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10.1371/journal.pone.0307725
PONE-D-23-41096
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Identifying symptom cluster in cancer patients undergoing chemotherapy-in Vietnam: A cross-sectional study
Symptom cluster in cancer patients undergoing chemotherapy
https://orcid.org/0000-0002-5248-0398
Hoang Huong Thi Xuan Formal analysis Methodology Project administration Supervision Validation Writing – original draft Writing – review & editing 1 *
Le Quyen Thi Le Data curation Formal analysis Investigation Writing – original draft 2
Do Vi Pham Nhat Formal analysis Writing – original draft 3
Nguyen Anh Thi Hong Data curation Formal analysis Methodology Writing – original draft 4
Bui Quang Vinh Conceptualization Formal analysis Investigation Writing – original draft 2
1 Nursing Faculty, Phenikaa University, Ha Dong District, Hanoi, Vietnam
2 Hanoi Oncology Hospital, Hai Ba Trung District, Hanoi, Vietnam
3 The Nethersole School of Nursing, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
4 Nursing Faculty, East Asia University of Technology, Hanoi, Vietnam
Wang Tao (Alison) Editor
Charles Darwin University, AUSTRALIA
Competing Interests: The authors have declared that no competing interests exist.

* E-mail: huong.hoangthixuan@phenikaa-uni.edu.vn
20 9 2024
2024
19 9 e030772514 1 2024
10 7 2024
© 2024 Hoang et al
2024
Hoang et al
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Background

Major cancer treatments can cause a wide range of unpleasant symptoms that burden oncology patients. Different symptom clusters (SC) among cancer patients have been reported in the literature. This study determined the prevalence of symptoms patients experience during chemotherapy treatment and identified symptom clusters among them.

Methods

A cross-sectional study was conducted among 213 cancer patients undergoing chemotherapy in three large hospitals in Vietnam. Symptoms were measured by the Memorial Symptom Assessment Scale.

Results

The most prevalent symptoms were lack of appetite (65.3%), difficulty sleeping (62.9%), dry mouth (57.7%), numbness (60.1%), hair loss (43.2%), change in the way food tastes (40.8%), and lack of energy (44.1%). Four symptom clusters were identified. Difficult concentration, pain, cough, and dizziness contributed to the first SC. The second one included lack of energy, numbness, change the food taste, and lack of appetite. Dry mouth, nausea, feeling bloated, problems with urination, hair loss, and constipation made up for the third SC. The final SC consisted of psychological symptoms, which were feeling nervous, feeling drowsy, feeling sad, worrying, problems with sexual interest or activity and difficulty sleeping.

Conclusion

The study demonstrated that respondents experienced various symptoms and symptom clusters during chemotherapy. These findings can be used to develop clinical guidelines for symptom assessment and management in oncology patients for healthcare professionals.

The author(s) received no specific funding for this work. Data AvailabilityThe data underlying the results presented in the study are available at https://doi.org/10.7910/DVN/1QCVHD.
Data Availability

The data underlying the results presented in the study are available at https://doi.org/10.7910/DVN/1QCVHD.
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pmcIntroduction

Approximately one in six fatalities worldwide is attributable to cancer, making it a leading cause of death World Health Organization [1]. The global cancer burden is estimated to be 28.4 million cases in 2040 [2, 3]. Major treatments for cancer, such as surgery, chemotherapy, and radiotherapy, improve patient survival but can also have a substantial negative psychosocial and physical effect by exacerbating unpleasant symptoms that burden oncology patients [4–6]. Nearly half of cancer patients reported at least two symptoms throughout their illness, and on average, those who were undergoing chemotherapy reported at least ten symptoms that had a negative impact on their functional status and quality of life [7]. Hence, the concept of “symptom clusters” has been investigated. A symptom cluster has been defined as at least two symptoms that occurred and related to each other at a certain time, share a significant variance in their cluster, and may not have the same etiology [8, 9]. Different symptom clusters among cancer patients have been reported, such as pain, fatigue, and sleep; anxiety and depression [10] fatigue, depression, and insomnia [11, 12]; pain, fatigue, and insomnia [13–16] or nausea and vomiting [9]. However, the majority of the earlier research were conducted in a small sample size, and some studies only measured only 13 to 15 symptoms, while cancer patients can experience up to 32 symptoms [17]. In addition, previous studies explored symptom clusters in specific cancers such as breast cancer [18, 19], lung cancer [20], and gastric cancer [21]. We found two studies which were conducted in a population that included various cancer diagnoses with large sample sizes. In the study conducted by Morse, Cooper [22] among 1329 patients with various cancer diagnoses, eight symptom clusters were identified (i.e., physical and cognitive fatigue, respiratory, psychological, hormonal, chemotherapy-related toxicity, weight gain, gastrointestinal, and epithelial). Harris, Kober [23] found five symptom clusters, including psychological, gastrointestinal, weight gain, respiratory and hormonal clusters among more than 1000 outpatients with different cancers. In addition, researchers also pointed out there is no consensus on which symptoms occur in the population of cancer patients [24]. As such, the correlation between symptoms reported by cancer patients during treatment has not been fully addressed in the current literature. Furthermore, no study has been done previously to explore symptom clusters among cancer patients during chemotherapy in Vietnam, where people tend to skip their local health providers to go straight to the central hospitals for treatment. As the results, they have dealt with the bed-sharing problem (two or three patients share one bed). This issue not only caused so many inconveniences for the patients during their hospitalisation (from eating to resting) but also made the hospital become overloaded. Travelling a long way to receive treatment and facing persistent overload at hospitals have added burden to their treatments. Therefore, we conducted this study to assess the prevalence of symptoms that cancer patients experience during chemotherapy treatment and identify symptom clusters among such patients in the context of Vietnam, a low-middle-income country.

Methods

Study design

A cross-sectional design was conducted.

Participants and settings

The study included 213 cancer patients from 3 large oncology hospitals in Vietnam (Vietnam National Cancer Institute, Bach Mai Hospital, and Hanoi Oncology Hospital). Vietnam National Cancer Institute: This is the largest cancer hospital in Vietnam, the hospital has 2400 beds and in charge of providing cancer treatments for patients from North and Middle of Vietnam (1700 patients per day on average). Bach Mai Hospital is one of the three largest general hospitals in Vietnam, its oncology unit has 300 beds and receives about 400 cancer patients per day on average. Hanoi Oncology Hospital is a public hospital in charge of providing cancer treatment for patients in Hanoi. The hospital has 680 beds and receives about 945 patients per day.

Inclusion and exclusion criteria

Patients were recruited if they were undergoing chemotherapy with any cancer diagnosis; had received at least one chemo-cycle, were 18–84 years old, and having a Karnofsky Performance Index ≥ 80. Patients were excluded if they had conditions that would prohibit completing the questionnaires, such as cognitive impairments or psychiatric disorders.

Sample size calculation

Since the symptom cluster was identified by the correlation, we used the formula N ≥104 + m with “m” referring to the number of independent variables to calculate the sample size for the study [25]. There were 106 independent variables in the study (72 variables to measure 24 symptoms in 3 dimensions, 16 to measure 8 symptoms in 2 dimensions, and 18 to measure participant’s characteristics). As such, the minimum sample size is 210. In this study, we sent out 250 invitations and received 213 responses. Therefore, the sample size of the study was 213.

Procedures

Data were collected from 30th May to 28th July 2017 by 3 researchers using the convenience sampling method. Potential participants were approached and invited to the study in their ward. The researchers explained the purpose of the study. Participants who agreed to participate were informed of the procedures in detail and were provided with the study information sheet. Each participant signed the consent form. Afterwards, they were given the questionnaires to complete.

Measurements

The Vietnamese version of the Memorial Symptom Assessment Scale (MSAS) (α = 0.79) was used to measure the symptom burden. The MSAS was translated into Vietnamese following the forward-backwards methods and had been validated by 5 experts in oncology. This is a self-reported questionnaire that measures 24 symptoms in 3 dimensions: frequency, severity, and distress; and eight symptoms were evaluated in terms of severity and distress (total of 32 symptoms). With each of the symptoms that the patients experienced, the frequency and severe dimensions were measured by a Likert scale from 1 to 4 (from “rarely” to “almost constantly” for the frequency and from “slight” to “very severe” for the severity). The distress dimension was a Likert scale from 0 to 4, with 0 referring to “not at all” and 4 referring to “very much”. If a symptom is absent, each of the dimensions is scored as 0.

The MSAS has three sub-scales including Physical Symptom Subscale (PHYS), Psychological Symptom Subscale (PSYCH) and Global Distress Index (GDI). The PHYS is the average of the score for the 12 symptoms (lack of appetite, lack of energy, pain, feeling drowsy, constipation, dry mouth, nausea, vomiting, change in food taste, weight loss, feeling bloated, and dizziness). The PSYCH is the average of the score of the 6 symptoms (worrying, feeling sad, feeling nervous, difficulty sleeping, feeling irritable, and difficulty concentrating). The GDI is the average of the frequency of 4 psychological symptoms (feeling sad, worrying, feeling irritable, feeling nervous) and the distress associated with 6 physical symptoms (lack of appetite, lack of energy, pain, feeling drowsy, constipation, dry mouth). The Total MSAS score (TMSAS) is the average of the symptom scores of all 32 symptoms [26]. The Cronbach’s alpha was reported to be high in the current study. The overall scale had α = 0.92, with the psychological subscale α = 0.80 and the physical subscale α = 0.83.

Ethical consideration

The study followed Helsinki’s rules of ethics in medical research. Participants gave written informed consent to participate in the study. Only the first and corresponding authors had access to information that could identify participants during and after data collection. The study obtained ethical approval from the Human Subject Ethics Committee of Hanoi School of Public Health (Vietnam) and The Hong Kong Polytechnic University under reference number HSEARS20170428003.

Data analysis

Data were analysed using SPSS 20.0. Descriptive statistics were used to report the prevalence and distress of the symptoms (number of participants and related percentage). It was also used to analyze the participant’s demographic and clinical characteristics. Symptom clusters were identified by using Principal Component Analysis (PCA). To identify clinically meaningful symptom clusters, only symptoms with >20% prevalence and distress from “Quite a bit” to “very much” were selected for PCA [27]. There was no consensus about the cut-off value for the Pearson coefficient in cluster analysis. As such, a Pearson coefficient of > 0.3 was defined for a cluster [28]. The Kaise-Meyer-Olkin of the results (KMO) was greater than 0.80, which verified the sampling adequacy for the analysis, the Barlett’s test of sphericity χ2 ranked from 2430.43 to 3651.06, p<0.001, indicated that correlation between symptoms was sufficiently large for PCA [29].

Results

Participants’ characteristics

The majority of the participants were in the age group of 46 to 60 years old (48.8%; mean age was 53.1 years old). Most of the participants were female (128 patients, 60%). In the survey, the majority of patients were married (198, 88.7%) and being farmers or workers (80, 37.6%). Most of the participants had no comorbidities (n = 177, 83.1%), while for those who had, the most common comorbidity was hypertension (6.1%), followed by diabetes (3.3%). The majority of participants were diagnosed with breast cancer (59 patients, 27.7%). More than half of the patients had their tumor removed (121, 56.8%). The mean time from diagnosis was 13.7 (21.0) months (1–156). Texan-based chemotherapy regimen was the most common cancer treatment regimen among participants (102, 47.9%). Details of the demographic and clinical characteristics of the sample are shown in Table 1.

10.1371/journal.pone.0307725.t001 Table 1 Demographic and clinical characteristics of the patients.

	Patients (n = 213)	%	
Age group			
    ≤ 45	54	25.4	
    46–60	104	48.8	
    > 60	55	25.8	
    Mean age (Mean ± SD)	53.14 ± 11.3 (21–80)	
BMI (Mean ± SD)	21.41 ± 2.53 (14.7–30.4)	
Marital status			
    Single	13	6.1	
    Married	189	88.7	
    Divorced/Widowed	11	5.1	
Occupation			
    Unemployed	30	14.1	
    Retired	51	23.9	
    Laborer	80	37.6	
    Officer	12	5.6	
    Teacher	11	5.2	
    Others (Medical staff, Engineer, Freelancer)	29	13.6	
Education			
    Primary school	18	8.5	
    High school or part of	145	68.1	
    College or part of	28	13.1	
    University or Higher	22	10.3	
Comorbidity			
    None	177	83.1	
    Diabetes	7	3.3	
    Hypertension	13	6.1	
    Hypertension and diabetes	3	1.4	
    Degenerative spine	5	2.3	
    Others (Adipose hepatica, Gout, Dyslipidemia)	8	3.8	
Cancer diagnosis			
    Breast cancer	59	27.7	
    Gynecologic cancer	24	11.3	
    Lung/Bronchial Cancer	41	19.2	
    Gastrointestinal Cancer	38	17.8	
    Non-Hopkin Lymphoma	30	14.1	
    Others (Nasopharyngeal cancer, Brain cancer,     Amygdales cancer, Laryngeal cancer, tongue cancer, Nasopharynx cancer, Urinary system cancer)	21	9.9	
Cancer stage			
    1	28	13.1	
    2	66	31.0	
    3	62	29.1	
    4	57	26.8	
Surgical debulking			
    Optimal	121	56.8	
    Sub-optimal	20	9.4	
    None	72	33.8	
Chemotherapy Regimen			
    Taxane based Chemotherapy	102	47.9	
    Cyclophosphamide and doxorubicin based Chemotherapy	50	23.5	
    Oxaliptatin based Chemotherapy	23	10.8	
    Gemcitabine based Chemotherapy	18	8.5	
    Others (Vinorelbine, Rituximab, Trastuzumab)	20	9.4	

Prevalence of symptoms

The common symptoms reported by participants were lack of appetite (65.3%); difficulty sleeping (62.9%), dry mouth (57.7%), numbness (60.1%), hair loss (43.2%), change in the way food tastes (40.8%), worrying (46%), feeling sad (41.8%), and lack of energy (44.1%).

The symptoms associated with distress (ranging from “quite a bit” to “very much”) reported by more than 40% of participants were numbness (43.2%), difficulty sleeping (60.6%), and lack of appetite (44.1%).

The symptoms associated with severe (ranging from “moderate” to “very severe”) were Lack of energy, dry mouth, numbness, difficulty sleeping, feeling bloated, problems with urination, vomiting, worrying, problems with sexual interests or activity, lack of appetite, feeling irritable, change in the way food tastes, hair loss, constipation, and “I don’t look like myself”. Details of the prevalence, distress and severity of symptoms reported by participants are shown in Table 2.

10.1371/journal.pone.0307725.t002 Table 2 Prevalence and distress of the symptom experienced by participants (n = 213).

Symptom	Prevalence %	Distress % (from “Quite a bit to ‘Very much)	Severity* Mean (SD)	
Difficult concertration	84 (39.4%)	45 (21.1%)	1.8 (0.94)	
Pain	71 (33.3%)	48 (22.5%)	1.9 (1.01)	
Lack of Energy	94 (44.1%)	65 (30.5%)	2.14 (1.21)	
Cough	82 (38.5%)	49 (23%)	1.95 (0.98)	
Feeling nervous	61 (28.6%)	43 (20.2%)	1.89 (0.93)	
Dry mouth	123 (57.7%)	76 (35.%)	2.08 (1.03)	
Nause	74 (34.7%)	50 (23.5%)	1.89 (0.99)	
Feeling drowsy	72 (33.8%)	43 (20.2%)	1.79 (8.85)	
Numbness	128 (60.1%)	92 (43.2%)	2.16 (1.04)	
Difficulty sleeping	134 (62.9%)	129 (60.6%)	2.2 (0.9)	
Feeling Bloated	66 (31%)	48 (22.5%)	2.21 (1.37)	
Problems with Urination	57 (26.8%)	43 (20.2%)	2.01 (0.97)	
Vomit	48 (22.5%)	35 (16.4%)	2.1 (1.11)	
Short of breath	65 (30.5%)	40 (18.8%)	1.83 (0.94)	
Diarrhea	38 (17.8%)	24 (11.3%)	1.65 (0.86)	
Feeling sad	89 (41.8%)	64 (30%)	1.98 (1.01)	
Sweats	63 (29.6%)	37 (17.4%)	1.83 (0.98)	
Worrying	98 (46%)	67 (31.5%)	2.03 (0.93)	
Problems with sexual interests or activity	74 (34.7%)	51 (23.9%)	2.5 (1.18)	
Itching	52 (24.4%)	32 (15%)	1.87 (1.04)	
Lack of appetite	139 (65.3%)	94 (44.1%)	2.1 (1.03)	
Dizziness	91 (42.7%)	65 (30.5%)	1.94 (0.95)	
Difficulty swallowing	56 (26.3%)	39 (18.3%)	1.95 (0.95)	
Feeling irritable	84 (39.4%)	63 (29.6%)	2.1 (0.98)	
Mouth sores	34 (16.0%)	33 (15.5%)	1.7 (0.89)	
Change in the way food tastes	87 (40.8%)	74 (34.7%)	2.01 (0.82)	
Weigh loss	36 (16.9%)	26 (12.2%)	1.58 (0.7)	
Hair loss	92 (43.2%)	82 (38.5%)	2.63 (1.17)	
Constipation	66 (31%)	56 (26.3%)	2.1 (0.88)	
Swelling of arms or legs	14 (6.6%)	13 (6.1%)	1.61 (0.89)	
I don’t look like myself	32 (15%)	31 (14.6%)	2.01 (0.94)	
Changes in skin	29 (16.3%)	24 (11.3%)	1.84 (0.86)	
* severity items ranged from one (slight) to four (very severe)

Among 3 subscales of MSAS, the Psychological subscale had the highest score (1.12 ± 0.78) (Table 3).

10.1371/journal.pone.0307725.t003 Table 3 The score of MSAS’s sub-scales.

Sub-scales	Mean ± SD (min-max)	
PHYS	0.96 ± 0.67 (0–2.96)	
PSYCH	1.12 ± 0.78 (0–3.44)	
GDI	1.08 ± 0.81 (0–3.6)	
TMSAS	0.91 ± 0.57 (0–2.65)	

Symptom clusters

Four symptom clusters were identified among participants. Most of the identified symptom clusters included physical symptoms. Difficult concentration, pain, cough, and dizziness contributed to the first SC. The second one included lack of energy, numbness, change the food taste, and lack of appetite. Dry mouth, nausea, feeling bloated, problems with urination, hair loss, and constipation made up for the third SC. The final SC consisted of psychological symptoms which were feeling nervous, feeling drowsy, feeling sad, worrying, problems with sexual interests or activity and difficulty sleeping (Table 4).

10.1371/journal.pone.0307725.t004 Table 4 Identified symptom clusters among participants.

	Symptom components r	
Symptom cluster 1	Difficult concentration	0.7	
Pain	0.51	
Cough	0.57	
Dizziness	0.64	
Symptom cluster 2	Lack of Energy	0.6	
Numbness	0.7	
Change food taste	0.7	
Lack of appetite	0.7	
Symptom cluster 3	Dry mouth	0.5	
Nausea	0.57	
Feeling Bloated	0.58	
Problems with urination	0.56	
Hair loss	0.48	
Constipation	0.7	
Symptom cluster 4	Feeling nervous	0.46	
Feeling drowsy	0.5	
Feeling sad	0.4	
Worrying	0.4	
Problems with sexual interests or activity	0.4	
Difficulty sleeping	0.7	
KMO	0.86	
χ 2	2435.52	
p	<0.001	

Discussion

Prevalence of symptoms

The first aim of this study was to assess the prevalence of symptoms that patients experienced during chemotherapy. The most prevalent symptoms (reported by more than 40% of participants) were lack of appetite, difficulty sleeping, dry mouth, numbness, hair loss, change in the way food tastes, and lack of energy. This was similar to findings from the study of Supaporn Chongkham-ang et al. (2018) performed on 20 breast cancer patients who were treated with chemotherapy. It included five prevalence symptoms: hair loss, lack of energy, lack of appetite, change in the way food tastes, and nausea [30]. The study conducted by Mohammad Al Qadire et al. (2023) showed that in 393 cancer patients, symptoms related to tiredness, lack of energy, and irritability were the most common [31]. In line with our results, Carolyn S Harris et al. (2022) found that lack of energy was the most prevalent symptom in 1329 outpatients with cancer during chemotherapy [32]. As such, our study indicated a similarity of common symptoms experienced by cancer patients in Vietnam with those in other countries.

The results indicated that the most prevalent symptoms were not the most distressing. Therefore, our findings revealed that difficulty sleeping, loss of appetite, and numbness were among the most distressing symptoms for cancer patients in Vietnam undergoing chemotherapy. This was similar to the study of Mohammad AI-Qadir et al. (2023), who indicated that the most distressing symptom was a lack of appetite among 393 participants (31). By contrast, in the study by Supaporn Chongkham-ang et al. (2018), hair loss was the symptom that caused the most distress, although lack of appetite was the most common symptom (30). In addition, Carolyn S Harris et al. (2022) indicated that “I don’t look like me” was a distressing symptom for cancer patients [32]. A survey of 232 gynaecological cancer patients during chemotherapy also indicated lack of energy, hair loss, and “I look not like myself” were the most common, severe, and distress symptoms of subjects [33]. The differences between the existing studies could be explained by cultural factors. This could be because cultural differences influence the response to symptoms among cancer patients [34]. Therefore, there were different results of symptoms causing distress to those who underwent chemotherapy.

Among 3 sub-scales of MSAS, the Psychological subscale has the highest score (1.12 ± 0.78), which revealed oncology patients under chemotherapy suffer a greater burden of psychological symptoms (worrying, feeling sad, feeling nervous, difficulty sleeping, feeling irritable, and difficulty concentrating) than other symptoms. Other studies also reported similar results. Research conducted among 4500 patients diagnosed with the 14 most prevalent types of cancer showed a significant psychological distress proportion ranging from 29 to 43% [35]. A recent survey also indicated about 25% of cancer patients experienced psychological distress that partly led to quality of life reduction [36]. These results indicate the need for psychological care and support during chemotherapy for cancer patients.

Symptom cluster

To the best of our knowledge, this study is the first to identify symptoms cluster in cancer patients undergoing chemotherapy in Vietnam–a low-middle-income country. We identified four symptom clusters among participants.

The first symptom cluster was pain, cough, dizziness, and difficult concentration. The correlation among these symptoms was moderate (r = 0.51–0.7). This finding was similar to studies conducted Atay, Conk and Bahar [27] and Yeh, Chiang [37], which found that cough and dizziness fell into the same cluster. In addition, Chen and Tseng [13] and also found pain, difficult concentration and dizziness appeared in the “sickness symptom cluster” which was mediated by proinflammatory cytokines [37, 38]. In this study, pain may contribute to dizziness and difficulty concentrating.

The second symptom cluster was lack of energy, numbness, change food taste, and lack of appetite. This symptom cluster was reported in other studies among different cancer populations [27, 38]. Perhaps the sentinel symptom of this cluster was lack of appetite which related to change food taster and led to lack of energy and numbness.

The third symptom cluster we found was dry mouth, nausea, feeling bloated, problem with urination, hair loss, and constipation. The symptom clusters related to hair loss and gastrointestinal symptoms could be the result of side effects during chemotherapy [39]. Doxorubicin, cyclophosphamide, and paclitaxel were included in chemo components and were reported to partly cause the symptom clusters [40]. This finding was in accordance with the results of the symptom cluster found among Taiwanese patients with various cancer diagnoses [13].

The last symptom cluster that appeared in the sample was included psychological symptoms such as feeling nervous, feeling drowsy, feeling sad, worrying, problems with sexual interests or acitivity, and difficulty sleeping. Other studies reported the similar findings [9, 13, 27, 41, 42]. The bidirectional relationship between sleep disturbances and depressive and anxious symptoms (feeling sad, worrying, feeling nervous) has been well documented in the literature [43, 44]. In this cluster, the core symptom that defines the cluster with the highest correlation is difficulty sleeping. Sleep disturbances lead to the development of feeling sad, worrying, feeling nervous, and make the patients have problems with sexual interests or acitivites. In addition, other studies indicated that psychology symptom clusters were the most prevalent and the most distressed ones [45]. This result explained the reason for the highest score of psychological subscale when using MSAS to measure symptoms in the current study.

Our study is characterised by several strengths, including the use of large sample size, multi-site data collection, sample diagnostic heterogeneity, and measuring a wide range of symptoms using a validated measurement. However, due to limitations of cross-sectional design, it was impossible to point out which symptom in each cluster occurred first nor how they influenced each other, or how these symptoms/symptom clusters changed over the course of the illness. Furthermore, the data was collected before the emergence of the COVID-19 pandemic. COVID-19 adversely affects cancer patients because they are immunocompromised [46]. As such, a repeating study is recommended to understand the change in the symptom burden experienced by cancer patients after the pandemic.

Findings from the study indicated cancer patients undergoing chemotherapy endure a wide range of symptoms. The most prevalent symptoms were lack of appetite, difficulty sleeping, dry mouth, numbness, hair loss, change in the way food tastes, and lack of energy. Four symptom clusters have been identified including different physical and psychological symptoms among participants. The findings shown that physical and psychological symptom clusters of those patients are inevitable. Symptoms could co-occur due to different pathophysiological reasons and mechanisms [47, 48], but they have an extremely negative impact on cancer patients. That could cause oncology patients to endure discomforts, the physical function would change, and their mental and emotional abilities would be reduced which reduce patient’s quality of life [49]. This current study highlights the burden of chemotherapy treatment faced by patients, providing valuable information to assist oncologists/clinicians in treatment planning, management of side effects, and caring for these patients. In addition, our study calls for further comprehensively assessing symptoms among patients undergoing chemotherapy regardless of durations, types, and toxicities of chemotherapy.

We would like to thank all the participants for their voluntary contribution to the study.

10.1371/journal.pone.0307725.r001
Decision Letter 0
Wang Tao (Alison) Academic Editor
© 2024 Tao (Alison) Wang
2024
Tao (Alison) Wang
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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PONE-D-23-41096Identifying Symptom Cluster in Cancer patients undergoing Chemotherapy in Vietnam: a cross-sectional studyPLOS ONE

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for the opportunity to read this manuscript.

This study aimed to assess the prevalence of symptoms experienced by cancer patients during chemotherapy and to identify symptom clusters during chemotherapy in such patients. The research topic is interesting and the manuscript is clearly written. However, there are several issues that need to be addressed. My suggestions are as follows:

Introduction

- Line 60: There should be more than one previous study investigating the symptom clusters in patients receiving chemotherapy. Please elaborate on results of previous studies to justify why this study is needed.

Methods

- Line 77: Please provide more information about the settings of Vietnam to allow reader to understand how representative the sample is. How many large oncology hospitals are there? How many patients do they serve?

- Line 79: Why recruit 20-84 years old? What about 18-19 years old?

- Line 66: Please elaborate on how bed-sharing issues affect the symptom cluster?

- Please provide the ethical approval reference no.

Discussion

- Please provide details on the implications of the study results, given that patients received varying durations, types, and toxicities of chemotherapy.

Reviewer #2: The premise of this study to identify symptom clusters among people undergoing chemotherapy for cancer in Vietnam is significant. Defining the clusters using principal component analysis was appropriate. Several areas warrant consideration, as follows:

1. The statement in the background (page 3, 59-61) that most of the early research measured only 13-15 symptoms is untrue. One of the seminal studies, among others, identified 25 commonly occurring symptoms (PMID: 24797450).

2. The methods section includes a description of the MSAS instrument, including the 3 dimensions the instrument measures. The manuscript reports occurrence and distress related to each symptom but not severity. Either include or justify why this dimension was excluded.

3. It would be helpful develop a table that includes all dimensions being measured and assessed for symptom clusters (e.g., PMID 34560709).

4. Statements such as the sentence on page 12 (lines 253-254) (i.e., “This proves that….”) is inaccurate to state based on one study. This should be rephrased to “The findings suggest….” Or something similar.

5. Overall, the level of grammatical errors and to a lesser degree, spelling errors detracted from the merits of this manuscript. Assistance from an English-speaking scientist is highly recommended.

Overall, this investigation is significant, and merits being reported in the literature. Addressing the above points would strengthen this manuscript tremendously.

Reviewer #3: The manuscript shows the prevalence of symptoms in oncology patients using the MSAS scale in Vietnam. The article is interesting but I have several considerations to mention.

Line 59-61. It cannot be stated that there are no studies assessing this prevalence of 32 symptoms because there are (e.g. doi: 10.3390/ijerph20031708).

There is no sample size calculation.

The inclusion criteria are not clear: as you may know the MSAS assesses the symptoms perceived during the week prior to the chemotherapy session, therefore, patients who are going to receive their first cycle of chemotherapy should not be included since the symptoms they may suffer will not be due to chemotherapy and may represent a bias.

It's been 7 years since the data were collected, are they still representative? haven't they changed even with a pandemic in the middle?

Line 95: "the symptom was measured using a Likert scale from 0 to 4 with a higher score" that is not true, the categories of frequency and intensity are measured from 1 to 4 while distress is measured from 0 to 4 (having 5 possible options).

Is the MSAS scale in Vietnamese validated in oncological patients? Since the only reference I have found is the short version and in HIV patients (10.1080/09540121.2021.1922577)

Line 107-109: these values have to be the reference values in the language in which it is to be used, not in the original.

When were the data collected? Where were they collected? Were they self-completed? Did you go through the MSAS on your own? Did someone help you to fill them in?

Results:

Has any stratified analysis been performed in relation to the sex or age of the participants, even taking into account the type of cancer?

Discussion:

In the introduction they comment that there are no studies with large samples, however, in the discussion reference 23 and 24 contradict this information.

Again, the reference doi: 10.3390/ijerph20031708 should be cited in the text.

Line 209: I am not very clear about the symptom cluster done on the basis of what, prevalence? Could you explain it better, please.

Line 238 “feeling nervour”; line 239 “acitivites.” please correct these words.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

**********

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10.1371/journal.pone.0307725.r002
Author response to Decision Letter 0
Submission Version1
10 May 2024

Dear Reviewers

On behalf of the research team, I would like to thank you for allowing us to submit a revised draft of the manuscript “Identifying Symptom Cluster in Cancer patients undergoing Chemotherapy in Vietnam: a cross-sectional study”. We appreciate the time and effort you dedicated to providing feedback on our manuscript and are grateful for the insightful comments that helped us improve our paper. We have incorporated most of the suggestions made by the reviewers. Those changes are highlighted within the manuscript. Please see below for a point-by-point response to the reviewers’ comments and concerns. All page numbers refer to the revised manuscript file with tracked changes.

Reviewers' Comments to the Authors:

Reviewer 1

Line 60: There should be more than one previous study investigating the symptom clusters in patients receiving chemotherapy. Please elaborate on results of previous studies to justify why this study is needed.

Thank you for pointing this out. The reviewers are correct and we have revised as following (Line 62 to 72)

In addition, previous studies explored symptom clusters in specific cancers such as breast cancer (1, 2), lung cancer (3), and gastric cancer (4). We found two studies which were conducted in a population that included various cancer diagnoses with large sample sizes. In the study conducted by Morse, Cooper (5) among 1329 patients with various cancer diagnoses, eight symptom clusters were identified (i.e., physical and cognitive fatigue, respiratory, psychological, hormonal, chemotherapy-related toxicity, weight gain, gastrointestinal, and epithelial). Harris, Kober (6) found five symptom clusters, including psychological, gastrointestinal, weight gain, respiratory and hormonal clusters among more than 1000 outpatients with different cancers. In addition, researchers also pointed out there is no consensus on which symptoms occur in the population of cancer patients (7). As such, the correlation between symptoms reported by cancer patients during treatment has not been fully addressed in the current literature.

Line 66: Please elaborate on how bed-sharing issues affect the symptom cluster?

As suggested, we have revised.

Line 73-78

Furthermore, no study has been done previously to explore symptom clusters among cancer patients during chemotherapy in Vietnam, where people tend to skip their local health providers to go straight to the central hospitals for treatment. As the results, they have dealt with the bed-sharing problem (two or three patients share one bed). This issue not only caused so many inconveniences for the patients during their hospitalisation (from eating to resting) but also made the hospital become overloaded.

Please provide the ethical approval reference no.

We have inserted the ethical approval reference (Line 157-163)

The study obtained ethical approval from the Human Subject Ethics Committee of Hanoi School of Public Health (Vietnam) and The Hong Kong Polytechnic University under reference number HSEARS20170428003

Line 77: Please provide more information about the settings of Vietnam to allow the reader to understand how representative the sample is. How many large oncology hospitals are there? How many patients do they serve?

Thank you for these comments, we have added details of the settings in the “Participants and settings” session (line 112-121)

The study included 213 cancer patients from 3 large oncology hospitals in Vietnam (Vietnam National Cancer Institute, Bach Mai Hospital, and Hanoi Oncology Hospital). Vietnam National Cancer Institute: This is the largest cancer hospital in Vietnam, the hospital has 2400 beds and in charge of providing cancer treatments for patients from North and Middle of Vietnam (1700 patients per day on average). Bach Mai Hospital is one of the three largest general hospitals in Vietnam, its oncology unit has 300 beds and receives about 400 cancer patients per day on average. Hanoi Oncology Hospital is a public hospital in charge of providing cancer treatment for patients in Hanoi. The hospital has 680 beds and receives about 945 patients per day.

Line 79: Why recruit 20-84 years old? What about 18-19 years old?

Thank you for pointing out this major issue of the manuscript. In fact, we recruited participants from 18-80 years old. However, none of the participants were in the age group of 18-19. Thanks to your comments we have revised the criteria. (line 123-124)

Patients were recruited if they were undergoing chemotherapy with any cancer diagnosis, had received at least one chemo-cycle, were 18–84 years old

Please provide details on the implications of the study results, given that patients received varying durations, types, and toxicities of chemotherapy

Thank to your comments, we have revised and highlighted the implication of the study

(Line 449-453)

This current study highlights the burden of chemotherapy treatment faced by patients, providing valuable information to assist oncologists/clinicians in treatment planning, management of side effects, and caring for these patients. In addition, our study calls for further comprehensively assessing symptoms among patients undergoing chemotherapy regardless of durations, types, and toxicities of chemotherapy.

Reviewer 2

The statement in the background (page 3, 59-61) that most of the early research measured only 13-15 symptoms is untrue. One of the seminal studies, among others, identified 25 commonly occurring symptoms (PMID: 24797450).

Thank you for your comments. We have done the literature review again and revised as following: (line 69-71)

However, the majority of the earlier research was conducted in a small sample size, and some studies only measured only 13 to 15 symptoms, while cancer patients can experience up to 32 symptoms (8).

The methods section includes a description of the MSAS instrument, including the 3 dimensions the instrument measures. The manuscript reports occurrence and distress related to each symptom but not severity. Either include or justify why this dimension was excluded.

Thank you for this comment. We have added a column to report the severity of the symptoms. Please see table 2 (page 240-265)

Statements such as the sentence on page 12 (lines 253-254) (i.e., “This proves that….”) is inaccurate to state based on one study. This should be rephrased to “The findings suggest….” Or something similar.

As suggested, we have paraphrased these statements

(Line 444-445)

The findings shown that physical and psychological symptom clusters of those patients are inevitable.

Overall, the level of grammatical errors and to a lesser degree, spelling errors detracted from the merits of this manuscript. Assistance from an English-speaking scientist is highly recommended

We acknowledge the limitation of being non-native English-speaking scientists. Since the project received no funds so we have invited an English-speaking scientist from the University of Queensland to check the manuscript before re-submitting. The grammatical errors and typos have been revised.

Review 3

Line 59-61. It cannot be stated that there are no studies assessing this prevalence of 32 symptoms because there are (e.g. doi: 10.3390/ijerph20031708).

While we appreciate the reviewer’s feedback, we respectfully disagree because we haven’t stated studies assessing this prevalence of 32 symptoms in the previous manuscript. Maybe our writing confused you. Sorry for that. We meant “no study has been done previously to explore symptom clusters among cancer patients during chemotherapy in Vietnam where people tend to skip their local health providers to go straight to the central hospitals for treatment” (line 82-84).

There is no sample size calculation.

Thank you for pointing out the major issue of the manuscript. We have added the sample size calculation

Line 127-134

Sample size calculation

Since the symptom cluster was identified by the correlation, we used the formula N ≥104 + m with “m” referring to the number of independent variables to calculate the sample size for the study (9). There were 106 independent variables in the study (72 variables to measure 24 symptoms in 3 dimensions, 16 to measure 8 symptoms in 2 dimensions, and 18 to measure participant’s characteristics). As such, the minimum sample size is 210. In this study, we sent out 250 invitations and received 213 responses. Therefore, the sample size of the study was 213.

The inclusion criteria are not clear: as you may know the MSAS assesses the symptoms perceived during the week prior to the chemotherapy session, therefore, patients who are going to receive their first cycle of chemotherapy should not be included since the symptoms they may suffer will not be due to chemotherapy and may represent a bias

The reviewer was right and we have edited the inclusion criteria to make it clear

(Line 122-126)

Inclusion and exclusion criteria:

Patients were recruited if they were undergoing chemotherapy with any cancer diagnosis; had received at least one chemo-cycle, 18–84 years old, and having a Karnofsky Performance Index ≥ 80.

It's been 7 years since the data were collected, are they still representative? haven't they changed even with a pandemic in the middle?

Thank you for your valuable questions. This is the limitation of the study, we have added to the discussion

Line 390-393

Furthermore, the data was collected before the emergence of the COVID-19 pandemic. COVID-19 adversely affects cancer patients because they are immunocompromised (10). As such, a repeating study is recommended to understand the change in the symptom burden experienced by cancer patients after the pandemic.

Line 95: "the symptom was measured using a Likert scale from 0 to 4 with a higher score" that is not true, the categories of frequency and intensity are measured from 1 to 4 while distress is measured from 0 to 4 (having 5 possible options).

Is the MSAS scale in Vietnamese validated in oncological patients? Since the only reference I have found is the short version and in HIV patients (10.1080/09540121.2021.1922577)

We think this is an excellent correction. We have revised in the manuscript

Line 144-164

The Vietnamese version of the Memorial Symptom Assessment Scale (MSAS) (α = 0.79) was used to measure the symptom burden. The MSAS was translated into Vietnamese following the forward-backward methods and had been validated by 5 experts in oncology. This is a self-reported questionnaire that measures 24 symptoms in 3 dimensions: frequency, severity, and distress; and eight symptoms were evaluated in terms of severity and distress (total of 32 symptoms). With each of the symptoms that the patients experienced, the frequency and severe dimensions were measured by a Likert scale from 1 to 4 (from “rarely” to “almost constantly” for the frequency and from “slight” to “very severe” for the severity). The distress dimension was a Likert scale from 0 to 4 with 0 referring to “not at all” and 4 refers to “very much”. If a symptom is absent, each of the dimensions is scored as 0.

Has any stratified analysis been performed in relation to the sex or age of the participants, even taking into account the type of cancer?

We conducted this study to assess the prevalence of symptoms that cancer patients experience during chemotherapy treatment and identify symptom clusters among such patients in the context of Vietnam. So no stratified analysis was performed in relation to sex or age and cancer type was taken.

In the introduction they comment that there are no studies with large samples, however, in the discussion reference 23 and 24 contradict this information.

Again, the reference doi: 10.3390/ijerph20031708 should be cited in the text.

Thank you for suggesting. We have revised.

(Line 73-80)

We found two studies which were conducted in a population that included various cancer diagonises with large sample size . In the study conducted by Morse, Cooper (5) among 1329 patients with various cancer diagnoses, eight symptom clusters were identified (i.e., physical and cognitive fatigue, respiratory, psychological, hormonal, chemotherapy-related toxicity, weight gain, gastrointestinal, and epithelial). Harris, Kober (6) found five symptom clusters including psychological, gastrointestinal, weight gain, respiratory and hormonal clusters among more than 1000 outpatients with different cancers. In addition, researchers also pointed out there is no consensus on which symptoms occur in the population of cancer patients (7).

Line 209: I am not very clear about the symptom cluster done on the basis of what, prevalence? Could you explain it better, please.

In according to the definition “A symptom cluster has been defined as at least two symptoms that occurred and related to each other at a certain time”, the symptom cluster was identified based on the prevalence of the symptom.

Line 238 “feeling nervous”; line 239 “acitivites.” please correct these words.

We have revised the typo. Thank you and sorry for these mistakes.

References

1. Browall M, Brandberg Y, Nasic S, Rydberg P, Bergh J, Rydén A, et al. A prospective exploration of symptom burden clusters in women with breast cancer during chemotherapy treatment. Supportive Care in Cancer. 2017;25(5):1423-9.

2. Wiggenraad F, Bolam KA, Mijwel S, van der Wall E, Wengström Y, Altena R. Long-Term Favorable Effects of Physical Exercise on Burdensome Symptoms in the OptiTrain Breast Cancer Randomized Controlled Trial. Integrative Cancer Therapies. 2020;19:1534735420905003.

3. Teng L, Zhou Z, Yang Y, Sun J, Dong Y, Zhu M, Wang T. Identifying central symptom clusters and correlates in patients with lung cancer post-chemotherapy: A network analysis. Asia-Pacific Journal of Oncology Nursing. 2024;11(4):100383.

4. Fu L, Feng X, Jin Y, Lu Z, Li R, Xu W, et al. Symptom Clusters and Quality of Life in Gastric Cancer Patients Receiving Chemotherapy. Journal of Pain and Symptom Management. 2022;63(2):230-43.

5. Morse L, Cooper BA, Ritchie CS, Wong ML, Kober KM, Harris C, et al. Stability and consistency of symptom clusters in younger versus older patients receiving chemotherapy. BMC Geriatrics. 2024;24(1):164.

6. Harris CS, Kober KM, Cooper B, Conley YP, Dhruva AA, Hammer MJ, et al. Symptom clusters in outpatients with cancer using different dimensions of the symptom experience. Support Care Cancer. 2022;30(8):6889-99.

7. Llamas-Ramos I, Alvarado-Omenat JJ, Rodrigo-Reguilón M, Llamas-Ramos R. Quality of Life and Side Effects Management in Cancer Treatment-A Cross Sectional Study. Int J Environ Res Public Health. 2023;20(3).

8. Lobchuk MM. The memorial symptom assessment scale: modified for use in understanding family caregivers' perceptions of cancer patients' symptom experiences. J Pain Symptom Manage. 2003;26(1):644-54.

9. Kupper LL, Hafner KB. How Appropriate Are Popular Sample Size Formulas? The American Statistician. 1989;43(2):101-5.

10. Linjawi M, Shakoor H, Hilary S, Ali HI, Al-Dhaheri AS, Ismail LC, et al. Cancer Patients during COVID-19 Pandemic: A Mini-Review. Healthcare (Basel). 2023;11(2).

Attachment Submitted filename: Responce to reviewers.docx

10.1371/journal.pone.0307725.r003
Decision Letter 1
Wang Tao (Alison) Academic Editor
© 2024 Tao (Alison) Wang
2024
Tao (Alison) Wang
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version1
10 Jul 2024

Identifying Symptom Cluster in Cancer patients undergoing Chemotherapy in Vietnam: a cross-sectional study

PONE-D-23-41096R1

Dear Dr. Huong Thi Xuan Hoang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Alison Wang

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thanks for the revision! It is well-written, and all of my comments were addressed. Thank you very much!

Reviewer #2: (No Response)

**********

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

10.1371/journal.pone.0307725.r004
Acceptance letter
Wang Tao (Alison) Academic Editor
© 2024 Tao (Alison) Wang
2024
Tao (Alison) Wang
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
20 Jul 2024

PONE-D-23-41096R1

PLOS ONE

Dear Dr. Hoang,

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on behalf of

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PLOS ONE
==== Refs
References

1 World Health Organization. Cancer fact sheet 2022 [updated 04/04/2023. Available from: https://www.who.int/news-room/fact-sheets/detail/cancer.
2 Sung H , Ferlay J , Siegel RL , Laversanne M , Soerjomataram I , Jemal A , et al . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. 2021;71 (3 ):209–49. doi: 10.3322/caac.21660 33538338
3 The Global Cancer Burden [Internet]. 2017 [cited 04/10/2017]. Available from: https://www.cancer.org/health-care-professionals/our-global-health-work/global-cancer-burden.html.
4 Cleeland CS . Symptom burden: multiple symptoms and their impact as patient-reported outcomes. Journal of the Natiomal Cancer Institude Monographs. 2007(37 ):16–21. doi: 10.1093/jncimonographs/lgm005 17951226
5 Dodd MJ , Janson S , Facione N , Faucett J , Froelicher ES , Humphreys J , et al . Advancing the science of symptom management. J Adv Nurs. 2001;33 (5 ):668–76. doi: 10.1046/j.1365-2648.2001.01697.x 11298204
6 Donovan HS , Hartenbach EM , Method MW . Patient-provider communication and perceived control for women experiencing multiple symptoms associated with ovarian cancer. Gynecol Oncol. 2005;99 (2 ):404–11. doi: 10.1016/j.ygyno.2005.06.062 16112174
7 Esther Kim J-E , Dodd MJ , Aouizerat BE , Jahan T , Miaskowski C . A Review of the Prevalence and Impact of Multiple Symptoms in Oncology Patients. J Pain Symptom Manage. 2009;37 (4 ):715–36. doi: 10.1016/j.jpainsymman.2008.04.018 19019626
8 Dodd MJ , Miaskowski C , Paul SM . Symptom clusters and their effect on the functional status of patients with cancer. Oncol Nurs Forum. 2001;28 (3 ):465–70. 11338755
9 Molassiotis A , Wengström Y , Kearney N . Symptom Cluster Patterns During the First Year After Diagnosis with Cancer. J Pain Symptom Manage. 2010;39 (5 ):847–58. doi: 10.1016/j.jpainsymman.2009.09.012 20226621
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