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

doi:10.21203/rs.3.rs-4987982/v1

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

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.

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).

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
	Respiratory tract SC	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
	Respiratory- tract SC	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.

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.

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.

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].

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No competing interests reported.

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

Status:

Version 1

Abstract

Introduction

Theoretical Framework

Methods

Sample and Setting

Measures

Demographic and Medical Characteristics Questionnaire

M.D. Anderson Symptom Inventory Lung Cancer-Specific Module

First Appearance of Symptoms Time Sheet

Procedures

Statistical Analysis

Results

Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

Version 1