| BackgroundAmong all the malignant cancers, lung cancer ranks the first in terms of morbidity and mortality rates. Despite the growing varieties of treatment methods, the effects of treatment on lung cancer remain unsatisfactory. The third national survey of causes of death shows that the mortality rate of lung cancer has increased by465%compared with30years ago and lung cancer has become the top cause of death among all the malignant cancers. Searching for scientific and effective methods to improve lung cancer treatment and extend the survival time of patients has become an urgent task for medical practi tioners.With the shift to a more comprehensive bio-socio-psychological medical model and a growing understanding of malignant cancer as a chronic disease, the primary criteria in evaluating the effect of lung cancer treatment has shifted from a tumor-free survival to improvement in quality of life and extension of survival time for patients. The aim of lung cancer treatment has gradually begun to shift from a simple pursuit of increasing the survival rate to weighing survival rate and quality of life equally. The Traditional Chinese Medicine methods, with its history of clinical practice for over two thousand years, have demonstrated unique treatment effects and advantages in improving the quality of life and extending the survival time of lung cancer patients. Many research and clinical experiences from experts have indicated that Traditional Chinese Medicine (TCM) methods are effective treatments for lung cancer. In our study for the "National Science and Technology Infrastructure Program for the10th Five-year Plan", the result shows that integrated treatment of Traditional Chinese Medicine and Western Medicine for Stage Ⅲ and IV Non-Small Cell Lung Cancer (NSCLC) patients can effectively extend the median survival time of patients and the method " Invigorating Qi and Expelling Phlegm" exhibits a particularly good treatment effect on advanced-stage NSCLC patients suffering from the syndrome of phlegm dampness due to spleen deficiency. Currently research on Traditional Chinese Medicine treatments for lung cancer has focused mainly on areas such as distribution of Traditional Chinese Medicine syndromes, improvement of symptoms, change of survival time and the optimal selection of treatment plan; however, there is few study analyzing the viability of survival with tumor. Therefore, the present study attempts to examine the treatment effects of the Traditional Chinese Medicine method "Invigorating Qi and Expelling Phlegm" on NSCLC patients by taking into account both short-term effect indicators and long-term survival time and analyze the viability of the method "Invigorating Qi and Expelling Phlegm" in helping NSCLC patients survive with tumor.ObjectivesThe objectives of this study are the following:(a) to observe the effects of the TCM method "Invigorating Qi and Expelling Phlegm" on Stage ⅢB and Ⅳ NSCLC patients in terms of indicators including their clinical symptoms, change of lesions, KPS score, change of weight and survival time;(b) to analyze the characteristics of the treatment effects of the method "Invigorating Qi and Expelling Phlegm" for advanced-stage lung cancer and the viability of the method in helping patients survive with tumor;(c) to explore and elaborate the clinical implications of the Traditional Chinese Medicine Theory of Survival with Tumor;(d) to conduct laboratory study to investigate the effects of the method on the telomerase activity of mice in order to uncover the possible mechanism of tumor inhibition of the method "Invigorating Qi and Expelling Phlegm" from the perspective of telomerase activity and discuss the implications of inhibiting telomerase activity in strategies for survival with tumor.Methods1Clinical study of the effects of treatment of the method "Invigorating Qi and expelling phlegm" on Stages ⅢB, Ⅳ NSCLC patientsThe clinical study examines both short-term and long-term effects of treatment of the method "Invigorating Qi and expelling phlegm". The examination of short-term effects is based on cases of Stage IIIB and IV NSCLC divided into two groups:the TCM group and the Western Medicine group. An open and non-randomized comparison method is adopted. The TCM group receive oral intake of Qing Jin De Sheng Pill along with other traditional Chinese medicine decoctions prescribed based on syndrome differentiation. The Western Medicine group receive chemotherapy as the only treatment. The short-term treatment effects of the method "Invigorating Qi and expelling phlegm" on Stages IIIB, IV NSCLC patients will then be examined through comparisons of the two groups in the following four indicators:change of clinical symptoms, change of lesions, KPS score, change of weight. The examination of long-term effects is based on a research study for the "11th Five-year Plan", with cases collected divided into two groups:the TCM group and the Western Medicine group. The survival time and Progression Free Survival (PFS) of these two groups will be compared and the results will be put in perspective with the aforementioned short-term effect study to analyze the viability of the Traditional Chinese Medicine method "Invigorating Qi and Expelling Phlegm" in helping patients survive with tumor, followed by an elaboration of the Traditional Chinese Medicine Theory of Survival with Tumor and its clinical implications.2Laboratory Study of the effects of treatment of the method "Invigorating Qi and expelling phlegm" on Stages IIIB, IV NSCLC patientsIn the laboratory study, a model of "Lewis Lung Cancer Cells Transplanted into C57BL/6J Mice" is established. With a complete randomized design, the mice are divided into two groups, Treatment group and Comparison group, with15mice in each group. Gastry lavage procedures are performed to both groups, with liquid Qing Jin De Sheng Pill to the Treatment group and the same dose of normal saline to the Comparison group, respectively. PCR-TRAP method is adopted to test the telomerase activity of these two groups, measure the weight and diameter of the lesions and calculate the inhabitation rate of lesions. This laboratory study will attempt to explore the possible mechanism of tumor inhibition of the method "Invigorating Qi and Expelling Phlegm" from the perspective of telomerase activity.3Statistical Data Analysis Methods Data in this study are processed by SPSS17.0Software. Scale data are represented in the form of x±s and are compared using t-tests or rank sum tests; Categorical data are analyzed using chi-square tests; Rank data are processed using Ridit analysis; In terms of survival analysis, Kaplna-Meier is used for single factor survival analysis and Cox Regession is used for multi-factor survival analysis. The significance level is set α=0.05.Results1Clinical study of the effects of treatment of the method "Invigorating Qi and expelling phlegm" on Stages IIIB, IV NSCLC patients(1) Baseline conditions:In the short-term effect study, a total of47qualified cases of Stages IIIB, IV NSCLC are collected, with25cases as the TCM group and22cases as the Western Medicine group. Prior to receiving treatments, the two groups have no statistical significant differences in gender, pathological type and clinical symptom score (P>0.05). In terms of age distribution, the TCM group has a larger average age than the Western Medicine group; in terms of the stage of NSCLC, the TCM group is mainly at Stage IV and the Western Medicine group mainly at Stage ⅢB; in terms of KPS score, the TCM group is lower than the Western Medicine group. The aforementioned differences between the two groups are statistically significant (P<0.05). However, these pre-treatment differences will not have a fundamental influence on the study itself, because the statistical analyses in the current study will mainly focus on comparing the amount of differences of the two groups before and after treatment. Therefore the data from the two groups are comparable. In the long-term effect study, prior to receiving treatments, the two groups, i.e., TCM group and Western Medicine group, have no statistical significant differences in gender, age and pathological type (P>0.05). The two groups are comparable.(2) Change of lesions:After treatment, the numbers of cases in the TCM group classified as PR, SD, PD are4,15,6, respectively; the numbers of cases in the Western Medicine group classified as PR, SD, PD are14,4,4, respectively. The TCM group perform less satisfactory than the Western Medicine group in terms of the treatment effects on lesions (P<0.05).(3) Clinical, symptom score:After treatment, the numbers of cases in the TCM group whose symptoms are classified as significantly relieved, partially relieved, stable, and aggravated are3,5,15,2, respectively; the numbers of cases in the Western Medicine group whose symptoms are classified as significantly relieved, partially relieved, stable, and aggravated are0,3,5,14, respectively. For the TCM group, all the symptoms have improved after treatment except that chest oppression and chest pain each aggravates one point. For the Western Medicine group, the following symptoms have evidently aggravated as compared to pre-treatment:phlegm expectoration, shortness of breath, mental fatigue and lack of strengths, lack of appetite, particularly in terms of mental fatigue and lack of strengths and appetite; the symptoms of coughing, hemoptysis and chest pain have been relieved; however, there is no significant difference in terms of chest oppression. The TCM group attain an evidently higher relief rate than the Western Medicine group (P<0.01).(4) KPS score:After treatment, the numbers of cases in the TCM group that are classified as remarkably effective, effective, stable, ineffective in terms of treatment effects on KPS are0,4,19,2, respectively. The numbers of cases in the Western Medicine group that are classified as remarkably effective, effective, stable, ineffective in terms of treatment effects on KPS are0,0,14,8, respectively. The TCM group perform better than the Western Medicine group in terms of treatment effects on KPS (P<0.01).(5) Weight Assessment:After treatment, the average weight in the TCM group is57.52KG and the Western Medicine group is54.59KG. The numbers of cases in the TCM group that are classified as effective, stable, ineffective in terms of treatment effects on weight are10,13,2, respectively. The numbers of cases in the Western Medicine group that are classified as effective, stable, ineffective in terms of treatment effects on weight are3,13,6, respectively. The TCM group perform better than the Western Medicine group in terms of treatment effects on weight (P<0.05).(6) Evaluation of the long-term effect of treatment (comparison of survival time):When the study is finished, the numbers of survival in the TCM group and the Western Medicine group are8and9, respectively. There is no difference between the two groups in terms of survival rate. The median survival time is20.3months for the TCM group and11.0months for the Western Medicine group. The average survival time is20.7months for the TCM group and12.2months for the Western Medicine group. The minimum survival time is3.2months for both TCM and Western Medicine groups. The maximum survival time is35months for the TCM group and21.4months for the Western Medicine group. The TCM group also has attained higher accumulative median survival time and accumulative survival rate than the Western Medicine group (P<0.05). In terms of analysis of Progression Free Survival (PFS), the average PFS is6.5months for the TCM group and5.1months for the Western Medicine group; the minimum PFS is1.3months for the TCM group and1.1months for the Western Medicine group; the maximum PFS is24.3months for the TCM group and15.8months for the Western Medicine group. There is no statistical difference in the PFS between the two groups (P>0.05).2Laboratory Study of the effects of treatment of the method "Invigorating Qi and expelling phlegm" on Stages ⅢB, Ⅳ NSCLC patients(1) Observation of conditions in general:After the model is establ ished, there are no abnormal symptoms such as coughing, shortness of breath and wheezing cough in the mice from both of the Treatment group and Comparison group. The mice of the Treatment group are generally in a better state than the Comparison group. They can act flexibly and respond quickly and their hairs are glossy. Although the amount of water and food they intake slightly decrease than before the model is established, no mouse is dead during the experiment. In contrast, the mice of the Comparison group have a declining mental state and frequency of activity and they like to gather together. They intake an evidently less amount of water and food than before the model is established. Their weight gain during the experiment is also slower than the Treatment group. Three mice were dead due to lung cancer during the experiment.(2) Weight Assessment:There are no statistical significant differences in the weights of these two groups of mice before the model is established and five days after the model is established (P>0.05). However,10days after the model is established, the mice of the Treatment group weigh heavier than the Comparison group (P<0.05).(3) Inhibition rate of tumor and change of lesions:The lesions in the Treatment group are smaller in diameter and weigh lighter than the Comparison group (P<0.05), with an inhibition rate of tumor28.2%.(4) Telomerase activity:The telomerase activity in the Treatment group is lower than the Comparison group (P<0.05).(5) Observation of the biological structure of Lewis lung cancer cells: Segments of lung cancer cells from the Treatment group and the Comparison group are examined under microscopy. For the Treatment group, the lung cancer cells are more regular in form than the ones in the Comparison group. No obvious development of adenoids and formation of keratin pearls are observed. The nuclei are dense. The chromatin are condensed but marginalized; In some cancer cells, the chromatins are ruptured into small pieces in varied sizes. In a few cancer cells, the nuclei and the outline of the cells are deformed, the cell membranes disappeared, the cytoplasms are condensed and vacuoles are growing. In areas where lymphocytes appear more than elsewhere, there are spotty necroses in the cancer cells. For the Comparison group, the lung cancer cells are irregular. No obvious development of adenoids and formation of keratin pearls are observed. The lung cancer cells are diffused. The nuclei are medium, with very clear nucleoli. The chromatins are like coarse particles. The cytoplasms are of a small amount. Karyokineses are frequent. Patchy necroses of cancer cells are observed. Interstitial tissues are scarce.ConelusionTo summarize the results of both the short-term and long-term effect studies, compared with using chemotherapy as the only treatment, the Traditional Chinese Medicine Method "Invigorating Qi and Expelling Phlegm" can benefit advanced-stage NSCLC patients in the following aspects:It can relieve their clinical symptoms, enhance their physical strengths, increase their weight, improve their quality of life as well as extend their survival time effectively, stabilize the lesions and slow down the development of the cancer. Therefore, the Traditional Chinese Medicine Method "Invigorating Qi and Expelling Phlegm" is a dependable treatment method on advanced-stage NSCLC which puts the theory of survival with tumor into practice. This method can achieve the goal of survival with tumor.In the case of advanced-stage lung cancer patients, their vital Qi are gradually deteriorating in the whole body, with excessive adverse Qi in the cancer areas. If proper treatment method is performed at this stage to amend the imbalance between adverse Qi and vital Qi and maintain the dynamic balance between them, it can decelerate the development of the cancer and enable the lesions and the body to live in harmony, and thus create a special stage for the patient to live with tumor to earn time for treatment and finally achieve the goal of survival with tumor. The theory of survival with tumor can be regarded as a development in pace with the individualization of medical treatment.In terms of laboratory study, the representative medicine of the method "Invigorating Qi and Expelling Phlegm" Qing Jin De Sheng Pill can evidently inhibit the telomerase activity in Lewis mice. It can also inhibit the growth of lesion sizes, in terms of diameters and weights, to a greater degree in the Treatment group than in the Comparison group. This result indicates that one of the possible mechanisms of the method "Invigorating Qi and Expelling Phlegm" is inhibiting the telomerase acti vi ty of cancer cells and prohibiting the telomeres from copying and lengthening, and thus inhabiting the development of the tumors and speeding up the death of cancer cells. This could be one of the possible mechanisms of the Traditional Chinese Medicine method "Invigorating Qi and Expelling Phlegm" for advanced-stage lung cancer treatment and an effective treatment to realize the goal of helping Stages ⅢB,Ⅳ NSCLC patients survive with tumor. |
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