Research On Symptom Clusters And TCM Syndromes Of Tumor Patients Treated With Immune Checkpoint Inhibitors

Research BackgroundCancer has emerged as a major public health concern worldwide.It is a leading cause of death in China.Immunotherapy can provide significant clinical benefit in cancer patients and have changed the paradigm of treatment of several cancer types.Immunotherapy has become the fifth largest treatment type after surgery,chemotherapy,radiotherapy,and targeted therapy,and has been approved for the treatment of lung cancer,melanoma,lymphoma,colorectal cancer and other types of malignant tumors.With the widespread application of immune checkpoint inhibitors,immune-related adverse reactions have gradually emerged.Activation of the immune system can occasionally cause life-threatening toxicity involving critical organs.Any organ system can be affected,including the skin,gastrointestinal tract,liver,endocrine system,and even the central nervous system.Among them,the incidence of symptomatic adverse reactions which affects the quality of life,lead to suspension of treatment,is high,but there is a lack of effective treatment methods.Clinicians tend to ignore these symptoms.Compared with CROs,PROs are any report of the status of a patient’s health condition that comes directly from the patient,without interpretation of the patient’s response by a clinician or anyone else,which are more sensitive to potential changes in functional status.Patients generally reported symptoms earlier and more frequently than clinicians.Emphasis on symptoms,whether the improvement of a single symptom or a group of symptoms is the key endpoint of TCM clinical research,reflects the characteristics of the "people-oriented" thinking system of TCM for thousands of years.Introducing symptom clusters as an evaluation index into the field of TCM tumor research can make up for the shortcomings of previous single-index evaluation methods and help to comprehensively evaluate the efficacy of TCM.Research Objective1.Investigate the incidence,severity,and degree of symptom interference in cancer patients during immune checkpoint inhibitor treatment.Determine symptom clusters and analyze the influencing factors of symptom burden and the relationship between symptom burden and quality of life.To provide reference for the management of symptom burden and improvement of long-term quality of life.2.Investigate the distribution of TCM syndrome elements and syndromes of lung cancer patients during the treatment of immune checkpoint inhibitors and analyze the influencing factors of TCM syndromes.To provide preliminary theoretical guidance for TCM syndrome differentiation and treatment.Research MethodsFrom January 2021 to March 2023,213 cancer patients treated with immune checkpoint inhibitors in the outpatient or inpatient department of Guang’anmen Hospital,China Academy of Chinese Medical Sciences were included.For patients who meet the research criteria,fill in the general information questionnaire,disease-related information sheet,symptom questionnaire,quality of life scale,and additionally fill in the syndrome element questionnaire for lung cancer patients.If the data conform to a normal distribution,they will be described as mean±standard deviation;otherwise,they will be described as median and quartile;count data are described by frequency and percentage.The symptom clusters were extracted and identified by exploratory factor analysis combined with variance maximum orthogonal rotation and systematic cluster analysis.The internal consistency of each symptom in the symptom cluster was evaluated by Cronbach’s a coefficient.The frequency and composition ratio were used to describe the distribution of TCM syndromes in lung cancer patients during the treatment of immune checkpoint inhibitors.Multiple linear regression method was used to analyze the influencing factors of symptom burden;multiple Logistic regression method was used to analyze the influencing factors of TCM syndromes.Research Results1.The incidence and severity of symptoms and symptom interferenceThe incidence of 31 symptoms ranged from 15.4%to 79.8%,among which 11 symptoms were more than 50%.The incidence of fatigue was the highest(79.8%).The severity of 31 symptoms ranged from 0.5± 1.6 to 4.0±2.8,and fatigue symptoms is the highest(4.0±2.8).The incidence of moderate to severe symptoms was lower in patients treated for>3 months than in patients within 3 months,in addition to the 7 symptoms of shortness of breath(29.4%vs.36.5%),difficulty remembering(22.9%vs.28.8%),bitter taste(18.3%vs.22.1%),sweating(18.3%vs.21.2%),rash(15.2%vs.1 5.3%),heat in palms/soles(11.0%vs.14.4%),and mouth ulcers(8.3%vs.1 1.5%).Especially for pain and nausea,there was a significant difference between the two groups in the incidence of moderate to severe symptoms.In cancer patients treated with immune checkpoint inhibitors,symptom interference with an incidence greater than 50%was walking(53.5%)and emotion(52.1%).The highest severity was walking(2.4±3.1),followed by work(2.3±3.1).The severity of activity subdimension was 2.3±2.6 points,and the severity of affective subdimension was 1.8±2.4 points.2.Symptom clusters analysisA total of five symptom clusters were extracted:Factor 1 is named as emotionfunction related symptom clusters,consisting of poor appetite,distress,sadness,sleep,pain,nausea,fatigue and constipation.Factor 2 is named as respiratory-related symptom clusters,consisting of coughing with sputum,cough,and shortness of breath.Factor 3 is named as autonomic nerve dysfunction symptom clusters,consisting of sweating,numbness,and increased enuresis.Factor 4 is named as mucosa-related symptom clusters,consisting of bitter taste,dry mouth,and drowsiness.Factor 5 is named as skin-related symptom clusters,consisting of rash and pruritus.3.Influencing factors of symptom burden and the relationship between symptom burden and quality of lifePatients with ECOG score≥2 had significantly higher symptom burden(B=0.894,95%CI 0.371～1.418;P<0.01).Symptom burden was significantly negatively correlated with its overall quality of life(r=-0.48,P<0.001),and symptom interference was significantly negatively correlated with its overall quality of life(r=-0.49,P<0.001).4.TCM syndrome elements and syndrome distribution in lung cancer patients during the treatment of immune checkpoint inhibitorsIn lung cancer patients treated with immune checkpoint inhibitors,Qi-deficiency syndrome elements was the most important,with 90 cases,accounting for 56.3%,followed by Yin-deficiency syndrome elements(32.5%),phlegm-dampness syndrome elements(21.3%),heat-toxin syndrome elements(8.8%)and blood stasis syndrome elements(7.5%).Most of the TCM syndrome was Qi deficiency syndrome,with 38 cases,accounting for 23.8%.The remaining syndrome are:Qi and Yin deficiency syndrome(18.8%),Qi deficiency and phlegm-dampness syndrome(13.1%),phlegm-dampness syndrome(8.8%),Yin deficiency syndrome(6.9%),Yin deficiency and heat-toxin syndrome(6.9%),Qi deficiency and blood stasis syndrome(4.4%),heat toxin syndrome(1.9%),blood stasis syndrome(1.9%),phlegm and blood stasis syndrome(1.9%).In Patients treated with ICI monotherapy,the top three syndromes are Qi deficiency syndrome(20.8%),Qi and Yin deficiency syndrome(18.9%),and phlegmdampness syndrome(11.3%);in patients with ICI combined with chemotherapy,the top three syndromes are Qi deficiency(26.9%),Qi and Yin deficiency(16.7%)and Qi deficiency and phlegm dampness(12.8%);in patients with ICI combined with targeted therapy,the top three syndromes were Qi deficiency(26.3%),Qi and Yin deficiency(21.1%),Qi deficiency and phlegm dampness(15.8%),and Yin deficiency(15.8%).5.Influencing factors of TCM syndromes in lung cancer patients treated with immune checkpoint inhibitorsThe treatment interval,age and stage are the influencing factors of TCM syndromes in lung cancer patients treated with immune checkpoint inhibitors.Patients with a duration of ≤3 months have a higher risk of suffering from Qi deficiency syndrome(OR=13.2,95%CI 1.26-137.57;P=0.03),phlegm dampness syndrome(OR=16.6,95%CI 1.22-225.96;P=0.03),Qi and Yin deficiency syndrome(OR=12.6,95%CI 1.21-131.57;P=0.03),and Yin deficiency and heat-toxin syndrome(OR=18.3,95%CI 1.19-282.55;P=0.04).The older the patients,the higher the risk of suffering from phlegm-dampness syndrome(OR=1.1,95%CI 1.00-1.23;P=0.04)and Yin deficiency and heat-toxin syndrome(OR=1.2,95%CI 1.01-1.31;P=0.03).Patients with Ⅰ to Ⅲ stage have a lower risk of Yin deficiency syndrome compared with stageⅣ(OR=0.07,95%CI 0.01-0.78;P=0.03).Research Conclusion1.The symptom burden of cancer patients treated of immune checkpoint inhibitors has the characteristics of multiple parts and multiple systems.Fatigue is the symptom with the highest incidence and severity,existing stably for a long time.Clinicians should pay more attention to patients-reported symptoms and targeted symptom management;2.Five symptom clusters were extracted:emotion-function related symptom clusters,respiratory-related symptom clusters,autonomic nerve dysfunction symptom clusters,mucosa-related symptom clusters and skin-related symptom clusters.Clinical treatment can be comprehensively regulated for symptom clusters to better achieve symptom control and side effects management.3.Patients with ECOG score≥2 had significantly higher symptom burden.Symptom burden was significantly negatively correlated with quality of life.Physicians should pay more attention to patients with poor physical condition and carry out targeted symptom intervention measures early in order to reduce the severity of ICI treatment toxicity and improve the quality of life of patients;4.Qi deficiency syndrome is the most frequently occurring syndrome element and TCM syndrome in lung cancer patients treated with immune checkpoint inhibitors,which is related to the duration of application for immune checkpoint inhibitors.Future research can further verify the efficacy and safety of Qi-increasing herbs combined with immune checkpoint inhibitors in the treatment of tumors.