| BackgroundsLung cancer poses a serious threat to human health and its incidence and mortality rates are on the rise globally and in China.Modern medical treatments such as surgery,chemotherapy,radiotherapy,targeted drug therapy and immunotherapy constitute the main treatment strategies for lung cancer.However,during the course of disease progression and treatment,lung cancer patients experience a variety of uncomfortable symptoms that adversely affect quality of life and are associated with poor prognosis.Both domestic and international scholars have reported on the symptom burden and symptom clusters of lung cancer patients,with more studies on the chemotherapy phase and a smaller number of studies on other treatment phases.Knowledge of the symptom burden and symptom clusters expressed in patients at different stages of treatment is an important prerequisite for designing appropriate symptom management measures.Thoracic radiotherapy(TRT)is an important local treatment for patients with lung cancer,but the disease itself and the symptom burden driven by treatment toxicity can be bothersome to patients,and the therapeutic agents available in modern medicine for symptom control are either associated with serious adverse effects or are still in the preliminary stages of research,resulting in an unmet clinical need to reduce symptom burden in patients at this stage.This has led to an unmet need for more effective symptom intervention strategies.Chinese medicine is an advantageous feature of anti-tumour treatment in China,and previous studies have confirmed the efficacy of Chinese medicine in improving the discomfort of tumour patients,reducing toxicity associated with modern medical treatment,improving patients’ quality of life and improving survival prognosis,among which improving symptoms,especially improving multiple symptoms at the same time and focusing on patients’ subjective experience are the outstanding advantages of the role of Chinese medicine.Chinese medicine scholars have also observed through clinical trials that Chinese medicines that benefit Qi and nourish Yin,clear heat and detoxify the body,and resolve phlegm and cough can alleviate multiple symptoms in lung cancer patients at the radiotherapy stage.However,symptom research in the field of TCM is still facing certain problems:firstly,symptoms are rarely used as the primary endpoint in clinical trials to evaluate the efficacy of TCM;secondly,the internationally used patient-reported outcome(PRO)tool is rarely used;thirdly,there is a lack of longitudinal study designs with repeated measurements and scientific and reasonable statistical methods to analyse symptom data.scientific research in TCM.Therefore,the aim of this study is to collect symptom data using the internationally accepted PRO tool,to conduct a study on symptom burden and symptom clusters during different treatment methods in lung cancer patients,and to evaluate the effectiveness of a comprehensive TCM treatment plan guided by the principles of "clearing heat and phlegm,activating blood circulation and detoxification,and benefiting qi and nourishing yin" in lung cancer patients receiving TRT to reduce symptom burden and symptom clusters.The study will also focus on evaluating the efficacy of TCM treatment protocols to reduce the symptom burden and severity of symptom clusters in patients receiving TRT,in order to promote the scientific evaluation of the advantages of TCM in improving symptoms.ObjectivesTo describe and compare patient-reported symptoms and functional status at different phases of lung cancer treatment,to extract symptom clusters,to gain a better understanding of symptom burden and symptom cluster expression characteristics at various stages of treatment,further to evaluate the effectiveness of an integrative TCM treatment regimen in reducing patient symptom burden and symptom clusters in lung cancer patients receiving TRT,providing reliable evidence that TCM improves patient-reported symptom outcomes.MethodsStudy of symptom burden and symptom clusters in lung cancer patients during different treatment approachesThe study was based on a prospective observational clinical study design with samples from lung cancer patients attending Guang’anmen Hospital of the Chinese Academy of Traditional Chinese Medicine between January 2020 and December 2021.Patients were divided into five subgroups(postoperative group,adjuvant group,chemotherapy group,radiotherapy group and targeted group)according to their different treatment stages.Data were collected at a single time point at the time of patient enrolment.The symptom assessment tool was the MD Anderson Symptom Inventory(MDASI).1.Study of symptom burden in different subgroupsThe incidence and severity of MDASI items were analyzed descriptively in distinct subgroups of patients to identify the TOP5 symptoms under each dimension,and WAW,REM,and total symptom interference scores were generated for each group.The chi-square test was used to evaluate the differences in incidence across groups,and the t-test,Kruskal-Wails test,or Wilcoxon rank test was used to compare the mean severity of symptoms and interference items between groups.2.Study of symptom clusters in different subgroupsTo depict the number of symptom clusters in each subgroup and the composition of symptoms within symptom clusters,and to name symptom clusters in an exploratory manner guided by TCM theory,the symptom clustering method employs principal component analysis,exploratory factor analysis,and hierarchical cluster analysis.Evaluation of the efficacy of an integrated Chinese medicine treatment programme to reduce symptom burden and symptom clusters during TRT in lung cancer patientsThe data on lung cancer patients in this study came from a multicentre randomised controlled trial.All patients received TRT and patients in the trial group received an integrated TCM treatment protocol intervention.The symptom assessment tool was the MD Anderson Chinese Medicine Symptom Scale(MDASI-TCM).Patients participating in the study completed the MDASI-TCM before the start of radiotherapy(T0),on day 14 of radiotherapy(T1),on day 28 of radiotherapy(T2),at the end of radiotherapy(T3),one month after the end of radiotherapy(T4)and four months after the end of radiotherapy(T5).mixed linear models were used to explain differences in trends in repeatedly measured symptom data over time in the two treatment groups,taking into account group and time interaction terms on symptom burden outcomes.1.Description and comparison of symptom burden in the two groups of patients at different time pointsDescribe the incidence and severity of the MDASI-TCM items in the two groups of patients at different time points,reporting the incidence TOP5 symptoms,mean severity TOP5 symptoms,incidence TOP5 moderate to severe symptoms,and WAW,REM and composite symptom interference scores.Symptoms with higher incidence and severity were selected for comparison between groups to understand differences in the expression of symptom burden between the two groups at different time points.The t-test and/or Wilcoxon rank test was used to compare the mean severity between groups and the chi-square test to compare the difference in incidence between groups.2.Longitudinal modelling analysis of the mean severity of symptoms and symptom interference in the two groupsA covariate-adjusted mixed-effects linear model was used to analyse trends over time in the MDASI-TCM data for the two groups of repeated measures.3.Comparison of symptom cluster severity between the two groupsThe 2 symptom clusters extracted from the radiotherapy group in the second part of the study were pre-set for comparison between groups.A tie-breaker composite score was calculated for each symptom cluster and differences between groups at different time points were analysed.4.Inter-group comparison of the incidence of acute radiation pneumonia(RP)and acute radiation oesophagitis(RE)Patients in both groups were graded for RP and RE according to RTOG criteria.The proportion of patients with grade 0-1 and≥2 RP and RE occurred in both groups throughout the study period was calculated and the chi-square test was used for comparison between groups.5.Quality of life(EORTC QLQ-C30)comparison between groupsQuality of life was assessed by the EORTC QLQ-C30 questionnaire.The questionnaire was measured once before the start of radiotherapy(T1),once at the end of radiotherapy(T2)and once at 4 months after the end of radiotherapy(T3).Differences between groups were compared for each structural domain score of the scale at different time points and further analysed for differences in change over time.ResultsStudy of symptom burden and symptom clusters in lung cancer patients during different treatment approaches1.In the postoperative group,shortness of breath was the most common(97.4%)and most severe symptom(4.71±2.24);the TOP5 incidence was:shortness of breath(97.4%),fatigue(94.7%),forgetfulness(92.1%),sleep disturbance(89.5%),and distress(84.2%).The TOP 5 average severity of symptoms were:shortness of breath(4.71±2.24),fatigue(4.03± 1.89),sleep disturbance(3.51±1.98),forgetfulness(3.49±2.17),and distress(3.29±2.35).The WAW(3.09±2.15)scored higher than the REM(2.95±2.28)on the symptom interference items.Three symptom clusters were extracted from the postoperative group:cluster 1(distress,sadness,nausea,shortness of breath,coughing,expectoration,pain),cluster 2(fatigue,sleep disturbance,forgetfulness,poor appetite,dry mouth)and cluster 3(drowsiness,vomiting).2.Sleep disturbance was the most common(94.4%)and most severe(3.89±2.32)symptom among patients in the ancillary group;the TOP5 incidence was:sleep disturbance(94.4%),shortness of breath(91.7%),distress(91.7%),fatigue(88.9%),and forgetfulness(88.9%).The TOP 5 average severity of symptoms were:sleep disturbance(3.89±2.32),fatigue(3.86±2.55),shortness of breath(3.69±2.44),dry mouth(3.36±2.34)and distress(3.31±2.11).The WAW(2.60±1.76)score was higher than the REM(2.43±1.66)for the symptom interference items.The auxiliary group extracted four symptom clusters:cluster 1(distress,sadness,sleep disturbance,poor appetite,drowsiness,dry mouth,fatigue),cluster 2(pain,numbness/tingling,forgetfulness),cluster 3(nausea and vomiting),cluster 4(coughing,expectoration,shortness of breath).3.In the chemotherapy group,fatigue was the most common(86.7%)and most severe(3.24±2.03)symptom;the TOP5 incidence were:fatigue(86.7%),poor appetite(85.7%),dry mouth(78.6%),sleep disturbance(76.5%),and coughing(74.5%).The TOP 5 average severity of symptoms were:fatigue(3.24±2.03),poor appetite(2.78± 1.82),sleep disturbance(2.50±1.97),dry mouth(2.13± 1.69)and coughing(2.02±1.88).The WAW(0.90± 1.42)score was higher than the REM(0.45±0.66)for the symptom interference items.Four symptom clusters were extracted from the chemotherapy group:cluster 1(drowsiness,fatigue,sadness,forgetfulness,sleep disturbance),cluster 2(nausea,vomiting,poor appetite,distress,pain),cluster 3(coughing,expectoration,shortness of breath),cluster 4(numbness/tingling,dry mouth).4.The severity of the"coughing,expectoration,distress,sadness,shortness of breath,fatigue,drowsiness and sleep disturbance" symptom group was lower than that of the control group at all four time points from day 28 of radiotherapy to the end of the study,with a statistically significant difference(P<0.05).The severity of the"vomiting,nausea,numbness,dry mouth,forgetfulness,pain and poor appetite"symptom group was lower than that of the control group only at the 28th day of radiotherapy and at the end of radiotherapy,with a statistically significant difference(P<0.05 for all).5.In the targeted group,fatigue was the most common(92.3%)and most severe(4.27±2.28)symptom;the TOP5 incidence were:fatigue(92.3%),forgetfulness(81.7%),dry mouth(75.9%),expectoration(75.0%)and shortness of breath(74.0%).The TOP 5 average severity of symptoms were:fatigue(4.27±2.28),poor appetite(2.89±2.69),sleep disturbance(2.88±2.65),forgetfulness(2.72±2.11)and shortness of breath(2.50±2.25).The WAW(2.31±2.02)score was higher than the REM(2.18±2.06)for the symptom interference items.Three symptom clusters were extracted from the target group:Cluster 1(distress,sadness,poor appetite,fatigue,shortness of breath,sleep disturbance and pain),Cluster 2(nausea,vomiting,numbness,drowsiness and forgetfulness)and Cluster 3(coughing and expectoration).Evaluation of the efficacy of an integrated Chinese medicine treatment programme to reduce symptom burden and symptom clusters during TRT in lung cancer patients1.Symptoms that occurred in>70%of patients in both groups before the start of TRT were fatigue,coughing,expectoration,distress,shortness of breath,sleep disturbance,sadness,poor appetite,pain,and irritability.Symptoms with a mean score>2 were fatigue,coughing,expectoration,distress,pain,sleep disturbance,shortness of breath.2.The mean severity of each of the seven symptoms(fatigue,coughing,expectoration,sleep disturbance,distress,shortness of breath and pain)at baseline was not significantly different between the two groups(P>0.05);the mean scores for expectoration,expectoration and distress were significantly lower in the test group than in the control group on day 14 of radiotherapy(P<0.05);the mean severity of the seven symptoms was significantly lower in the test group than in the control group on day 28 of radiotherapy,at the end of radiotherapy and 1 month after radiotherapy(P<0.05).At day 28 of radiotherapy,at the end of radiotherapy and 1 month after radiotherapy,the mean severity of all seven symptoms was significantly lower in the test group than in the control group(all P<0.05);at 4 months after the end of radiotherapy,the mean severity of the other six symptoms was significantly lower in the test group than in the control group(all P<0.05),except for the mean severity of pain,which was not statistically different between the two groups(P>0.05).3.Mixed-effects model analysis showed that scores for fatigue,coughing,expectoration,sleep disturbance,shortness of breath,pain,distress,poor appetite symptoms and WAW,REM and combined symptom disturbance all decreased significantly over time from baseline levels in the test group(all P<0.001),and the downward trend in symptoms and symptom disturbance was significantly lower than in the control group(all P<0.05),and no significant decreases were found for the eight symptoms in the control group from A significant decrease in baseline over time was found,but a progressive increase in WAW,REM and composite interference scores was found in the control group(all P<0.05).The presence or absence of concurrent chemotherapy significantly affected changes in scores for coughing,sputum,sleep disturbance,shortness of breath,WAW,REM and combined symptom interference(all P<0.05);the combined medication parameter also had a significant effect on the mean change in severity of coughing and expectoration(all p<0.01).The gender variable was only a significant influence on the change in shortness of breath symptoms(P=0.0422).4.The results of the generalized estimating equation model revealed that there were significant differences between the two groups in the incidence of moderate-to-severe fatigue(P<.0001),expectoration(P=0.0034),shortness of breath(P=0.0228),and pain(P=0.0056),as well as WAW(P=0.0047)and total symptom interference(P=0.0491).In the trial group,the incidence of moderate-to-severe fatigue(P=0.0014),expectoration(P=0.0006),expectoration(P=0.0363),pain(P<.0001),shortness of breath(P=0.0298),and WAW(P=0.0272)decreased significantly over time from baseline,whereas in the control group,the incidence of moderate-to-severe fatigue tended to increase significantly(P=0.0177).Whether or not chemotherapy was combined in all individuals had a substantial impact on the occurrence of moderateto-severe expectoration and expectoration(P values 0.0493 and 0.0243,respectively).Incidence of moderate-to-severe expectoration and expectoration was also significantly influenced by the medication combination(P=0.0249).The incidence of moderate to severe shortness of breath was also found to be influenced by age(P=0.0024)and gender(P=0.0253).The incidence of moderate to severe distress in the trial group was considerably lower than in the control group(P=0.0321)towards the end of the trial,but neither group showed a significant change over time,and the slope of change between the two groups was not significant.5.Grade≥2 RP occurred in 7(6.4%)patients in the trial group and 23(21.7%)in the control group,with a significant difference between the two groups(chi-squared value 10.613,P=0.001).6.Physical,emotional,cognitive,and social functioning ratings in the trial group had grown from baseline by the end of the trial,whereas they had dropped in the control group,with a statistically significant difference between the two groups(all P<0.05).Scores in the trial group declined from baseline in the areas of nausea and vomiting,dyspnea,diarrhea,and financial difficulties,whereas they increased in the control group,with a statistically significant difference in the trend between the two groups(P<0.05 for all).ConclusionsStudy of symptom burden and symptom clusters in lung cancer patients during different treatment approachesThe symptom burden of lung cancer patients during different treatment approaches is characterised differently,with differences mainly reflected in dimensions such as symptom incidence,the average severity of symptoms and symptom disturbances,and differences in the number and composition of symptom clusters extracted during different treatment approaches.The understanding of these characteristics is an important prerequisite for the design of specific TCM interventions and provides accurate and reliable symptomatology indicators for the scientific evaluation of the clinical efficacy of TCM.Evaluation of the efficacy of an integrated Chinese medicine treatment programme to reduce symptom burden and symptom clusters during TRT in lung cancer patients1.An integrated TCM treatment regimen can significantly reduce the symptom burden and severity of symptom clusters during TRT in lung cancer patients,with efficacy lasting at least until 4 months after the end of radiotherapy.2.For lung cancer patients receiving TRT,the implementation of the TCM integrated treatment programme can reduce the incidence of grade 2 and above acute RP.3.Integrated TCM treatment protocols are beneficial in improving the quality of life(somatic function,emotional function,cognitive function,shortness of breath domains)of lung cancer patients receiving TRT. |
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