Screening for Patients with Non-small Cell Lung Cancer Who Could Survive Long Term Chemotherapy

Lung cancer is one of most common cancer in both man and women all over the word. Non-small cell lung cancer (NSCLC) represents about 80% of all lung cancer cases. And in China, more than 75% of patients with NSCLC are diagnosed at locally advanced (stage IIIB) or metastatic (stage IV) stage for which curative treatments are not available (Zhou et al., 2011). Although currently no standard regimen is established, first-line treatment for advanced NSCLC is a regimen containing cisplatin on the basis of its favourable efficacy and tolerability profile (Smit et al., 2003, Le et al., 2005). Docetaxel and pemetrexed are approved by the Food and Drug Administration (FDA)


Introduction
Lung cancer is one of most common cancer in both man and women all over the word. Non-small cell lung cancer (NSCLC) represents about 80% of all lung cancer cases. And in China, more than 75% of patients with NSCLC are diagnosed at locally advanced (stage IIIB) or metastatic (stage IV) stage for which curative treatments are not available (Zhou et al., 2011). Although currently no standard regimen is established, first-line treatment for advanced NSCLC is a regimen containing cisplatin on the basis of its favourable efficacy and tolerability profile (Smit et al., 2003, Le et al., 2005. Docetaxel and pemetrexed are approved by the Food and Drug Administration (FDA)

Screening for Patients with Non-small Cell Lung Cancer Who Could Survive Long Term Chemotherapy
Xue-Yan Wu, Xin-En Huang* for use as the second-line chemotherapy. Some studys showed non-inferior efficacy and better tolerability for pemetrexed plus cisplatin than for cisplatin plus other chemotherapy agents e.g., gemcitabine or docetaxel especially, for patients with adenocarcinoma (Reck et al., 2009;Scagliotti et al., 2009;Klein et al., 2010). In recent years, Erlotinib has been approved in more than 80 countries for the treatment of NSCLC patients who have received at least one prior chemotherapy (Mok et al., 2010;Reck et al., 2010). Although these efforts for treating NSCLC, expected 1-year survival for patients with advanced NSCLC is still low.
It is hypothesized that a set of basic demographic features (e.g., performance status, age, gender and ethnicity), histopathological information (e.g., tumor stage and grade) and life style information (e.g., tobacco use and alcohol use) could be used to make therapeutic decisions and prognostic predictions (Kankesan et al., 2013;van et al., 2010;Dehing-Oberije et al., 2011). And further hypothesized that these decisions and predictions could be more presice after incorporated various genetic and molecular biomarkers to develop new prognostic models for lung cancer (Lee et al., 2008;Donovan et al., 2009;Kawaguchi et al., 2010). In this study, regression analysis were used to analyze the relationships between these variables and survival time of patients with advanced NSCLC who had received long term chemotherapy. We also contrast the longterm survival and short-term survival cohort in order to screening out stage IV patients who could survival longer after long term chemotherapy. Survival analysis went on simultaneously.

Patients
Stage IV NSCLC patients who underwent comprehensive treatment including long-term chemotherapy with or without radiotherapy/targeted therapy between Jun 2006 to Nov 2014 in Jiangsu Cancer Hospital were enrolled in this study. Eligible patients had histologically or cytologically documented, advanced or recurrent NSCLC. Information on clinical parameters was obtained from the complete medical records, and the overall survival time was verified by call visits and the local police registration data. Further inclusion criteria were: Chinese; aged at least 18 years; life expectancy for more than 9 weeks; no less than one detectable metastatic lesion; adequate hematological, hepatic and renal functions. Exclusion criteria included: pregnant or breast-feeding women; patients with small-cell tumor. Patient characteristics are given in Table 1.

Outcome Assessment
Patients were followed through call visits and the local police registration data and any deaths were recorded. Final survival status was confirmed on 30 November 2014, so that all patients had at least 3 years and up to 4 years of follow up.

Statistical Analysis
Survival times were censored at 30 November 2014, providing a minimum follow-up of 36 months. Survival analysis and calculation of survival rates used the Kaplan-Meier method. Hazard ratios were calculated using Cox regression. Initially, all variables were considered individually, with those variables with a likelihood ratio test p<0.05 considered for inclusion in a multiple-variable model. Forward selection was used until inclusion of further variables did not significantly improve the fit of the model. Logistic regression analysis and Cox regression analysis were used to analyze the relationships between these variables and survival time. Analysis was performed using Statistica version 8.0 software (StatSoft Inc., Tulsa, OK) with p<0.05 described as statistically significant. We have enough experience in conducting medical researches, and have published some results elsewhere (Qian et al., 2014;Ji et al., 2014;Huang et al., 2014;Wu et al., 2014;Xiao et al., 2014;Lu et al., 2014;Xu et al., 2014;Gong et al., 2014;Wu et al., 2013;.

Baseline characteristics of patients
Summaries of baseline patient characteristics are shown in Table 1. Overall, 69 patients survived less than 1 year (short-term group), 45 in one to two years, and 72 survived longer than 3 years (long-term group). In logistic regression analysis, the short-term group was taken as control group and the long-term group as case group. Kaplan-Meier survival estimates of survival rate was shown in Figure 1. In long-term group, 61 patients still alive. Odds ratios for baseline variables assessed for their association with long-term group are given in Table  2&3, and hazard ratios for overall survival in Table 4.

Age and gender
The mean age of the patients in long-term group was 58 years (range=38-78), and in short-term group was 62 years (range=34-79). Patients with age less than 60 years were significantly associated with overall survival (P<0.05) in univariate cox regression analysis. 45 patients (62.5%) were male in long-term group and 56 patients (81.2%) were male in another group, and gender was associated with long-term survival (P<0.05) in logistic regression analysis. A tentative inference on this result is that female patients with stage IV NSCLC might survive longer than male patients.

Histology and Metastatic sites
Fifty-eight percents (107/186) of patients had adenocarcinoma and 42% (79/186) had squamous cell carcinoma. Adenocarcinoma was significantly associated with overall survival. In long-term group, 49 patients (68.1%) had less than 4 metastases and 23 patients (31.9%) had 4 or more than 4 metastases. In short-term group, 44 patients (63.8%) had less than 4 metastases and 25 patients (36.2%) had 4 or more than 4 metastases. In all metastatic sites, only lung and liver were associated with overall survival (P<0.05) which reached statistical significance. Both of lung and liver metastases were risk factors for patients with advanced NSCLC who had suffered long term chemotherapy, and these two metastatic sites may reduce survival of patients with advanced NSCLC.

Radiotherapy and targeted therapy
75 of 186 (40.32%) patients received radiotherapy during the long term chemotherapy, and 79 of 186 (42.47%) received targeted therapy. There was evidence that both of these two treatments were associated with overall survival (P<0.05). But it showed weak relationship with long-term survival.

Discussion
In this paper, comprehensively evaluation of a range of different factors in a reasonably sized population of advanced NSCLC patients from Jiangsu Cancer Hospital has been made to determine their effects on long-term survival after long term chemotherapy. All patients received long term chemotherapy, more than third-line chemotherapy. 40.32% (75/186) of patients underwent radiotherapy, and 42.47% (79/186) of patients received targeted therapy.
Acquiring consecutive prospective data from a single center has aided the consistency of investigation and thus made it easier to compare the effects of the different factors assessed. Using multiple-variable models, it was possible to identify the strongest prognostic factors over 3-4 years of follow-up. Assessing prognostic factors is very important because it can help screen out who can survival longer and what make this happen. In univariate cox regression analysis, age, histology of adenocarcinoma, metastatic site (e.g. lung and liver), treatments (e.g. targeted therapy and radiotherapy), LYR, the decreasing tendency of LYR and chronic bronchitis were significantly associated with overall survival. After multivariate cox regression analysis of these factors, histology of adenocarcinoma, metastatic site (lung and liver), treatments (targeted therapy and radiotherapy) and chronic bronchitis showed more association with overall survival (P<0.05). Factors significantly (P<0.05) associated with long-term survival in individual-variable logistic regression model were gender, metastatic site (lung and liver), LYR and the decreasing tendency of LYR. And in multivariate logistic regression analysis, gender, metastatic site (lung and liver) and the decreasing tendency of LYR were associated with long-term survival.
In conclusion, we found that female patients with stage IV adenocarcinoma NSCLC who had accepted multiple therapies more than third-line chemotherapy, radiotherapy and/or targeted therapy could live longer. Metastatic sites (e.g. lung and liver) and medical history of chronic bronchitis were risk factors for patients with advanced NSCLC. And when the LYR showed a downward trend during the therapy, patients could survive longer.
In addition to demographic and basic clinical information, this study identified the effects of other related factors. The fact that chronic bronchitis was associated with overall survival (P<0.05) should focus the attention of the clinician on these patients and careful management will be necessary. Through this, we speculate patients with stage IV NSCLC who had a history of chronic bronchitis simultaneously may survive shorter relatively.
In our study, histology of adenocarcinoma was significantly associated with overall survival. Among all metastatic sites, only lung and liver were associated with overall survival (P<0.05) which reached statistical significance. Both of lung and liver metastases were risk factors for patients with advanced NSCLC who had suffered long term chemotherapy, and these two metastatic sites may reduce survival.

Comorbidity
Eight of 72 (11.11%) patients had hypertension in longterm group and 12 of 69 (17.39%) patients in short-term group. 4/72 (5.56%) patients had diabetes in long-term group and 2/69 (2.90%) patients in short-term group. The presence of both hypertension and diabetes were not significantly associated with survival. 4 of 72 (5.56%) patients had chronic bronchitis in long-term group and 11 of 69 (15.94%) patients in short-term survival group, and chronic bronchitis was significantly associated with overall survival which means the clinical history of chronic bronchitis could raise the risk of death.

Physiologic Testing
Baseline functional variable assessed for their association with long term survival after long term chemotherapy and the odds ratios from logistic regression are summarized in Table 2. There was evidence that LYR and the decreasing tendency of LYR were associated with overall survival significantly. And patients with advanced NSCLC who had a decreasing tendency of LYR might live longer. DOI:http://dx.doi.org/10.7314/APJCP.2015.16.2.647 Screening for Patients with Non-Small Cell Lung Cancer Who Could Survive Long Term Chemotherapy A positive link between smoking and unfavorable survival in lung cancer patients was noted in a large number of previous studies, (Ferketich et al., 2013;Kogure et al., 2013) although there is some controversy regarding this finding (Li et al., 2011). In our study, smoking history had weak association with long term survival for advanced NSCLC patients who suffered long term chemotherapy, but the results were not statistically significant (Supporting Information Table 2 and Table 4). This might because the present study was focused on advanced-stage patients in which the effect of smoking on survival was overshadowed by other more prominent factors. It might also be partly accounted for by the relatively large number of never-smokers in this study.
The main limitation of this study is the relatively small sample size, which allowed identification of major factors that are associated with long term survival but which may have missed more moderate risk factors. Thus, negative findings should be interpreted with caution.
In conclusion, female patients with stage IV adenocarcinoma of NSCLC who had decreasing tendency of LYR during the course therapy and had accepted multiple therapies e.g. more than third-line chemotherapy, radiotherapy and/or targeted therapy could live longer. Lung and liver metastases were risk factors for patients with advanced NSCLC who had suffered long term chemotherapy. Careful attention is required when managing patients with chronic bronchitis, which might reduce the survival time of patients with stage IV NSCLC. While considering the sample size of this study is not large enough to detect minor difference of these variables regarding the influence on the response, a further study containing sufficient number of cases is needed to re-confirm this result.