate analysis showed that the LNR staging, smoking status and chemotherapy were revealed to be independent prognostic factors.5、The AUC was 0.678 for LNR staging,0.665 for MLN staging, and 0.672 for the 7th edition UICC N staging. The 95% CI for the three AUCs are crossed, suggesting that there were no statistically significant among the three staging methods. Conclusions: 1、Lymph node ratio is an independent predictor of survival in NSCLC patients undergoing radical resection; the prognostic significance is more valuable in pathology N1 patients. 2、we still can’t reach the conclusion that LNR staging has a superiority than the pN staging in NSCLC. The combination of the LNR and pN status provides a valuable help with prognosis. chemotherapy were revealed to be independent prognostic factors.5、The AUC was 0.678 for LNR staging,0.665 for MLN staging, and 0.672 for the 7th edition UICC N staging. The 95% CI for the three AUCs are crossed, suggesting that there were no statistically significant among the three staging methods. Conclusions: 1、Lymph node ratio is an independent predictor of survival in NSCLC patients undergoing radical resection; the prognostic significance is more valuable in pathology N1 patients. 2、we still can’t reach the conclusion that LNR staging has a superiority than the pN staging in NSCLC. The combination of the LNR and pN status provides a valuable help with prognosis.CHAPTER Ⅱ:Sublobectomy versus Lobectomy for Stage I Non-Small Cell Lung Cancer in the elderlyBackground:Lung cancer remains the most commonly diagnosed cancer as well as a leading cause of cancer death. Of the estimated 1.6 million people with lung cancer worldwide, approximately 55% are aged 65 years or older and constitutes the fastest-growing segment. Comorbid illness and adverse medical conditions due to aging is a significant concern to treat elderly patients with lung cancer. Lobectomy is the current standard treatment for early-stage non-small cell lung cancer (NSCLC) in the general population.Sublobar resection such as wedge resection and segmentectomy could be indicated in patients with stage I NSCLC, who may tolerate operative intervention but not a lobar or greater lung resection because of comorbid disease or decreased cardiopulmonary function. When treating elderly patients, decisions regarding the treatment strategy, lobectomy, or sublobar resection, must therefore carefully balance the risks of postsurgical morbidity and mortality with those affecting cancer recurrence and long-term survival.Methods:A retrospective study was performed analysing data of 245 consecutive eligible patients treated at our institution from January 2006 to December 2012. The inclusion criteria were:aged≥65 years, definitive postoperative diagnosis of stage I NSCLC according to the 7th edition NCCN tumour-node-metastasis (TNM) classification, underwent lobectomy or sublobectomy for NSCLC. The hospital and office records of each patient were reviewed and demographic and clinical data were recorded. We collected data on basic demographics (age, gender), patient comorbidities (coronary artery disease, chronic obstructive pulmonary disease [COPD], diabetes), operative details (operative time, blood loss, type of surgery, anatomic location), postoperative complications (pneumonia, atrial arrhythmia, wound infection, strokes), tumour pathological characteristics (histology, differentiation), length of postoperative hospital stay, and disease recurrence. The Kaplan-Meier method was used to plot the survival curves, and the log-rank test was used to evaluate differences among the subgroups. Results:1、According to the types of resection,245 patients were divided into two groups. 39 (15.9%) patients underwent limited resection as segmentectomy or wedge resection, 206 (84.1%) had lobectomy. Patient who underwent sublobectomy were more likely to have COPD than those who underwent lobectomy (17.9% v.7.7%, p= 0.046). The forced expiratory volume in 1 second (% predicted FEV1) was 87.86 for lobectomy versus 79.27 for sublobectomy (p=0.034).2、The two groups did differ in operative details. The mean operating time was 123.6 minutes with the lobectomy and 101.8 minutes with the sublobectomy (p=0.001). The lobectomy group had a median blood loss of 121.07ml, which was significantly more than that of the sublobectomy group, which had a median value of 68.08 ml (p= 0.000). The number of total lymph nodes removed was greater in the lobectomy group (13.3 v. 2.9, p=0.000). The difference in major postoperative complications between the two groups were clinically significant, but not statistically significant. In addition, there was a trend that patients who underwent lobectomy had more chest tube days (6.37d v.4.41d, p=0.001) and a longer stay in hospital (11.79 d v.9.67 d, p= 0.030) than those who underwent sublobectomy.3、The 1-,3-, and 5-year survival rates in patients with lobectomy were 91.0,79.3, and 66.4%, respectively, and has no significantly difference with those underwent sublobectomy (86.7,76.5, and 57.3%, respectively, p=0.494). Consistent with overall survival, there was no significant difference between the two groups for disease-free survival (p=0.336). When the cohorts were stratified by tumour size, there was no significant difference in OS and DFS for patients with tumours less than 2 cm in diameter (p= 0.674; p= 0.675), There was, however, a significant difference in disease-free survival in favour of lobectomy for patients with tumours larger than 2 cm in diameter (p=0.010), we also found that OS and DFS were equal between lobectomy and sublobectomy with% FEV1<80%(p=0.024 p=0.200; p=0.887), however, in relatively strong lung function group (% FEV1≥80%), lobectomy was associated with a significantly increased OS compared to sublobectomy (p=0.024).Conclusions:In conclusion, as for older patients with cardio-pulmonary impairment or small peripheral tumours, limited resection may achieve similar survival rates when compared with lobectomy. Considering the favorable operative details and shorter hospital length of stay, sublobectomy can be safely and effectively performed for elderly patients with early stage NSCLC to achieve a satisfying long-term survival.CHAPTERⅢ The expression and prognostic value of ERa36 in non-small cell lung cancerBackground:Lung cancer has long been thought of as a cancer that mainly affects men, but over the past several decades, with the incidence rate of lung cancer in male decreasing, there is a slow but steady increase in female. Women were more likely to develop lung cancer when consuming the same amount of cigarettes compared to men, in addition, women non-smokers are at a 2.5-fold greater risk than male non-smokers for developing lung adenocarcinoma (AC). Estrogen has been proposed to be responsible for such gender difference. A number of epidemiological studies reported that women undertaking estrogen replacement therapy had a higher risk of lung cancer, especially in lung adenocarcinoma. Recently, ERa36, a novel ERa variant was discovered, and has been proved to play an active role in a series of malignant diseases. In this study, we detected the expression of ERa36 in 126 NSCLC patients by immunohistochemistry to see if this novel receptor for estrogen is to any extent related to the clinical features of NSCLC and compared it with that of ERa66.Method:Tumor samples were randomly obtained from 126 patients who underwent complete surgical resection for NSCLC in Provincial Hospital Affiliated to Shandong University in 2008. Clinical and pathological features (including sex, smoking history, family history, histological type, pathologic stage, lymph node metastasis, and tumor stage) were abstracted from the patients’ charts. ERa36 expression was examined using immunohistochemical methods with sections from 126 resected NSCLC specimens. The immunoreactivity of ERa66 was also studied as a comparison. Kaplan-Meier method and multivariable Cox proportional hazards regression analyses were used to examine the relationship between ERa36 and survival.Result:1、Staining of the ERα36 protein was identified in the cytoplasm and cell membrane of cancer cells, ERa66, however, existed mostly in cytoplasma of tumor cells and no membrane distribution was observed.2、ERα36 was more highly expressed in NSCLC patients compared to ERa66. ERa36 expression has a strong correlation with histology (AC:53/70, SCC:16/56, P<0.000) and had a significantly positive correlation with lymphatic metastasis (P=0.014) in adenocarcinoma.3、High ERa36 expression was correlated with poorer overall survival (OS) (P= 0.020) and disease-free survival (DFS) (P= 0.024) in adenocarcinoma. Furthermore, ERa36 status was a significant independent prognostic factor of OS (P= 0.018, HR: 3.142,95% CI:1.215-8.128) and DFS (P= 0.024, HR:2.720,95% CI:1.141-6.486) in lung adenocarcinoma patients.4、Multivariate survival analysis demostrated that gender, smoking status, LNR, pT stage and ERa36 status were recognized as independent prognostic factors for overall survival, and the LNR, pT stage and ERa36 status also emerged as the independent prognostic parameters for disease-free survival.Conclusion:In conclusion, our study suggested a close relation between ERα36 expression and NSCLC, and the ERa36 expression level significantly correlate lymph node metastases and poor survival in patients with lung adenocarcinoma. Furthermore, Cox regression model analysis showed that ERa36 was a meaningful independent prognostic factor for both overall and disease-free survival. If further studies can confirm the underlying biology of ERα36 in the development and/or metastasis of lung cancer, it will be very likely that endocrine therapy be applied to NSCLC patients, just as it has done in breast cancer.