The effect of long-term traditional Chinese medicine treatment on disease-free survival of postoperative stage I-III lung cancer patients:a retrospective cohort study

Su-Tong Liu,Su-Fang Zhang,2,Kai-Qi Su,Ying-Bin Luo,Zhi-Hong Fang,Yuan Fang,Jing Xu,Jian-Chun Wu*,Yan Li*

1Department of Oncology,Shanghai Municipal Hospital of Traditional Chinese Medicine,Shanghai University of Traditional Chinese Medicine,Shanghai,China.2Department of Traditional Chinese and Western Medicine,Shanghai Pulmonary Hospital of Tongji University School of Medicine,Shanghai,China.3Shanghai University of Traditional Chinese Medicine,Shanghai,China.

Background

Lung cancer is one of the most common malignancies with morbidity and mortality ranking first in malignant tumors[1].According to the global cancer statistics in 2012,there were 1.92 million newly diagnosed lung cancer patients worldwide with 1.6 million deaths,of which more than 60%were in developing countries[2].In China,there were 733,000 new cases of lung cancer and about 610,000 fatalities in 2015[3].A variety of treatments have been widely used to treat lung cancer,such as surgery, chemotherapy, radiotherapy,immunotherapy and targeted therapy[1,4].Although considerable progress in the early diagnosis and treatment of lung cancer has been made,its recurrence and metastasis rates are still on the rise[5],the 5-year survival rate is still less than 16.6%[6].Under such circumstance, personalized multidisciplinary comprehensivetreatmentshaveemerged and are recommended for the treatment of lung cancer patients[7,8].

Traditional Chinese medicine(TCM)has been widely used as an alternative therapy for several cancers in China because of it has a comprehensive ability in enhancing the effect of treatment,improving the quality of life,and reducing the risk of recurrence and metastasis[9-15].A number of studies have shown that oral Chinese herbal medicine can benefit patients with colorectalcancer[16],gastriccancer[17],non-small cell lung cancer(NSCLC)[18,19],ovarian cancer[20]and liver cancer[21].However,most of current studies are based on short-term efficacy and the impact on quality of life and side effects,it is not been explored as to whether long-term TCM treatment is effective and worth to be recommended to different stages of lung cancer patients[18,22].

Therefore,this study was undertaking to clarify the effect of long-term TCM treatment on disease-free survival(DFS)of different stages lung cancer patients.

Figure 1 The flow chart of patients selection and censoring for this study

Methods

Study design and participants.

This study was designed as a multicenter,retrospective observational cohort study involving Shanghai Pulmonary Hospital of Tongji University School of Medicine and ShanghaiMunicipalHospitalof Traditional Chinese Medicine,and the study protocol was approved by the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine.867 lung cancer patients between January 2007 and September 2015 were screened and 575 were included in this study.Among them,299 patients who were treated with TCM systematically after radical surgery were divided into TCM group and 276 who were not treated with TCM after radical surgery were into the control group(Figure 1).

Systematic TCM treatment.

Systematic TCM treatment was defined as that patients regularly taking traditional Chinese herbal decoction,while the process was recommended to take at least six months continuously.Two weeks were defined as one cycle of treatment,and the dosage of each herbal medicine was adjusted by clinicians,which varies with different clinical symptoms of patients.

Follow-up and data collection.

Depending on different observation time of all patients,several researchers regularly followed them each six months at different intervals by clinic appointment or phone.The minimum and maximum follow-up were 2 years and 6 years.Clinical data were collected including the patient’s gender,age,pathology type,TNM stage, histodifferentiation, radiotherapy,chemotherapy,comorbidities,prescriptions of TCM,clinical symptoms,tongue and pulse,recurrence or metastasis.DFS was identified as the time between radical surgery and metastasis recurrence or death.All survival data were collected from the Epidata and excel database after the last follow-up in October 2017.

Statistical analysis

Person’s χ²test was used to examine differences in proportion between TCM group and control group.If P value was more than 0.05 then the difference between two groups can be considered is trivial.Survival analysis was performed using Kaplan-Meier curve to evaluate DFS for TCM group and control group,the differences of survival between the two groups were calculated using log-rank tests.In addition,propensity score was used to perform a 1:1 match on all eligible subjects of the two groups,including gender,age,pathologic type,TNM stage,histodifferentiation,with stage II in the TCM group and the control group,radiotherapy,chemotherapy and comorbidities.By the way,the match tolerance of propensity score matching(PSM)was set at 0.01 and replacement was not allowed.The values of P were two-sides and the statistical significance level was set at P<0.05.SPSS 24.0(IBM,Armonk,New York,USA)and STATA 12.0(Stata Corporation,College Station,TX,USA)were utilized to perform this statistical analysis.

Results

Baseline characteristics

A total of 575 patients were enrolled in this cohort study,baseline characteristics and clinical features before and after PSM between both groups were shown in table 1.Before matching,there were 299 cases in the TCM group and 276 cases in the control group.In the classification of pathology types,55(18.4%)of 299 patients with squamous carcinoma in the TCM group compared with 71(25.7%)of 276 in the control group(P=0.009).At the same time,differences also exist in the terms of whether received adjuvant chemotherapy,among them,229(76.6%)of 299 patients received chemotherapy in the TCM group and 231(83.7%)of 276 patients in the control group(P=0.037).After PSM,233 patients in each group were matched,baseline characteristics and clinical features were also shown in table 1.

Effect of TCM on I-III lung cancer patients

For the original data before matching,the results of survival analysis showed that 1-6 year DFSs of patients in TCM group were 95.7%,85.3%,76.7%,70.2%,62.2%and 51.8%respectively,while in control group were 87.0%,67.0%,58.4%,49.5%,42.1%,35.4%respectively(Figure 2).The results of survival analysis also showed that the median disease-free survival(mDFS)was 48.0 months in control group and it was not calculated in TCM group due to less than 50%of patients with tumor recurrence or death(HR=0.51,95%CI:0.40 to 0.66,log-rank P≤0.001,Figure 3A).After matching,compared with control group,although the mDFS in TCM group was still not calculated,the DFS of TCM group was significantly improved(HR=0.66,95%CI:0.50 to 0.87,log-rank P=0.003,Figure 3B).

Effect of TCM on different stage lung cancer patients.

Based on the results of analysis in all patients,we also performed survival analysis in patients with different stages and the results showed that 5-year DFSs for 317 patients with stage I were 83.7%(TCM group)and 57.5%(control group)and 6-year DFSs were 73.7%and 51.9%,respectively(HR=0.30,95%CI:0.18 to 0.50,log-rank P≤0.001,Figure 4A).For 115 patients 5-year DFSs were 59.4%and 17.6%and 6-year DFSs were 44.7%and 17.6%,respectively(HR=0.31,95%CI:0.19 to 0.52,log-rank P≤0.001,Figure 4B).For 143 patients with stage III,5-year and 6-year DFSs in the TCM group were 18.7%and 12.5%compared with 28.4%and 20.3%in the control group(HR=1.06,95%CI:0.72 to 1.56,log-rank P=0.76,Figure 4C).

Discussion

In recent years,TCM is increasingly accepted and applied to cancer patients and is becoming one of the most popular adjuvant treatments in different countries[23-25].At present,more randomized controlled trials(RCTs)comparing TCM plus chemotherapy with chemotherapy for lung cancer patients were focused on NSCLC,and were mainly based on 1-year survival analysis[18,26,27].As for non-RCTs,a retrospective cohort study involving 111,564 lung cancer patients from Taiwan,China,observed the effect of TCM on the survival of lung cancer patients and the results showed that adjunctive TCM treatment may improve overall survival of lung cancer patients[28].

Table 1 The baseline characteristics and clinical features in the TCM group and control group.

Figure 2 1-6 year disease-free survival in the TCM and control group

Figure 3 Disease-free survival curves for all patients before(A)and after(B)propensity scoring

Figure 4 Disease-free survival curves for patients with stage I(A),II(B)and III(C)disease

Our study not only further explored the impact of long-term TCM treatment on survival of lung cancer patients,but also provided evidence for the role of long-term treatment TCM in patients with different stages lung cancer,and the results showed that TCM is independently associated with significantly improved DFS of postoperative stag e I-III lung cancer patients,especially in patients with stage I and II disease.

Before PSM,the baseline characteristics of TCM and control groups were not comparable,so we adopted PSM to reduce the imbalance between two groups of data by imitating randomization,making an unbiased estimating of TCM.In terms of DFS,our results in this study proved the significant effect of TCM treatment on lung cancer patients.We consider that may be the efficacy of TCM through body enhancing,toxicity reducing and improving the quality of life.At the same time,we found that from the third year,DFSs of lung cancer patients with stage III disease in the control group were higher than that stage III patients in TCM group and stage II patients in the control group,this may be related to the small sample size and may be associated with more lung cancer patients receiving chemotherapy and radiotherapy in stage III disease,this may result in some stage III patients living longer than some patients in stage II,and this requires further study.

Several limitations were existed in our study.First,as a retrospective study,the lack of randomization and the inherent disadvantages of this type of study resulted in a reduction in the credibility.Second,although we did propensity score match for baseline characteristics to be comparable on terms of gender,age,pathologic type,TNM stage,histodifferentiation,radiotherapy, chemotherapy and comorbidities,relatively accurate assessment of the efficacy was achieved.However,some confounding factors that not be considered made this study potentially biased,such as personal smoking history,family medical history and therapeutic history other than TCM treatment.If one individual has a history of smoking or a family history of lung cancer,he may have delayed the timely and effective treatment due to delayed diagnosis,so a poor survival will exist.In addition,if one patient did chemotherapy,radiotherapy or targeted drug therapy before receiving TCM treatment,his survival could be prolonged,otherwise the effect would be reversed.Third,due to the natural characteristics of TCM,it was complex in dialecticalanalysisand selection of prescription drugs,different patients’syndromes were treated differently at each visit.We did not classify the syndromes and medication,so we couldn’t identify what prescriptions and components were truly helpful.Finally,our sample size is not large enough and the majority of the population involved are come from Shanghai,China.There is currently no sufficient evidence that long-term TCM treatment is effective for alllung cancerpatientsin allregionsand all ethnicities.

Conclusion

This retrospective cohort study showed that long-term TCM treatment can improve the DFS of postoperative lung cancer patients,especially in patients with stage I and II disease.However,these observational findings need being validated by large sample RCTs.

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