Symptom Clusters and Sentinel Symptoms During the Third and Fourth Cycles of Postoperative Chemotherapy in Lung Cancer Patients

Symptom Clusters and Sentinel Symptoms During the Third and Fourth Cycles of Postoperative Chemotherapy in Lung Cancer Patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Symptom Clusters and Sentinel Symptoms During the Third and Fourth Cycles of Postoperative Chemotherapy in Lung Cancer Patients Jingshuang Ma, Yanjie Wang, Wei Li, Aiping Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4987982/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: Lung cancer has the highest incidence and mortality in China, and patients after lobectomy experience serious physical and psychological symptoms during chemotherapy. Studies are lacking about symptom clusters and sentinel symptoms during the postoperative chemotherapy period in lung cancer patients. Objective: To explore the stability of symptom clusters and sentinel symptoms during the 3nd and 4th cycles of postoperative chemotherapy in patients with lung cancer. Methods: The study was a longitudinal study. Lung cancer patients after lobectomy were measured at 2 separate points:chemotherapy cycle 3 and chemotherapy cycle 4. The measures administered included M.D.Anderson Symptom Inventor Lung Cancer Specific Module and Self-made First Appearance of Symptoms Time Sheet. Results : A total of 180 postoperative patients with lung cancer participated in the study. Five symptom clusters and three sentinel symptoms were identified at chemotherapy cycle 3. Four symptom clusters and three sentinel symptoms were identified at chemotherapy cycle 4. Conclusions: Symptom clusters and sentinel symptoms were relatively stable during the 3nd and 4th cycles of postoperative chemotherapy in patients with lung cancer. Implications for practice: The understanding of symptom clusters and sentinel symptoms could be beneficial for clinicians to assess and manage symptoms in postoperative patients with lung cancer during chemotherapy. Clinicians should pay close attention to sentinel symptoms and develop effective interventions to reduce the symptom burden of patients. Apriori algorithm Chemotherapy Lung cancer Sentinel symptom Symptom cluster Introduction Lung cancer is the most common malignant tumor endangering human health in the world, and it is the second most prevalent cancer globally and the leading cause of cancer-related death(Sung et al., 2021 ). In China, it was predicted that lung cancer would have the highest incidence and mortality rates among all malignant tumors(Xia et al., 2022 ). Commonly used lung cancer treatments include targeted therapy, immunotherapy, surgery, chemotherapy, and radiotherapy. Although the short-term curative effects are significant, the side effects—low immune function, bone marrow suppression, liver and kidney function damage, and gastrointestinal reactions—seriously affect the survival time and prognosis of lung cancer patients(Harðardottir et al., 2022 ). Currently, surgery is the preferred treatment for early lung cancer, with the 5-year survival rate being as high as 67%(Lee et al., 2018 ). However, there is a risk of adverse reactions, which can seriously affect the patient’s quality of life. A study has shown that lung cancer patients experience various symptoms post-lobectomy, the most severe of which are fatigue, pain, shortness of breath, disturbed sleep, and drowsiness(Huang et al., 2015 ). Lung cancer patients often experience multiple, concurrent, and dynamic symptoms, usually in symptom clusters (SCs)(Kirkova et al., 2011 ). Kim et al.(Kim et al., 2005 ) defined a “symptom cluster” as two or more symptoms with a stable correlation that are distinct from other symptom clusters and may be caused by a common pathological mechanism. These SCs not only reduce quality of life but also shorten the survival time of patients(Chow et al., 2019). Several longitudinal studies have helped identify SCs among patients with lung cancer during chemotherapy. Li et al.(Li et al., 2020 ) explored the SCs of lung cancer patients two weeks before chemotherapy and at chemotherapy cycles 1 and 4. Results demonstrated that there were both similarities and differences between symptom clusters at the three individual time points. Three symptom clusters were stable, while another three could change during perichemotherapy. While research has provided an overall deeper understanding of the changes to SCs during chemotherapy, studies have mostly focused on patients with advanced lung cancer(Russell et al., 2019 ; Buck et al., 2020 ), and there are few studies about post-lobectomy lung cancer patients, whose survival time is longer(Lee et al., 2005). A “sentinel symptom” is defined as an indicator or marker of a symptom cluster that can help predict or boost the occurrence of other symptoms within the symptom cluster(Brown et al., 2011 ; Jim et al., 2013 ). Recognizing sentinel symptoms can help us to better understand the underlying mechanisms of SCs, which may help provide an entry point for effective symptom management(Rha et al., 2005). Rha et al.(Rha et al., 2005) explored sentinel symptoms during the first two cycles of adjuvant chemotherapy in cancer patients and found that sentinel symptoms included anxiety, loss of appetite, and fatigue during the 1st cycle and loss of appetite, depression, and fatigue during the 2nd. Sentinel symptoms can also be useful assessment indicators in clinical practice and can help simplify the assessment and management of SCs. As the number of studies that have tried to identify sentinel symptoms is limited(Brown et al., 2011 ; Rha et al., 2019 ; Aktas et al., 2013; Kirkova et al., 2010 ; Ju et al., 2023 ), the relationship between sentinel symptoms and the additional symptoms in the SC needs to be further studied. Different studies have used different methods to identify the sentinel symptom. For example, Brown et al(Brown et al., 2011 ) applied Pearson correlation analyses, while principal variable analysis was conducted in Rha(Rha et al., 2019 ). Notably, the sentinel symptom onset time was neglected in these studies(Brown et al., 2011 ; Rha et al., 2019 ). In our study, based on the definition of “sentinel symptom,”(Brown et al., 2011 ; Jim et al., 2013 ) we tried to associate symptom onset time with the relationship between symptoms within a cluster to identify the sentinel symptom, which we believe may be a more scientific method. We previously investigated SCs and sentinel symptoms during the first two cycles of postoperative chemotherapy in patients with lung cancer and found that symptom clusters and sentinel symptoms were stable during both cycles(Ma et al., 2022 ). This study continues this research. Here, we aimed to explore the SCs of lung cancer patients and identify the sentinel symptoms within them during the third and fourth cycles of postoperative chemotherapy. Theoretical Framework The symptom management model was first proposed by Larson et al.(Froelicher et al., 1994 ) in 1994 at the Center for Symptom Management, University of California, San Francisco, which was later developed and improved by Dodd et al.(Dodd et al., 2001 ) in 2001 and renamed Symptom Management Theory (SMT) in 2008. Symptom experience, symptom management, and symptom outcome are three interrelated dimensions in this theory. This study focuses on the symptom experience portion of the model, particularly the individual’s evaluation and perception of symptoms, by identifying symptom clusters based on symptom severity and determining sentinel symptoms within symptom clusters by exploring the relationship between symptoms based on symptom occurrence. Methods Sample and Setting This study is a longitudinal study. The sample size was estimated by an item (or variable) ratio of 5:1, i.e., five cases for each item(Gorsuch et al., 1983; Stevens et al., 2002). By adopting a convenience sampling method, 180 patients were recruited from two hospitals in Shenyang. Inclusion criteria included (1) a clear primary non-small cell lung cancer diagnosis by pathology and cytology; (2) the patient be undergoing chemotherapy after surgery; (3) an age of 18 or above; and (4) a clear awareness, an informed diagnosis, independent communication skills, and a signed informed consent. Exclusion criteria included (1) a recurrence of lung cancer or metastasis to distant organs; (2) the patient receiving radiotherapy, immunotherapy, targeted therapy, and/or other treatments; (3) the presence of other malignant tumors requiring treatment; and (4) the presence of serious diseases of various important organs. Measures Demographic and Medical Characteristics Questionnaire The demographic and Mmedical characteristics questionnaire consisted of two parts. The first part included demographic information—such as age, gender, education level, and medical payment method—while the second part included disease-related information—such as pathological type, tumor stage, chemotherapy regimen, and chemotherapy cycle. M.D. Anderson Symptom Inventory Lung Cancer-Specific Module The M.D. Anderson Symptom Inventory (MDASI) was developed at the University of Texas Anderson Cancer Center for most patients with malignancy(Cleeland et al., 2000 ). The questionnaire consists of two parts: the first part measures the severity of 13 common cancer symptoms, such as pain, fatigue, and drowsiness, over the past 24 hours, and the second part evaluates the interference of the above symptoms with the patient’s daily life. In 2004, Wang et al(Wang et al., 2000) translated it into Chinese and evaluated Chinese cancer patients, showing that the Cronbach α coefficient of the MDASI’s scale was 0.87. The Lung cancer-specific module(Zhang et al., 2013) of the MDASI added 6 lung cancer-specific symptoms to the 13 core items—including coughing, expectoration, hemoptysis, chest tightness, constipation, and body mass decline—making a total of 19 items with a Cronbach α coefficient of 0.773 and content validity of 0.944. The inventory uses a score of 0 to 10 for each item, where 0 represents "asymptomatic or no interference" and 10 represents "the most severe imaginable or complete interference,” and thus the total score for the inventory has a range of 0 to 190. The Cronbach α coefficient of this scale in the formal survey was 0.805. First Appearance of Symptoms Time Sheet The First Appearance of Symptoms Time Sheet was a self-made questionnaire with the same 19 symptom entries as the MDASI lung cancer-specific module. Patients recorded the time between chemotherapy drug infusion and the first onset of each symptom on the questionnaire in hours. Procedures This study was approved by the hospital ethics committee [(2020)2020-280-2]. Before the investigation, the investigators explained the significance and content of the study, and all study subjects signed the informed consent form. The demographic and medical characteristics questionnaire was completed by the investigators using the electronic medical record system. The MDASI Lung Cancer Specific Module and the First Appearance of Symptoms Time Sheet were completed by the study subjects. For subjects who were unable to fill out their own content, investigators read the questions one by one in a neutral tone and filled out the answers. The questionnaire collection method included a live face-to-face survey and a telephone survey. The MDASI Lung Cancer Specific Module was carried out on day 7 of chemotherapy cycle 3 and day 7 of chemotherapy cycle 4 (the day of the chemotherapy infusion was counted as day 1). The First Appearance of Symptoms Time Sheet was given to patients prior to chemotherapy cycles 3 and 4 and was collected on day 7 of each cycle. Statistical Analysis The data were analyzed using SPSS Statistics 22.0 and SPSS Modeler 18.0. Count data were described by the frequency and composition ratio and measurement data conforming to the normal distribution by the mean ± standard deviation. Non-normally distributed data were expressed as M (P25, P75). Exploratory factor analysis was used to identify SCs based on the symptom severity dimension. To have sufficient differences in the data for exploratory factor analysis, symptoms with an incidence greater than 20% were included in the analysis(Kim et al., 2009 ). Factors with feature values greater than 1, symptom factor loads greater than 0.5, and loads on at least two factors were selected for the analysis(Emerson et al., 2017). A P -value < 0.05 was considered statistically significant. Association rule analysis is a data mining technique that explores the basic rules and underlying relationships between variables. In recent years, association rule analysis algorithms have been applied in several studies in the medical field(Xia et al., 2020 ; Lu et al., 2020 ). In order to improve the computational efficiency of association analysis, Agrawal and Strikant proposed the Apriori algorithm in 1994. After years of development and improvement, the Apriori algorithm has become the core algorithm of association analysis in data mining. In this study, the Apriori algorithm was used to generate effective symptom connectivity within the symptom clusters, which helps to identify sentinel symptoms. Support and confidence are evaluation metrics used to measure the relationship between symptoms in the Apriori algorithm. Support represents the concurrent proportion of previous and posterior symptoms in all samples, while confidence indicates the proportion of posterior symptoms in the sample with only previous symptoms, and an appropriate association rule should have both high support and confidence(Bayardo et al., 1999). Sentinel symptom identification was based on two points: first, the symptom was the earliest symptom in the SC(Jim et al., 2013 ); second, in the Apriori algorithm, the priority support was > 40%, the confidence was > 60% (i.e., there is a valid relationship between the two symptoms). Results Patient and Treatment Characteristics From the total sample (N = 180), six patients withdrew at chemotherapy cycle 2, and four patients withdrew at chemotherapy cycle 3 due to significant adverse effects. The average age of the patients was 52.16±10.36 years, with most of them being men (112, 62.22%). The proportion of patients with at least a junior high education level was 66.67%, and medical insurance was the main source of medical payment (158, 88.78%). In addition, adenocarcinoma accounted for 47.78% of patients, with most being in stage I (52, 28.89%) and stage II (98, 54.44%). Demographic and treatment characteristics are showcased in Table 1. SCs and Sentinel Symptoms of Chemotherapy Cycle 3 During the third chemotherapy cycle, five SCs were extracted by exploratory factor analysis (KMO, 0.79): a digestive tract symptom group (nausea, vomiting, and lack of appetite), respiratory tract symptom group (coughing and shortness of breath), psychological symptom group (sadness and distress), physical symptom group (drowsiness, pain, and fatigue), and neurological symptom group (numbness and forgetfulness). The contribution rate of the cumulative variance was 78.62%(Table 2). In cycle 3, nausea was found to be the first symptom appearing in the gastrointestinal SC (Table 3). The Apriori algorithm–based association rules analysis demonstrated that when nausea was the antecedent and the other symptoms were consequences, the support value was greater than 40%, and the confidence value was greater than 60% (Table 4). Based on these 2 points, nausea was identified as the sentinel symptom of the gastrointestinal SC. According to the same selection criteria, coughing was identified as the sentinel symptom for the respiratory tract SC, and fatigue for the physical SC. SCs and Sentinel Symptoms of the Chemotherapy Cycle 4 During the fourth chemotherapy cycle, four SCs were extracted by exploratory factor analysis (KMO, 0.81): digestive tract symptoms (nausea, vomiting, constipation, and lack of appetite), respiratory tract symptoms (coughing and shortness of breath), psychological symptoms (sadness and distress), and physical symptoms (drowsiness, pain, and fatigue). The contribution of the cumulative variance was 76.71%(Table 5). In cycle 4, nausea was the first symptom appearing in the gastrointestinal SC (Table 3). The association rules analysis demonstrated that, with nausea as the antecedent and the other symptoms consequences, the support was greater than 40% and the confidence was greater than 60% (Table 4). Thus, nausea was considered to be the sentinel symptom of the gastrointestinal SC. Based on the same selection criteria, coughing was identified as the sentinel symptom for the respiratory tract SC, and fatigue for the physical SC. Table 1 Patient and Treatment Characteristics(n=180) Variable Categories n(%) Age Gender Education Medical payment Stage a Pathological type Chemotherapy regimen Length after surgery Mean Male Female Elementary Junior high Senior high College or above Self-paid Medical insurance I II III Adenocarcinoma Squamous carcinoma Large cell carcinoma Adenosquamous carcinoma Pemetrexed + Cisplatin Gemcitabine + Cisplatin Docetaxel + Cisplatin Etoposide + Cisplatin ＜1 month 1-2months ＞2 months 52.16±10.36 112(62.22) 68(37.78) 23(12.78) 77(42.78) 43(23.89) 37(20.55) 22(12.22) 158(87.78） 52(28.89) 98(54.44) 30(16.67) 86(47.78) 65(36.11) 18(10.00) 11(6.11) 64(35.56) 54(30.00) 52(28.89) 10(5.55) 66(36.67) 78((43.33) 36(20.00) a:According to the AJCC cancer staging manual 8th ed. Table 2 Symptom Clusters in the 3rd Cycle Symptom Digestive tract SC Respiratory tract SC Psychological SC Physical SC Neurological SC Nausea Vomiting Lack of appetite 0.683 0.667 0.814 0.236 0.142 0.246 0.143 0.162 0.133 0.195 0.256 0.311 0.205 0.146 0.181 Cough Shortness of breath 0.191 0.204 0.813 0.795 0.243 0.208 0.133 0.176 0.231 0.139 Sadness Distress 0.198 0.095 0.255 0.109 0.765 0.804 0.129 0.264 0.098 0.103 Drowsiness Pain Fatigue 0.204 0.163 0.399 0.299 0.115 0.187 0.283 0.334 0.333 0.766 0.608 0.647 0.201 0.190 0.207 Numbness Forgetfulness Cronbach’s α Variance explained(%) 0.104 0.203 .75 18.18 0.205 0.301 .72 16.12 0.198 0.276 .67 14.29 0.398 0.288 .65 14.38 0.698 0.635 .65 15.65 Abbreviations: EFA, exploratory factor analysis; SC, symptom cluster. Seven symptoms present in fever than 20% of the patients did not meet our criteria for inclusion in the EFA: sleep disturbance, dry mouth, constipation，hemoptysis, expectoration, chest tightness, and weight loss. Boldface indicates 5 SCs were identified via EFAs utilizing 12 symptoms In cycle 3. Table 3 The time of Symptom First Appearance Time Symptom Cluster Symptom First Appearance (mean±SD, h) F P Cycle 3 Digestive tract SC Nausea Vomiting Loss of appetite 20.02±8.16 23.96±7.01 30.22±5.30 9.221 .001 Respiratory tract SC Cough Shortness of breath 10.62±9.45 20.12±6.90 14.203 .000 Psychological SC Sadness Distress 12.54±10.66 11.55±11.29 2.379 .110 Physical SC Fatigue Drowsiness Pain 19.16±6.08 25.84±5.08 30.23±6.24 11.923 .000 Neurological SC Numbness Forgetfulness 30.32±10.26 29.64±12.09 2.531 .109 Cycle 4 Digestive tract SC Nausea Vomiting Loss of appetite Constipation 22.42±10.15 25.46±9.21 29.12±6.34 40.54±5.64 7.231 .002 Respiratory tract SC Cough Expectoration Shortness of breath 15.82±9.63 18.14±7.48 23.62±5.74 4.213 .018 Psychological SC Sadness Distress 16.34±10.67 19.25±7.25 2.391 .118 Physical SC Fatigue Drowsiness Pain Numbness 21.56±9.48 27.34±9.28 28.52±7.34 30.32±10.26 6.379 .010 Abbreviation: SC, symptom cluster. Table 4 Apriori Algorithm-based Association Rules Time Symptom Cluster Antecedent Consequent Support Confidence Cycle 3 Digestive tract SC Nausea Vomiting 68.5 70.9 Nausea Lack of appetite 71.2 76.1 Vomiting Nausea 68.5 77.3 Lack of appetite Vomiting 65.4 70.2 Respiratory tract SC Cough Shortness of breath 66.8 75.2 Shortness of breath Cough 66.8 82.2 Physical SC Fatigue Drowsiness 77.2 86.1 Fatigue Pain 58.8 68.6 Drowsiness Pain 52.9 61.1 Cycle 4 Digestive tract SC Nausea Vomiting 75.8 82.3 Nausea Constipation 50.3 65.5 Nausea Lack of appetite 78.2 81.4 Vomiting Nausea 75.8 89.9 Lack of appetite Vomiting 62.3 74.3 Respiratory- tract SC Cough Shortness of breath 75.8 71.3 Shortness of breath Cough 75.8 82.3 Physical SC Fatigue Drowsiness 71.3 88.4 Fatigue Pain 53.4 60.1 Drowsiness Fatigue 71.3 89.1 Pain Drowsiness 61.3 71.2 Abbreviation: SC, symptom cluster. Table 5 Symptom Clusters in the 4th Cycle Symptom Digestive tract SC Respiratory tract SC Psychological SC Physical SC Nausea Vomiting Constipation Lack of appetite 0.690 0.678 0.728 0.802 0.219 0.083 0.154 0.261 0.139 0.212 0.249 0.193 0.179 0.246 0.134 0.231 Cough Shortness of breath 0.289 0.159 0.882 0.805 0.243 0.206 0.153 0.206 Sadness Distress 0.198 0.099 0.241 0.187 0.767 0.753 0.193 0.254 Drowsiness Pain Fatigue Cronbach’s α Variance explained(%) 0.198 0.191 0.318 .72 21.28 0.116 0.203 0.186 .75 17.08 0.233 0.242 0.189 .69 18.98 0.609 0.698 0.628 .65 19.27 Abbreviations: EFA, exploratory factor analysis; SC, symptom cluster. Eight symptoms present in fewer than 20% of the patients did not meet our criteria for inclusion in the EFA: sleep disturbance, dry mouth, forgetfulness, numbness, hemoptysis, expectoration, chest tightness, and weight loss. Boldface indicates 4 SCs were identified via EFAs utilizing 12 symptoms In cycle 4. Discussion The Stability of SCs During Cycle 3 and Cycle 4 Combined with the results of our previous study, this study showed that among the four cycles of postoperative chemotherapy for lung cancer patients, five different symptom groups were found: digestive tract, respiratory tract, psychological, physical, and neurological symptom groups. Except for the neurological SC, which only presented in cycle 3, the remaining four SCs remained stable across the cycles. Nausea, vomiting, and lack of appetite are stable digestive tract symptoms, occurring in digestive tract SCs, chemotherapy-induced nausea and vomiting (CINV) are the most common serious clinical adverse effects despite global and domestic guidelines consistently recommending serotonin receptor antagonist (5HT3RA) and dexamethasone for moderate emetic-risk chemotherapy and these two drugs plus aprepitant or fosaprepitant for hyperemetic chemotherapy. However, the clinical practice context of these guidelines and the proportion and extent of the occurrence of CINV under antiemetic applications following the most appropriate guidelines have not been well studied. Coughing, expectoration, and dyspnea were the stable respiratory symptoms of the respiratory tract SCs. Some studies have found that coughing, dyspnea, and shortness of breath were common within this symptom group(Henoch et al., 2009; Choi et al., 2018), corroborating the findings of this study. These studies highlight the clinical importance of this symptom group in patients with lung cancer. Moreover, another study found that lung cancer patients with a higher incidence of respiratory symptoms at initial diagnosis had a worse prognosis(Ban et al., 2016). Respiratory SCs can interfere with patients’ daily activities and ability to maintain their quality of life(Tanaka et al., 2002). Sadness and distress were stable symptoms in the psychological SCs(Faye-Schjøll et al., 2019). Because lung cancer is difficult to cure and requires long-term treatment, patients are prone to suffer negative emotions. Emotional problems in lung cancer patients can increase symptom burden and affect cognitive function. Therefore, there is a need to provide systematic psychological support and effective symptom management for these patients, and clinicians need to screen for psychological symptoms and recommend effective interventions, such as cognitive-based therapy, mindfulness training, and participation in support groups(Hulbert-Williams et al., 2018). Our study found that fatigue, drowsiness, pain were stable symptoms of the physical SCs. Drowsiness and numbness may be related to the peripheral neurotoxicity caused by the application of platinum-based chemotherapeutic agents. Lynch et al(Lynch et al., 2018). showed that fatigue, pain, and sleep disturbances often develop as a symptom aggregation, which is similar to the results of this study. Although this cluster has been found less in previous studies of lung cancer patients, it is a common SC in many other cancer studies. More research is needed to confirm the presence of this symptomatic cluster in patients with lung cancer. In this study, neurological SCs were only present in cycle 3. Chemotherapy-induced peripheral neuropathy is a common side effect in cancer patients treated with neurotoxic agents(Staff et al., 2017). As the chemotherapy regimen of the study subjects is mainly platinum-based, the forgetfulness and numbness may be related to peripheral nerve toxicity caused by the application of platinum-based chemotherapy drugs. These symptoms often exist together and affect cancer patients by causing paresthesia, functional impairment, and hearing and vision impairment(Kieffer et al., 2017). Several studies have also shown that neurological SCs can cause psychological problems—such as anxiety, depression, and stress disorders—thereby further reducing the quality of life for cancer patients(Miaskowski et al., 2018). Severe neurological symptoms may force patients to stop chemotherapy prematurely, reducing the anticancer treatment efficacy and possibly overall survival(Robertson et al., 2018). A recent literature review summarizing 19 studies of chemotherapy-related SCs found that very few studies clearly delineate neurological SCs(Sullivan et al., 2018). Future studies are warranted to identify the nature of neurospecific SCs. The Stability of Sentinel Symptoms During Cycle 3 and Cycle 4 The results of this study showed that nausea is a sentinel symptom of digestive tract SCs. Despite significant progress in the prevention of CINV over the past 40 years, they remain highly prevalent in chemotherapy patients. Nausea and vomiting are also the two most feared side effects of cancer treatment, both, but especially nausea, placing a heavy burden on patients(Herrstedt et al., 2021). The reason for this may be that chemotherapeutic drugs are often cytotoxic and can stimulate the medulla emesis center, which transmits signals through peripheral and central pathways, thus leading to nausea and vomiting. During chemotherapy, antiemetic drugs are usually used, but these often inhibit gastrointestinal peristalsis and cause constipation. When people feel nausea, gastric tension, and weakened peristalsis accompanied by increased duodenal tension and associated epigastric discomfort, this often leads to a loss of appetite. Therefore, medical staff need to pay more attention to the development and severity of nausea and develop individualized prevention and treatment plans according to the chemotherapy regimen—which can help relieve nausea, improve digestive tract symptoms, reduce food intake, and increase meal frequency—and administer timely interventions for nausea sufferers, such as relaxation training or TCM intervention(Hunter et al., 2020). Coughing is a sentinel symptom of respiratory tract SCs. Chemotherapy drugs stimulate bronchi and cause decreased white blood cell counts, decreased immunity, coughing, respiratory infection, respiratory mucosa damage, and increased mucosal secretion resulting in sputum. Rapid and frequent coughing can result in a transient lack of oxygen and symptoms of shortness of breath. Studies have shown that the prevalence of coughing at diagnosis is 70%, while that before death is 81%(Harle et al., 2020). The incidence of coughing in lung cancer patients seems to be underestimated, and the treatment of coughing in patients remains an important unmet need(Smith et al., 2021), with two-thirds of the lung cancer patient population perceiving coughing as severe enough to require therapy(Harle et al., 2020). Therefore, medical staff should strengthen the evaluation of coughing; keep the environment comfortable and clean; and inform patients that they should drink more water, eat more fruits and vegetables, and avoid overly sweet or sour foods. At the same time, patients can be guided to perform cough training to relieve coughing symptoms and improve respiratory SCs. Fatigue is a sentinel symptom of physical SCs. The reason for this may be that fatigue leads to decreased physical strength and activity, and sleep can help patients recover their physical strength. Furthermore, the occurrence of pain, fatigue, and sleep disturbance is associated with a common proinflammatory cytokine(Wang et al., 2014). Fatigue can lead to a temporary loss of local nerve function, resulting in lameness and numbness. Cancer-related fatigue is one of the most common subjectively unpleasant side effects in patients during chemotherapy, affecting up to 90% of lung cancer patients, and is an intractable symptom(Ebede et al., 2017). However, despite extensive research efforts to address this issue, including patient education and physical exercise, clinicians, caregivers, and patients themselves still regard cancer-related fatigue as an inevitable consequence of cancer treatment and a difficult-to-treat symptom(Wu et al., 2019). A systematic review highlighted the efficacy of some non-pharmacological interventions, including physical activity, psychotherapy, and acupuncture, in overcoming fatigue(Bootsma et al., 2020). Attitudes play an important role in patient perception, and psychological adaptation strategies, such as adapting to and receiving fatigue, can help patients cope with physical symptoms and side effects. 52 Medical staff should give a high priority to relieving fatigue in their health management. When patients develop fatigue, medical staff should consider other possible symptoms and intervene as soon as possible to slow down fatigue and reduce the severity of other symptoms caused by fatigue. Implications for Practice An understanding of SCs and sentinel symptoms may be beneficial for clinicians in assessing and managing symptoms in postoperative patients with lung cancer during chemotherapy. Clinicians need to pay close attention to sentinel symptoms and develop effective interventions to reduce the symptomatic burden of patients. Limitations Due to multiple measurements of the same patient, some sample size loss and some selection bias resulting from loss to follow-up occurred. Here, we only explored the SCs and their sentinel symptoms during the end of chemotherapy, and the sentinel symptoms of later chemotherapy cycles and the whole chemotherapy treatment need further study. Additionally, only one statistical analysis method was used to identify sentinel symptoms, and more analysis methods are needed to improve sentinel symptom identification in the future. Conclusion This study shows that most of the SCs and sentinel symptoms were stable during chemotherapy, but the neurological symptom group only appeared in the third cycle, and the mechanism behind the occurrence and development of the neurological symptom group needs to be further explored in future studies. At present, the study of sentinel symptoms in the field of SCs is still in its infancy, and this study can provide new ideas and new methods to improve future research on the sentinel symptoms of SCs. Declarations Funding The study was supported by Liaoning Province Department of Education Basic Scientific Research Projects in Colleges and Universities (LJKQZ20222411). The authors have no conflicts of interest to disclose. CRediT authorship contribution statement Jingshuang Ma: Methodology, Investigation, Funding acquisition, Data analysis, Writing-original draft. Yanjie Wang: Investigation Resources, Writing-original draft. Wei Li: Data gathering, Data analysis. Aiping Wang: Project administration, Writing-review & editing, Ethical approval advice, Supervision. Declaration of competing interest The authors have no conflicts of interest to disclose. Ethics approval This study adhered to the Helsinki Declaration and obtained approval from the Ethics Committee of The First affiliate Hospital of China Medical University[(2020)2020-280-2]. References Aktas A, 2013. Cancer symptom clusters:current concepts and controversies. 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A cross sectional study to determine the prevalence of cough and its impact in patients with lung cancer: a patient unmet need. BMC Cancer. 20,9. https://doi: 10.1186/s12885-019-6451-1. Henoch I, Ploner A, Tishelman C, 2009. Increasing stringency in symptom cluster research: a methodological exploration of symptom clusters in patients with inoperable lung cancer. Oncol Nurs Forum . 36,E282eE292. https://doi: 10.1188/09. Herrstedt J, Lindberg S, Petersen PC, 2021. Prevention of Chemotherapy-Induced Nausea and Vomiting in the Older Patient: Optimizing Outcomes. Drugs Aging. 39,1-21. https://doi: 10.1007/s40266-021-00909-8. Huang XP, Zhou WH, Zhang YF,2015. Features of fatigue in patients with early-stage non-small cell lung cancer. J Res Med Sci. 20,268-72. Hulbert-Williams NJ, Beatty L, Dhillon HM, 2018. Psychological support for patients with cancer: evidence review and suggestions for future directions. Curr Opin Support Palliat Care. 12,276-292. https://doi:10.1097/SPC.0000000000000360 Hunter JJ, Maunder RG, Sui D,et al, 2020. A randomized trial of nurse administered behavioral interventions to manage anticipatory nausea and vomiting in chemotherapy. Cancer Med. 9(5),1733-1744. https://doi: 10.1002/cam4.2863. Jim HS, Jacobsen PB, Phillips KM, Wenham RM, Roberts W, Small BJ, 2013. Lagged relationships among sleep disturbance, fatigue, and depressed mood during chemotherapy. Health Psychol. 32(7),768-774. https://doi: 10.1037/a0031322. Epub 2013 Feb 25. Ju XD, Bai JY, She YW, et al, 2023. Symptom cluster trajectories and sentinel symptoms during the first cycle of chemotherapy in patients with lung cancer. Eur J Oncol Nurs. 63, 102282. https://doi: 10.1016/j.ejon.2023.102282. Kieffer JM, Postma TJ, van de Poll-Franse L, et al, 2017. Evaluation of the psychometric properties of the EORTC chemotherapy-induced peripheral neuropathy questionnaire (QLQ-CIPN20). Qual Life Res . 26(11),2999-3010. https://doi: 10.1007/s11136-017-1626-1. Kim E, Jahan T, Aouizerat BE, et al, 2009. Changes in symptom clusters in patients undergoing radiation therapy. Support Care Cancer . 17(11),1383–1391. https://doi: 10.1007/s00520-009-0595-5. Kim HJ, McGuire DB, Tulman L, Barsevick AM,2005. Symptom clusters: concept analysis and clinical implications for cancer nursing. Cancer Nurs . 28,270–282quiz 274-283.https://doi: 10.1097/00002820-200507000-00005. Kirkova J, Aktas A, Walsh D, et al, 2011. Cancer symptom clusters: clinical and research methodology. J Palliat Med . 14,1149–1166. https://doi:10.1089/jpm.2010.0507. Kirkova J, Aktas A, Walsh D, et al, 2010. Consistency of symptom clusters in advanced cancer. Am J Hosp Palliat Care. 27(5),342-346. https://doi: 10.1016/j.jpainsymman.2013.10.027. Lee HW, Lee CH, Park YS, 2018. Location of Stage I-III Non-small Cell Lung Cancer and Survival Rate:Systematic Review and Meta Analysis. Thorac Cancer. 9(12),1614-1622. https://doi:10.1111/1759-7714.12869 Li N, Wu J, Zhou J, Wu C, et al, 2020. Symptom Clusters Change Over Time in Patients With Lung Cancer During Perichemotherapy. Cancer Nurs.30(1). https://doi: 10.1097/NCC.0000000000000787. Lu PH, Keng JL, Kuo KL, et al, 2020. An Apriori algorithm–based association rule analysis to identify herb combinations for treating uremic pruritus using Chinese herbal bath therapy. Evid Based Complement Alternat Med . 8854772. https://doi: 10.1155/2020/8854772. Lynch KD, Dickinson K, Hsiao C, et al, 2016. Biological basis for the clustering of symptoms. Semin Oncol Nurs. 32(4),351-360．https://doi:10.1016/j.soncn.2016.08.002. Ma JS, Xu H, Liu S, et al, 2022. An investigation of symptom clusters and sentinel symptoms during the first 2 cycles of postoperative chemotherapy in patients with lung cancer. Cancer Nurs. 45(6):488-496. https://doi: 10.1097/NCC.0000000000001058. Miaskowski C, Mastick J, Paul SM, et al, 2018. Impact of chemotherapy-induced neurotoxicities on adult cancer survivors’ symptom burden and quality of life. J Cancer Surviv. 12(2),234–245. https://doi: 10.1007/s11764-017-0662-8. Rha SY, Park M, Lee J, 2019. Stability of symptom clusters and sentinel symptoms during the first two cycles of adjuvant chemotherapy. Support Care Cancer. 27,1687-1695. https://doi: 10.1007/s00520-018-4413-9. Robertson J, Raizer J, Hodges JS, et al, 2018. Risk factors for the development of paclitaxel-induced neuropathy in breast cancer patients. J Peripher Nerv Syst. 23(2),129–133. https://doi: 10.1111/jns.12271. Russell J, Wong ML, Mackin L, et al, 2019. Stability of symptom clusters in patients with lung cancer receiving chemotherapy. J Pain Symptom Manage. 57(5),909–922. https://doi: 10.1016/j.jpainsymman.2019.02.002. Smith JA, Harle A, Dockry R, et al, 2021. Aprepitant for Cough in Lung Cancer. A Randomized Placebo-controlled Trial and Mechanistic Insights. Am J Respir Crit Care Med . 203, 737-745. https://doi: 10.1164/rccm.202006-2359OC. Staff NP, Grisold A, Grisold W, et al, 2017. Chemotherapy-induced peripheral neuropathy: a current review. Ann Neurol. 81(6),772–781. https://doi: 10.1002/ana.24951. Stevens J, 2002. Applied Multivariate Statistics for the Social Sciences. Mahwah, NJ: Lawrence Erlbaum & Associates. Sullivan CW, Leutwyler H, Dunn LB, et al, 2018. A review of the literature on symptom clusters in studies that included oncology patients receiving primary or adjuvant chemotherapy. J Clin Nurs. 27(3–4),516–545. https://doi: 10.1111/jocn.14057. Sung H, Ferlay J, Siegel RL, et al, 2021. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 71(3), 209-249.https://doi:10.3322/caac.21660 Tanaka K, Akechi T, Okuyama T, et al, 2002. Impact of dyspnea, pain, and fatigue on daily life activities in ambulatory patients with advanced lung cancer. J Pain Symptom Manage. 23,417-423. https://doi: 10.1016/s0885-3924(02)00376-7. Wang DD, Fu JF., 2014. Symptom clusters and quality of life in China patients with lung cancer undergoing chemotherapy. Afr Health Sci . 14(1),49-55. Wang XS, Wang Y, Guo H, et al, 2004. Chinese version of the M.D. Anderson Symptom Inventory. Cancer. 101(8),1890–1901. Wu C, Zheng Y, Duan Y, et al, 2019. Nonpharmacological interventions for cancer-related fatigue: a systematic review and Bayesian network meta analysis. Worldviews Evid Based Nurs. 16,102–110. https://doi: 10.1111/wvn.12352. Xia C, Dong X, Li H, et al, 2022. Cancer statistics in China and United States: profiles, trends, and determinants. Chin. Med. J. 135, 584–590. Xia P, Gao K, Xie J, et al, 2020. Data mining-based analysis of Chinese medicinal herb formulae in chronic kidney disease treatment. Evid Based Complement Alternat Med . 9719872. https://doi: 10.1155/2020/9719872. Zhang LL, Zang Y, 2013. Revision and evaluation of the lung cancer module of the MD Anderson Symptom Inventory [in Chinese]. Tumor . 33(5),434–438. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4987982","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":349323194,"identity":"5c036085-52aa-428a-83d7-19375fa59bbb","order_by":0,"name":"Jingshuang Ma","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/0lEQVRIiWNgGAWjYBACAwSTsQFEyrGxtx8goIUZohSmxZiP50wCsVogIHGehIMBDsUQYM7ef/zBxz13Erf3H257+KXGLr1NgiGB4UfFNpxaLHsOMzbOePYscc6NxHZjmWPJuW3SjQcYe87cxu2wG8mMzTwHDifOkGBsk5ZgY85tkzmQwMzYhkfL/ceMzX9AWvgPArX8q09nk0gwwK/lBjNjMwNIC0Nim+THtsMJBLVY9iQbzuw5cNh4hkRimzRj33HDNmAgH8TnF3P2gw8+/DhwWHYG//Fnkj++VcvLt7cffPCjArcWFMDMA2UcIE49EDD+IFrpKBgFo2AUjCQAANXEXaKvD3deAAAAAElFTkSuQmCC","orcid":"","institution":"Liaoning University of Traditional Chinese Medicine","correspondingAuthor":true,"prefix":"","firstName":"Jingshuang","middleName":"","lastName":"Ma","suffix":""},{"id":349323195,"identity":"2f44e464-0324-4136-8105-72f9b477947d","order_by":1,"name":"Yanjie Wang","email":"","orcid":"","institution":"Liaoning University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yanjie","middleName":"","lastName":"Wang","suffix":""},{"id":349323196,"identity":"b61bd615-74d1-4529-a6ef-090c8be67621","order_by":2,"name":"Wei Li","email":"","orcid":"","institution":"Liaoning University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Li","suffix":""},{"id":349323197,"identity":"e622045a-b8ad-44b7-9d9a-eaee917a8926","order_by":3,"name":"Aiping Wang","email":"","orcid":"","institution":"Liaoning University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Aiping","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2024-08-28 04:15:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4987982/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4987982/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":67020109,"identity":"adbe3a93-ec4b-4b59-8293-571dfd201a18","added_by":"auto","created_at":"2024-10-19 14:01:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":821133,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4987982/v1/3023c1fd-7334-41cf-8857-5a6c0d1a8efb.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Symptom Clusters and Sentinel Symptoms During the Third and Fourth Cycles of Postoperative Chemotherapy in Lung Cancer Patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLung cancer is the most common malignant tumor endangering human health in the world, and it is the second most prevalent cancer globally and the leading cause of cancer-related death(Sung et al., \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). In China, it was predicted that lung cancer would have the highest incidence and mortality rates among all malignant tumors(Xia et al., \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Commonly used lung cancer treatments include targeted therapy, immunotherapy, surgery, chemotherapy, and radiotherapy. Although the short-term curative effects are significant, the side effects\u0026mdash;low immune function, bone marrow suppression, liver and kidney function damage, and gastrointestinal reactions\u0026mdash;seriously affect the survival time and prognosis of lung cancer patients(Har\u0026eth;ardottir et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Currently, surgery is the preferred treatment for early lung cancer, with the 5-year survival rate being as high as 67%(Lee et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). However, there is a risk of adverse reactions, which can seriously affect the patient\u0026rsquo;s quality of life. A study has shown that lung cancer patients experience various symptoms post-lobectomy, the most severe of which are fatigue, pain, shortness of breath, disturbed sleep, and drowsiness(Huang et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2015\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eLung cancer patients often experience multiple, concurrent, and dynamic symptoms, usually in symptom clusters (SCs)(Kirkova et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). Kim et al.(Kim et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2005\u003c/span\u003e) defined a \u0026ldquo;symptom cluster\u0026rdquo; as two or more symptoms with a stable correlation that are distinct from other symptom clusters and may be caused by a common pathological mechanism. These SCs not only reduce quality of life but also shorten the survival time of patients(Chow et al., 2019). Several longitudinal studies have helped identify SCs among patients with lung cancer during chemotherapy. Li et al.(Li et al., \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2020\u003c/span\u003e) explored the SCs of lung cancer patients two weeks before chemotherapy and at chemotherapy cycles 1 and 4. Results demonstrated that there were both similarities and differences between symptom clusters at the three individual time points. Three symptom clusters were stable, while another three could change during perichemotherapy. While research has provided an overall deeper understanding of the changes to SCs during chemotherapy, studies have mostly focused on patients with advanced lung cancer(Russell et al., \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Buck et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2020\u003c/span\u003e), and there are few studies about post-lobectomy lung cancer patients, whose survival time is longer(Lee et al., 2005).\u003c/p\u003e \u003cp\u003eA \u0026ldquo;sentinel symptom\u0026rdquo; is defined as an indicator or marker of a symptom cluster that can help predict or boost the occurrence of other symptoms within the symptom cluster(Brown et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Jim et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). Recognizing sentinel symptoms can help us to better understand the underlying mechanisms of SCs, which may help provide an entry point for effective symptom management(Rha et al., 2005). Rha et al.(Rha et al., 2005) explored sentinel symptoms during the first two cycles of adjuvant chemotherapy in cancer patients and found that sentinel symptoms included anxiety, loss of appetite, and fatigue during the 1st cycle and loss of appetite, depression, and fatigue during the 2nd. Sentinel symptoms can also be useful assessment indicators in clinical practice and can help simplify the assessment and management of SCs. As the number of studies that have tried to identify sentinel symptoms is limited(Brown et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Rha et al., \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Aktas et al., 2013; Kirkova et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Ju et al., \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), the relationship between sentinel symptoms and the additional symptoms in the SC needs to be further studied. Different studies have used different methods to identify the sentinel symptom. For example, Brown et al(Brown et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2011\u003c/span\u003e) applied Pearson correlation analyses, while principal variable analysis was conducted in Rha(Rha et al., \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Notably, the sentinel symptom onset time was neglected in these studies(Brown et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Rha et al., \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). In our study, based on the definition of \u0026ldquo;sentinel symptom,\u0026rdquo;(Brown et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Jim et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2013\u003c/span\u003e) we tried to associate symptom onset time with the relationship between symptoms within a cluster to identify the sentinel symptom, which we believe may be a more scientific method.\u003c/p\u003e \u003cp\u003eWe previously investigated SCs and sentinel symptoms during the first two cycles of postoperative chemotherapy in patients with lung cancer and found that symptom clusters and sentinel symptoms were stable during both cycles(Ma et al., \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). This study continues this research. Here, we aimed to explore the SCs of lung cancer patients and identify the sentinel symptoms within them during the third and fourth cycles of postoperative chemotherapy.\u003c/p\u003e\n\u003ch3\u003eTheoretical Framework\u003c/h3\u003e\n\u003cp\u003eThe symptom management model was first proposed by Larson et al.(Froelicher et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e1994\u003c/span\u003e) in 1994 at the Center for Symptom Management, University of California, San Francisco, which was later developed and improved by Dodd et al.(Dodd et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2001\u003c/span\u003e) in 2001 and renamed Symptom Management Theory (SMT) in 2008. Symptom experience, symptom management, and symptom outcome are three interrelated dimensions in this theory. This study focuses on the symptom experience portion of the model, particularly the individual\u0026rsquo;s evaluation and perception of symptoms, by identifying symptom clusters based on symptom severity and determining sentinel symptoms within symptom clusters by exploring the relationship between symptoms based on symptom occurrence.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSample and Setting\u003c/h2\u003e \u003cp\u003eThis study is a longitudinal study. The sample size was estimated by an item (or variable) ratio of 5:1, i.e., five cases for each item(Gorsuch et al., 1983; Stevens et al., 2002). By adopting a convenience sampling method, 180 patients were recruited from two hospitals in Shenyang. Inclusion criteria included (1) a clear primary non-small cell lung cancer diagnosis by pathology and cytology; (2) the patient be undergoing chemotherapy after surgery; (3) an age of 18 or above; and (4) a clear awareness, an informed diagnosis, independent communication skills, and a signed informed consent. Exclusion criteria included (1) a recurrence of lung cancer or metastasis to distant organs; (2) the patient receiving radiotherapy, immunotherapy, targeted therapy, and/or other treatments; (3) the presence of other malignant tumors requiring treatment; and (4) the presence of serious diseases of various important organs.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eMeasures\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eDemographic and Medical Characteristics Questionnaire\u003c/h2\u003e \u003cp\u003eThe demographic and Mmedical characteristics questionnaire consisted of two parts. The first part included demographic information\u0026mdash;such as age, gender, education level, and medical payment method\u0026mdash;while the second part included disease-related information\u0026mdash;such as pathological type, tumor stage, chemotherapy regimen, and chemotherapy cycle.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003eM.D. Anderson Symptom Inventory Lung Cancer-Specific Module\u003c/h2\u003e \u003cp\u003eThe M.D. Anderson Symptom Inventory (MDASI) was developed at the University of Texas Anderson Cancer Center for most patients with malignancy(Cleeland et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2000\u003c/span\u003e). The questionnaire consists of two parts: the first part measures the severity of 13 common cancer symptoms, such as pain, fatigue, and drowsiness, over the past 24 hours, and the second part evaluates the interference of the above symptoms with the patient\u0026rsquo;s daily life. In 2004, Wang et al(Wang et al., 2000) translated it into Chinese and evaluated Chinese cancer patients, showing that the Cronbach α coefficient of the MDASI\u0026rsquo;s scale was 0.87. The Lung cancer-specific module(Zhang et al., 2013) of the MDASI added 6 lung cancer-specific symptoms to the 13 core items\u0026mdash;including coughing, expectoration, hemoptysis, chest tightness, constipation, and body mass decline\u0026mdash;making a total of 19 items with a Cronbach α coefficient of 0.773 and content validity of 0.944. The inventory uses a score of 0 to 10 for each item, where 0 represents \"asymptomatic or no interference\" and 10 represents \"the most severe imaginable or complete interference,\u0026rdquo; and thus the total score for the inventory has a range of 0 to 190. The Cronbach α coefficient of this scale in the formal survey was 0.805.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003eFirst Appearance of Symptoms Time Sheet\u003c/h2\u003e \u003cp\u003eThe First Appearance of Symptoms Time Sheet was a self-made questionnaire with the same 19 symptom entries as the MDASI lung cancer-specific module. Patients recorded the time between chemotherapy drug infusion and the first onset of each symptom on the questionnaire in hours.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eProcedures\u003c/h2\u003e \u003cp\u003e This study was approved by the hospital ethics committee [(2020)2020-280-2]. Before the investigation, the investigators explained the significance and content of the study, and all study subjects signed the informed consent form. The demographic and medical characteristics questionnaire was completed by the investigators using the electronic medical record system. The MDASI Lung Cancer Specific Module and the First Appearance of Symptoms Time Sheet were completed by the study subjects. For subjects who were unable to fill out their own content, investigators read the questions one by one in a neutral tone and filled out the answers. The questionnaire collection method included a live face-to-face survey and a telephone survey. The MDASI Lung Cancer Specific Module was carried out on day 7 of chemotherapy cycle 3 and day 7 of chemotherapy cycle 4 (the day of the chemotherapy infusion was counted as day 1). The First Appearance of Symptoms Time Sheet was given to patients prior to chemotherapy cycles 3 and 4 and was collected on day 7 of each cycle.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eThe data were analyzed using SPSS Statistics 22.0 and SPSS Modeler 18.0. Count data were described by the frequency and composition ratio and measurement data conforming to the normal distribution by the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. Non-normally distributed data were expressed as M (P25, P75). Exploratory factor analysis was used to identify SCs based on the symptom severity dimension. To have sufficient differences in the data for exploratory factor analysis, symptoms with an incidence greater than 20% were included in the analysis(Kim et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). Factors with feature values greater than 1, symptom factor loads greater than 0.5, and loads on at least two factors were selected for the analysis(Emerson et al., 2017). A \u003cem\u003eP\u003c/em\u003e-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003cp\u003eAssociation rule analysis is a data mining technique that explores the basic rules and underlying relationships between variables. In recent years, association rule analysis algorithms have been applied in several studies in the medical field(Xia et al., \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Lu et al., \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). In order to improve the computational efficiency of association analysis, Agrawal and Strikant proposed the Apriori algorithm in 1994. After years of development and improvement, the Apriori algorithm has become the core algorithm of association analysis in data mining.\u003c/p\u003e \u003cp\u003eIn this study, the Apriori algorithm was used to generate effective symptom connectivity within the symptom clusters, which helps to identify sentinel symptoms. Support and confidence are evaluation metrics used to measure the relationship between symptoms in the Apriori algorithm. Support represents the concurrent proportion of previous and posterior symptoms in all samples, while confidence indicates the proportion of posterior symptoms in the sample with only previous symptoms, and an appropriate association rule should have both high support and confidence(Bayardo et al., 1999).\u003c/p\u003e \u003cp\u003eSentinel symptom identification was based on two points: first, the symptom was the earliest symptom in the SC(Jim et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2013\u003c/span\u003e); second, in the Apriori algorithm, the priority support was \u0026gt;\u0026thinsp;40%, the confidence was \u0026gt;\u0026thinsp;60% (i.e., there is a valid relationship between the two symptoms).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient and Treatment Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFrom the total sample (N = 180), six patients withdrew at chemotherapy cycle 2, and four patients withdrew at chemotherapy cycle 3 due to significant adverse effects. The average age of the patients was 52.16\u0026plusmn;10.36 years, with most of them being men (112, 62.22%). The proportion of patients with at least a junior high education level was 66.67%, and medical insurance was the main source of medical payment (158, 88.78%). In addition, adenocarcinoma accounted for 47.78% of patients, with most being in stage I (52, 28.89%) and stage II (98, 54.44%). Demographic and treatment characteristics are showcased in Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSCs and Sentinel Symptoms of Chemotherapy Cycle 3\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the third chemotherapy cycle, five SCs were extracted by exploratory factor analysis (KMO, 0.79): a digestive tract symptom group (nausea, vomiting, and lack of appetite), respiratory tract symptom group (coughing and shortness of breath), psychological symptom group (sadness and distress), physical symptom group (drowsiness, pain, and fatigue), and neurological symptom group (numbness and forgetfulness). The contribution rate of the cumulative variance was 78.62%(Table 2).\u003c/p\u003e\n\u003cp\u003eIn cycle 3, nausea was found to be the first symptom appearing in the gastrointestinal SC (Table 3). The Apriori algorithm\u0026ndash;based association rules analysis demonstrated that when nausea was the antecedent and the other symptoms were consequences, the support value was greater than 40%, and the confidence value was\u0026nbsp;\u003c/p\u003e\n\u003cp\u003egreater than 60% (Table 4). Based on these 2 points, nausea was identified as the sentinel symptom of the gastrointestinal SC. According to the same selection criteria, coughing was identified as the sentinel symptom for the respiratory tract SC, and fatigue for the physical SC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSCs and Sentinel Symptoms of the Chemotherapy Cycle 4\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the fourth chemotherapy cycle, four SCs were extracted by exploratory factor analysis (KMO, 0.81): digestive tract symptoms (nausea, vomiting, constipation, and lack of appetite), respiratory tract symptoms (coughing and shortness of breath), psychological symptoms (sadness and distress), and physical symptoms (drowsiness, pain, and fatigue). The contribution of the cumulative variance was 76.71%(Table 5).\u003c/p\u003e\n\u003cp\u003eIn cycle 4, nausea was the first symptom appearing in the gastrointestinal SC (Table 3). The association rules analysis demonstrated that, with nausea as the antecedent and the other symptoms consequences, the support was greater than 40% and the confidence was greater than 60% (Table 4). Thus, nausea was considered to be the sentinel symptom of the gastrointestinal SC. Based on the same selection criteria, coughing was identified as the sentinel symptom for the respiratory tract SC, and fatigue for the physical SC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1 \u0026nbsp;Patient and Treatment Characteristics(n=180)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.2746%;\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.331%;\"\u003e\n \u003cp\u003eCategories\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.3944%;\"\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.2746%;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eEducation\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMedical payment\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eStage\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ePathological type\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eChemotherapy regimen\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eLength after surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 34.331%;\"\u003e\n \u003cp\u003eMean\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003cp\u003eElementary\u003c/p\u003e\n \u003cp\u003eJunior high\u003c/p\u003e\n \u003cp\u003eSenior high\u003c/p\u003e\n \u003cp\u003eCollege or above\u003c/p\u003e\n \u003cp\u003eSelf-paid\u003c/p\u003e\n \u003cp\u003eMedical insurance\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;I\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;II\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;III\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Adenocarcinoma\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Squamous carcinoma\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eLarge cell carcinoma\u003c/p\u003e\n \u003cp\u003eAdenosquamous carcinoma\u003c/p\u003e\n \u003cp\u003ePemetrexed + Cisplatin\u003c/p\u003e\n \u003cp\u003eGemcitabine + Cisplatin\u003c/p\u003e\n \u003cp\u003eDocetaxel + Cisplatin\u003c/p\u003e\n \u003cp\u003eEtoposide + Cisplatin\u003c/p\u003e\n \u003cp\u003e＜1 month\u003c/p\u003e\n \u003cp\u003e1-2months\u003c/p\u003e\n \u003cp\u003e＞2 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.3944%;\"\u003e\n \u003cp\u003e52.16\u0026plusmn;10.36\u003c/p\u003e\n \u003cp\u003e112(62.22)\u003c/p\u003e\n \u003cp\u003e68(37.78)\u003c/p\u003e\n \u003cp\u003e23(12.78)\u003c/p\u003e\n \u003cp\u003e77(42.78)\u003c/p\u003e\n \u003cp\u003e43(23.89)\u003c/p\u003e\n \u003cp\u003e37(20.55)\u003c/p\u003e\n \u003cp\u003e22(12.22)\u003c/p\u003e\n \u003cp\u003e158(87.78）\u003c/p\u003e\n \u003cp\u003e52(28.89)\u003c/p\u003e\n \u003cp\u003e98(54.44)\u003c/p\u003e\n \u003cp\u003e30(16.67)\u003c/p\u003e\n \u003cp\u003e86(47.78)\u003c/p\u003e\n \u003cp\u003e65(36.11)\u003c/p\u003e\n \u003cp\u003e18(10.00)\u003c/p\u003e\n \u003cp\u003e11(6.11)\u003c/p\u003e\n \u003cp\u003e64(35.56)\u003c/p\u003e\n \u003cp\u003e54(30.00)\u003c/p\u003e\n \u003cp\u003e52(28.89)\u003c/p\u003e\n \u003cp\u003e10(5.55)\u003c/p\u003e\n \u003cp\u003e66(36.67)\u003c/p\u003e\n \u003cp\u003e78((43.33)\u003c/p\u003e\n \u003cp\u003e36(20.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003ea:According to the AJCC cancer staging manual 8th ed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2 \u0026nbsp;Symptom Clusters in the 3rd Cycle\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"662\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 21.148%;\"\u003e\n \u003cp\u003eSymptom\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.8248%;\"\u003e\n \u003cp\u003eDigestive tract SC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.0332%;\"\u003e\n \u003cp\u003eRespiratory tract\u003c/p\u003e\n \u003cp\u003eSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.0121%;\"\u003e\n \u003cp\u003ePsychological\u003c/p\u003e\n \u003cp\u003eSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.0272%;\"\u003e\n \u003cp\u003ePhysical SC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.9547%;\"\u003e\n \u003cp\u003eNeurological\u003c/p\u003e\n \u003cp\u003eSC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 21.148%;\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003cp\u003eLack of appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.8248%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.683\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.667\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.814\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19.0332%;\"\u003e\n \u003cp\u003e0.236\u003c/p\u003e\n \u003cp\u003e0.142\u003c/p\u003e\n \u003cp\u003e0.246\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.0121%;\"\u003e\n \u003cp\u003e0.143\u003c/p\u003e\n \u003cp\u003e0.162\u003c/p\u003e\n \u003cp\u003e0.133\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.0272%;\"\u003e\n \u003cp\u003e0.195\u003c/p\u003e\n \u003cp\u003e0.256\u003c/p\u003e\n \u003cp\u003e0.311\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.9547%;\"\u003e\n \u003cp\u003e0.205\u003c/p\u003e\n \u003cp\u003e0.146\u003c/p\u003e\n \u003cp\u003e0.181\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 21.148%;\"\u003e\n \u003cp\u003eCough\u003c/p\u003e\n \u003cp\u003eShortness of breath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.8248%;\"\u003e\n \u003cp\u003e0.191\u003c/p\u003e\n \u003cp\u003e0.204\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.0332%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.813\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.795\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0121%;\"\u003e\n \u003cp\u003e0.243\u003c/p\u003e\n \u003cp\u003e0.208\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0272%;\"\u003e\n \u003cp\u003e0.133\u003c/p\u003e\n \u003cp\u003e0.176\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.9547%;\"\u003e\n \u003cp\u003e0.231\u003c/p\u003e\n \u003cp\u003e0.139\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 21.148%;\"\u003e\n \u003cp\u003eSadness\u003c/p\u003e\n \u003cp\u003eDistress\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.8248%;\"\u003e\n \u003cp\u003e0.198\u003c/p\u003e\n \u003cp\u003e0.095\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.0332%;\"\u003e\n \u003cp\u003e0.255\u003c/p\u003e\n \u003cp\u003e0.109\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0121%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.765\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.804\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0272%;\"\u003e\n \u003cp\u003e0.129\u003c/p\u003e\n \u003cp\u003e0.264\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.9547%;\"\u003e\n \u003cp\u003e0.098\u003c/p\u003e\n \u003cp\u003e0.103\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 21.148%;\"\u003e\n \u003cp\u003eDrowsiness\u003c/p\u003e\n \u003cp\u003ePain\u003c/p\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.8248%;\"\u003e\n \u003cp\u003e0.204\u003c/p\u003e\n \u003cp\u003e0.163\u003c/p\u003e\n \u003cp\u003e0.399\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.0332%;\"\u003e\n \u003cp\u003e0.299\u003c/p\u003e\n \u003cp\u003e0.115\u003c/p\u003e\n \u003cp\u003e0.187\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0121%;\"\u003e\n \u003cp\u003e0.283\u003c/p\u003e\n \u003cp\u003e0.334\u003c/p\u003e\n \u003cp\u003e0.333\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0272%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.766\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.608\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.647\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.9547%;\"\u003e\n \u003cp\u003e0.201\u003c/p\u003e\n \u003cp\u003e0.190\u003c/p\u003e\n \u003cp\u003e0.207\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 21.148%;\"\u003e\n \u003cp\u003eNumbness\u003c/p\u003e\n \u003cp\u003eForgetfulness\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eCronbach\u0026rsquo;s \u0026alpha; Variance explained(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.8248%;\"\u003e\n \u003cp\u003e0.104\u003c/p\u003e\n \u003cp\u003e0.203\u003c/p\u003e\n \u003cp\u003e.75\u003c/p\u003e\n \u003cp\u003e18.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.0332%;\"\u003e\n \u003cp\u003e0.205\u003c/p\u003e\n \u003cp\u003e0.301\u003c/p\u003e\n \u003cp\u003e.72\u003c/p\u003e\n \u003cp\u003e16.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.0121%;\"\u003e\n \u003cp\u003e0.198\u003c/p\u003e\n \u003cp\u003e0.276\u003c/p\u003e\n \u003cp\u003e.67\u003c/p\u003e\n \u003cp\u003e14.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0272%;\"\u003e\n \u003cp\u003e0.398\u003c/p\u003e\n \u003cp\u003e0.288\u003c/p\u003e\n \u003cp\u003e.65\u003c/p\u003e\n \u003cp\u003e14.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.9547%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.698\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.635\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e.65\u003c/p\u003e\n \u003cp\u003e15.65\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: EFA, exploratory factor analysis; SC, symptom cluster.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSeven symptoms present in fever than 20% of the patients did not meet our criteria for inclusion in the EFA: sleep disturbance, dry mouth, constipation，hemoptysis, expectoration, chest tightness, and weight loss.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBoldface indicates 5 SCs were identified via EFAs utilizing 12 symptoms In cycle 3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3 The time of Symptom First Appearance\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"627\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTime\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSymptom Cluster\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSymptom\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 147px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFirst Appearance\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(mean\u0026plusmn;SD, h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eF\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003eCycle 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eDigestive tract\u003c/p\u003e\n \u003cp\u003eSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003cp\u003eVomiting\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eLoss of appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 147px;\"\u003e\n \u003cp\u003e20.02\u0026plusmn;8.16\u003c/p\u003e\n \u003cp\u003e23.96\u0026plusmn;7.01\u003c/p\u003e\n \u003cp\u003e30.22\u0026plusmn;5.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9.221\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eRespiratory tract\u003c/p\u003e\n \u003cp\u003eSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003eCough\u003c/p\u003e\n \u003cp\u003eShortness of breath\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 147px;\"\u003e\n \u003cp\u003e10.62\u0026plusmn;9.45\u003c/p\u003e\n \u003cp\u003e20.12\u0026plusmn;6.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14.203\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003ePsychological SC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003eSadness\u003c/p\u003e\n \u003cp\u003eDistress\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 147px;\"\u003e\n \u003cp\u003e12.54\u0026plusmn;10.66 11.55\u0026plusmn;11.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2.379\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e.110\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003ePhysical SC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003cp\u003eDrowsiness\u003c/p\u003e\n \u003cp\u003ePain \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 147px;\"\u003e\n \u003cp\u003e19.16\u0026plusmn;6.08 \u0026nbsp;25.84\u0026plusmn;5.08\u003c/p\u003e\n \u003cp\u003e30.23\u0026plusmn;6.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11.923\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eNeurological\u0026nbsp;SC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003eNumbness\u003c/p\u003e\n \u003cp\u003eForgetfulness\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 147px;\"\u003e\n \u003cp\u003e30.32\u0026plusmn;10.26\u003c/p\u003e\n \u003cp\u003e29.64\u0026plusmn;12.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2.531\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e.109\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003eCycle 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eDigestive tract\u003c/p\u003e\n \u003cp\u003eSC\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003cp\u003eVomiting\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eLoss of appetite\u003c/p\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 147px;\"\u003e\n \u003cp\u003e22.42\u0026plusmn;10.15\u003c/p\u003e\n \u003cp\u003e25.46\u0026plusmn;9.21\u003c/p\u003e\n \u003cp\u003e29.12\u0026plusmn;6.34\u003c/p\u003e\n \u003cp\u003e40.54\u0026plusmn;5.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7.231\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eRespiratory tract\u003c/p\u003e\n \u003cp\u003eSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003eCough\u003c/p\u003e\n \u003cp\u003eExpectoration Shortness of breath\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 147px;\"\u003e\n \u003cp\u003e15.82\u0026plusmn;9.63\u003c/p\u003e\n \u003cp\u003e18.14\u0026plusmn;7.48\u003c/p\u003e\n \u003cp\u003e23.62\u0026plusmn;5.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4.213\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e.018\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003ePsychological SC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003eSadness\u003c/p\u003e\n \u003cp\u003eDistress\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 147px;\"\u003e\n \u003cp\u003e16.34\u0026plusmn;10.67 19.25\u0026plusmn;7.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2.391\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e.118\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003ePhysical SC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003cp\u003eDrowsiness\u003c/p\u003e\n \u003cp\u003ePain \u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNumbness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 147px;\"\u003e\n \u003cp\u003e21.56\u0026plusmn;9.48 \u0026nbsp;27.34\u0026plusmn;9.28\u003c/p\u003e\n \u003cp\u003e28.52\u0026plusmn;7.34\u003c/p\u003e\n \u003cp\u003e30.32\u0026plusmn;10.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6.379\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e.010\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviation: SC, symptom cluster.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4 \u0026nbsp;Apriori Algorithm-based Association Rules\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"626\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTime\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSymptom Cluster\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAntecedent\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConsequent\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSupport\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConfidence\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"9\" valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003eCycle 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003eDigestive tract\u003c/p\u003e\n \u003cp\u003eSC\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNausea\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e68.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e70.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNausea\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eLack of appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e71.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e76.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e68.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e77.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003eLack of appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e65.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e70.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003eRespiratory tract\u003c/p\u003e\n \u003cp\u003eSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCough\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eShortness of breath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e66.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e75.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003eShortness of breath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eCough\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e66.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e82.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003ePhysical SC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFatigue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eDrowsiness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e77.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e86.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFatigue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003ePain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e58.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e68.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003eDrowsiness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003ePain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e52.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e61.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"11\" valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003eCycle 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003eDigestive tract\u003c/p\u003e\n \u003cp\u003eSC\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNausea\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e75.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e82.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNausea\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e50.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e65.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNausea\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eLack of appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e78.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e81.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e75.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e89.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003eLack of appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e62.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e74.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003eRespiratory- tract\u003c/p\u003e\n \u003cp\u003eSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCough\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eShortness of breath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e75.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e71.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003eShortness of breath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eCough\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e75.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e82.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003ePhysical SC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFatigue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eDrowsiness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e71.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e88.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFatigue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003ePain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e53.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e60.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003eDrowsiness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e71.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e89.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 138px;\"\u003e\n \u003cp\u003ePain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eDrowsiness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 73px;\"\u003e\n \u003cp\u003e61.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e71.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviation: SC, symptom cluster.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5 \u0026nbsp;Symptom Clusters in the 4th Cycle\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"574\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25.829%;\"\u003e\n \u003cp\u003eSymptom\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5462%;\"\u003e\n \u003cp\u003eDigestive tract SC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2914%;\"\u003e\n \u003cp\u003eRespiratory tract\u003c/p\u003e\n \u003cp\u003eSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.1501%;\"\u003e\n \u003cp\u003ePsychological\u003c/p\u003e\n \u003cp\u003eSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.1832%;\"\u003e\n \u003cp\u003ePhysical SC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25.829%;\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003cp\u003eLack of appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5462%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.690\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.678\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.728\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.802\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2914%;\"\u003e\n \u003cp\u003e0.219\u003c/p\u003e\n \u003cp\u003e0.083\u003c/p\u003e\n \u003cp\u003e0.154\u003c/p\u003e\n \u003cp\u003e0.261\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.1501%;\"\u003e\n \u003cp\u003e0.139\u003c/p\u003e\n \u003cp\u003e0.212\u003c/p\u003e\n \u003cp\u003e0.249\u003c/p\u003e\n \u003cp\u003e0.193\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.1832%;\"\u003e\n \u003cp\u003e0.179\u003c/p\u003e\n \u003cp\u003e0.246\u003c/p\u003e\n \u003cp\u003e0.134\u003c/p\u003e\n \u003cp\u003e0.231\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25.829%;\"\u003e\n \u003cp\u003eCough\u003c/p\u003e\n \u003cp\u003eShortness of breath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5462%;\"\u003e\n \u003cp\u003e0.289\u003c/p\u003e\n \u003cp\u003e0.159\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2914%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.882\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.805\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.1501%;\"\u003e\n \u003cp\u003e0.243\u003c/p\u003e\n \u003cp\u003e0.206\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.1832%;\"\u003e\n \u003cp\u003e0.153\u003c/p\u003e\n \u003cp\u003e0.206\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25.829%;\"\u003e\n \u003cp\u003eSadness\u003c/p\u003e\n \u003cp\u003eDistress\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5462%;\"\u003e\n \u003cp\u003e0.198\u003c/p\u003e\n \u003cp\u003e0.099\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2914%;\"\u003e\n \u003cp\u003e0.241\u003c/p\u003e\n \u003cp\u003e0.187\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.1501%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.767\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.753\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.1832%;\"\u003e\n \u003cp\u003e0.193\u003c/p\u003e\n \u003cp\u003e0.254\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25.829%;\"\u003e\n \u003cp\u003eDrowsiness\u003c/p\u003e\n \u003cp\u003ePain\u003c/p\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003cp\u003eCronbach\u0026rsquo;s \u0026alpha; Variance explained(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19.5462%;\"\u003e\n \u003cp\u003e0.198\u003c/p\u003e\n \u003cp\u003e0.191\u003c/p\u003e\n \u003cp\u003e0.318\u003c/p\u003e\n \u003cp\u003e.72\u003c/p\u003e\n \u003cp\u003e21.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21.2914%;\"\u003e\n \u003cp\u003e0.116\u003c/p\u003e\n \u003cp\u003e0.203\u003c/p\u003e\n \u003cp\u003e0.186\u003c/p\u003e\n \u003cp\u003e.75\u003c/p\u003e\n \u003cp\u003e17.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.1501%;\"\u003e\n \u003cp\u003e0.233\u003c/p\u003e\n \u003cp\u003e0.242\u003c/p\u003e\n \u003cp\u003e0.189\u003c/p\u003e\n \u003cp\u003e.69\u003c/p\u003e\n \u003cp\u003e18.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.1832%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.609\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.698\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.628\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e.65\u003c/p\u003e\n \u003cp\u003e19.27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: EFA, exploratory factor analysis; SC, symptom cluster.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEight symptoms present in fewer than 20% of the patients did not meet our criteria for inclusion in the EFA: sleep disturbance, dry mouth, forgetfulness, numbness, hemoptysis, expectoration, chest tightness, and weight loss.\u003c/p\u003e\n\u003cp\u003eBoldface indicates 4 SCs were identified via EFAs utilizing 12 symptoms In cycle 4.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cstrong\u003eThe Stability of SCs During Cycle 3 and Cycle 4\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCombined with the results of our previous study, this study showed that among the four cycles of postoperative chemotherapy for lung cancer patients, five different symptom groups were found: digestive tract, respiratory tract, psychological, physical, and neurological symptom groups. Except for the neurological SC, which only presented in cycle 3, the remaining four SCs remained stable across the cycles.\u003c/p\u003e\n\u003cp\u003eNausea, vomiting, and lack of appetite are stable digestive tract symptoms, occurring in digestive tract SCs, chemotherapy-induced nausea and vomiting (CINV) are the most common serious clinical adverse effects despite global and domestic guidelines consistently recommending serotonin receptor antagonist (5HT3RA) and dexamethasone for moderate emetic-risk chemotherapy and these two drugs plus aprepitant or fosaprepitant for hyperemetic chemotherapy. However, the clinical practice context of these guidelines and the proportion and extent of the occurrence of CINV under antiemetic applications following the most appropriate guidelines have not been well studied.\u003c/p\u003e\n\u003cp\u003eCoughing, expectoration, and dyspnea were the stable respiratory symptoms of the respiratory tract SCs. Some studies have found that coughing, dyspnea, and shortness of breath were common within this symptom group(Henoch\u0026nbsp;et al., 2009;\u0026nbsp;Choi\u0026nbsp;et al., 2018), corroborating the findings of this study. These studies highlight the clinical importance of this symptom group in patients with lung cancer. Moreover, another study found that lung cancer patients with a higher incidence of respiratory symptoms at initial diagnosis had a worse prognosis(Ban\u0026nbsp;et al., 2016). Respiratory SCs can interfere with patients’ daily activities and ability to maintain their quality of life(Tanaka\u0026nbsp;et al., 2002).\u003c/p\u003e\n\u003cp\u003eSadness and distress were stable symptoms in the psychological SCs(Faye-Schjøll\u0026nbsp;et al., 2019). Because lung cancer is difficult to cure and requires long-term treatment, patients are prone to suffer negative emotions. Emotional problems in lung cancer patients can increase symptom burden and affect cognitive function. Therefore, there is a need to provide systematic psychological support and effective symptom management for these patients, and clinicians need to screen for psychological symptoms and recommend effective interventions, such as cognitive-based therapy, mindfulness training, and participation in support groups(Hulbert-Williams\u0026nbsp;et al., 2018).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur study found that fatigue, drowsiness, pain were stable symptoms of the physical SCs. Drowsiness and numbness may be related to the peripheral neurotoxicity caused by the application of platinum-based chemotherapeutic agents. Lynch et al(Lynch\u0026nbsp;et al., 2018). showed that fatigue, pain, and sleep disturbances often develop as a symptom aggregation, which is similar to the results of this study. Although this cluster has been found less in previous studies of lung cancer patients, it is a common SC in many other cancer studies. More research is needed to confirm the presence of this symptomatic cluster in patients with lung cancer.\u003c/p\u003e\n\u003cp\u003eIn this study, neurological SCs were only present in cycle 3. Chemotherapy-induced peripheral neuropathy is a common side effect in cancer patients treated with neurotoxic agents(Staff\u0026nbsp;et al., 2017). As the chemotherapy regimen of the study subjects is mainly platinum-based, the forgetfulness and numbness may be related to peripheral nerve toxicity caused by the application of platinum-based chemotherapy drugs. These symptoms often exist together and affect cancer patients by causing paresthesia, functional impairment, and hearing and vision impairment(Kieffer\u0026nbsp;et al., 2017). Several studies have also shown that neurological SCs can cause psychological problems—such as anxiety, depression, and stress disorders—thereby further reducing the quality of life for cancer patients(Miaskowski\u0026nbsp;et al., 2018). Severe neurological symptoms may force patients to stop chemotherapy prematurely, reducing the anticancer treatment efficacy and possibly overall survival(Robertson\u0026nbsp;et al., 2018). A recent literature review summarizing 19 studies of chemotherapy-related SCs found that very few studies clearly delineate neurological SCs(Sullivan\u0026nbsp;et al., 2018). Future studies are warranted to identify the nature of neurospecific SCs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe Stability of Sentinel Symptoms During Cycle 3 and Cycle 4\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results of this study showed that nausea is a sentinel symptom of digestive tract SCs. Despite significant progress in the prevention of CINV over the past 40 years, they remain highly prevalent in chemotherapy patients. Nausea and vomiting are also the two most feared side effects of cancer treatment, both, but especially nausea, placing a heavy burden on patients(Herrstedt\u0026nbsp;et al., 2021). The reason for this may be that chemotherapeutic drugs are often cytotoxic and can stimulate the medulla emesis center, which transmits signals through peripheral and central pathways, thus leading to nausea and vomiting. During chemotherapy, antiemetic drugs are usually used, but these often inhibit gastrointestinal peristalsis and cause constipation. When people feel nausea, gastric tension, and weakened peristalsis accompanied by increased duodenal tension and associated epigastric discomfort, this often leads to a loss of appetite. Therefore, medical staff need to pay more attention to the development and severity of nausea and develop individualized prevention and treatment plans according to the chemotherapy regimen—which can help relieve nausea, improve digestive tract symptoms, reduce food intake, and increase meal frequency—and administer timely interventions for nausea sufferers, such as relaxation training or TCM intervention(Hunter\u0026nbsp;et al., 2020).\u003c/p\u003e\n\u003cp\u003eCoughing is a sentinel symptom of respiratory tract SCs. Chemotherapy drugs stimulate bronchi and cause decreased white blood cell counts, decreased immunity, coughing, respiratory infection, respiratory mucosa damage, and increased mucosal secretion resulting in sputum. Rapid and frequent coughing can result in a transient lack of oxygen and symptoms of shortness of breath. Studies have shown that the prevalence of coughing at diagnosis is 70%, while that before death is 81%(Harle\u0026nbsp;et al., 2020). The incidence of coughing in lung cancer patients seems to be underestimated, and the treatment of coughing in patients remains an important unmet need(Smith\u0026nbsp;et al., 2021), with two-thirds of the lung cancer patient population perceiving coughing as severe enough to require therapy(Harle\u0026nbsp;et al., 2020). Therefore, medical staff should strengthen the evaluation of coughing; keep the environment comfortable and clean; and inform patients that they should drink more water, eat more fruits and vegetables, and avoid overly sweet or sour foods. At the same time, patients can be guided to perform cough training to relieve coughing symptoms and improve respiratory SCs.\u003c/p\u003e\n\u003cp\u003eFatigue is a sentinel symptom of physical SCs. The reason for this may be that fatigue leads to decreased physical strength and activity, and sleep can help patients recover their physical strength. Furthermore, the occurrence of pain, fatigue, and sleep disturbance is associated with a common proinflammatory cytokine(Wang\u0026nbsp;et al., 2014). Fatigue can lead to a temporary loss of local nerve function, resulting in lameness and numbness. Cancer-related fatigue is one of the most common subjectively unpleasant side effects in patients during chemotherapy, affecting up to 90% of lung cancer patients, and is an intractable symptom(Ebede\u0026nbsp;et al., 2017). However, despite extensive research efforts to address this issue, including patient education and physical exercise, clinicians, caregivers, and patients themselves still regard cancer-related fatigue as an inevitable consequence of cancer treatment and a difficult-to-treat symptom(Wu\u0026nbsp;et al., 2019). A systematic review highlighted the efficacy of some non-pharmacological interventions, including physical activity, psychotherapy, and acupuncture, in overcoming fatigue(Bootsma\u0026nbsp;et al., 2020). Attitudes play an important role in patient perception, and psychological adaptation strategies, such as adapting to and receiving fatigue, can help patients cope with physical symptoms and side effects.\u003csup\u003e52\u003c/sup\u003e Medical staff should give a high priority to relieving fatigue in their health management. When patients develop fatigue, medical staff should consider other possible symptoms and intervene as soon as possible to slow down fatigue and reduce the severity of other symptoms caused by fatigue.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplications for Practice\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAn understanding of SCs and sentinel symptoms may be beneficial for clinicians in assessing and managing symptoms in postoperative patients with lung cancer during chemotherapy. Clinicians need to pay close attention to sentinel symptoms and develop effective interventions to reduce the symptomatic burden of patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDue to multiple measurements of the same patient, some sample size loss and some selection bias resulting from loss to follow-up occurred. Here, we only explored the SCs and their sentinel symptoms during the end of chemotherapy, and the sentinel symptoms of later chemotherapy cycles and the whole chemotherapy treatment need further study. Additionally, only one statistical analysis method was used to identify sentinel symptoms, and more analysis methods are needed to improve sentinel symptom identification in the future.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study shows that most of the SCs and sentinel symptoms were stable during chemotherapy, but the neurological symptom group only appeared in the third cycle, and the mechanism behind the occurrence and development of the neurological symptom group needs to be further explored in future studies. At present, the study of sentinel symptoms in the field of SCs is still in its infancy, and this study can provide new ideas and new methods to improve future research on the sentinel symptoms of SCs.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was supported by Liaoning Province Department of Education Basic Scientific Research Projects in Colleges and Universities (LJKQZ20222411). The authors have no conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRediT authorship contribution statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJingshuang Ma:\u003c/strong\u003e Methodology, Investigation, Funding acquisition, Data analysis, Writing-original draft. \u003cstrong\u003eYanjie Wang:\u0026nbsp;\u003c/strong\u003eInvestigation Resources, Writing-original draft. \u003cstrong\u003eWei Li:\u003c/strong\u003e Data gathering, Data analysis. \u003cstrong\u003eAiping Wang:\u003c/strong\u003e Project administration, Writing-review \u0026amp; editing, Ethical approval advice, Supervision.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of competing interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to disclose.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study adhered to the Helsinki Declaration and obtained approval from the Ethics Committee of The First affiliate Hospital of China Medical University[(2020)2020-280-2].\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAktas A, 2013. 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Tumor\u003cem\u003e.\u003c/em\u003e 33(5),434\u0026ndash;438.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Apriori algorithm, Chemotherapy, Lung cancer, Sentinel symptom, Symptom cluster","lastPublishedDoi":"10.21203/rs.3.rs-4987982/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4987982/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eLung cancer has the highest incidence and mortality in China, and patients after lobectomy experience serious physical and psychological symptoms during chemotherapy. Studies are lacking about symptom clusters and sentinel symptoms during the postoperative chemotherapy period in lung cancer patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective: \u003c/strong\u003eTo explore the stability of symptom clusters and sentinel symptoms during the 3nd and 4th cycles of postoperative chemotherapy in patients with lung cancer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThe study was a longitudinal study. Lung cancer patients after lobectomy were measured at 2 separate points:chemotherapy cycle 3 and chemotherapy cycle 4. The measures administered included M.D.Anderson Symptom Inventor Lung Cancer Specific Module and Self-made First Appearance of Symptoms Time Sheet.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: A total of 180 postoperative patients with lung cancer participated in the study. Five symptom clusters and three sentinel symptoms were identified at chemotherapy cycle 3. Four symptom clusters and three sentinel symptoms were identified at chemotherapy cycle 4.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eSymptom clusters and sentinel symptoms were relatively stable during the 3nd and 4th cycles of postoperative chemotherapy in patients with lung cancer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplications for practice: \u003c/strong\u003eThe understanding of symptom clusters and sentinel symptoms could be beneficial for clinicians to assess and manage symptoms in postoperative patients with lung cancer during chemotherapy. Clinicians should pay close attention to sentinel symptoms and develop effective interventions to reduce the symptom burden of patients.\u003c/p\u003e","manuscriptTitle":"Symptom Clusters and Sentinel Symptoms During the Third and Fourth Cycles of Postoperative Chemotherapy in Lung Cancer Patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-04 17:04:22","doi":"10.21203/rs.3.rs-4987982/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c5223cc3-6871-473a-a076-405bb79c08ec","owner":[],"postedDate":"October 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-19T13:53:44+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-04 17:04:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4987982","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4987982","identity":"rs-4987982","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}