Factors associated with palliative care symptoms in cancer patients in Palestine

Palliative care is critical to redundancy in cancer patients seeking to improve their quality of life. Evaluation should be incorporated into clinical practice routines at all stages of cancer. The Edmonton Symptom Assessment System (ESAS) was used to rate the intensity of ten symptom evaluations designed and validated for cancer patients in various languages and cultures. Therefore, the study aims to assess the symptoms reported using ESAS scores to identify patients who would benefit from palliative care that can improve the integration of palliative care into standard cancer care at An-Najah National University Hospital (NNUH). A cross-sectional study was selected for 271 cancer patients using a convenience sampling method at NNUH. Demographic, clinical, and lifestyle characteristics are described. Furthermore, patients' moderate to severe symptoms (score > 4) were obtained using ESAS-R. The survey consisted of 271 patients, with a response rate of 95%. The average age of the patients was 47 ± 17.7 years, ranging from 18 to 84 years. The male-to-female ratio was approximately 1:1, 59.4% of the patients were outpatients, and 153 (56.5%) had hematologic malignancies. Fatigue (62.7%) and drowsiness (61.6%) were the most common moderate to severe symptoms in ESAS. Furthermore, pain (54.6%), nausea (40.2%), lack of appetite (55.0%), shortness of breath (28.5%), depression (40.6%), anxiety (47.2%) and poor well-being (56.5%) were reported. In conclusion, fatigue and drowsiness were the most reported symptoms according to the ESAS scale among cancer patients, while moderate to severe symptoms were reported in cancer patients using the ESAS. The ESAS is a functional tool for assessing cancer patients' symptoms and establishing palliative care services.


Study population
Cancer patients in NNUH consult outpatient oncology clinics and receive treatment in outpatient oncology clinics.Inpatients may come for diagnosis, chemotherapy cycle, and autologous bone marrow transplant or treatment of side effects/complications.

Sample size
The NNUH was visited by approximately 600 cancer patients monthly during the study period (April 2021-August 2021).This population size was used to determine the sample size needed for the analysis.A sample size of 235 was calculated using the Raosoft sample size calculator by setting the response distribution at 0.50, the error margin at 5%, and the confidence interval at 95%.When we calculated using Raosoft, 259 patients were needed to cover the dropout.Therefore, we added 10% of the sample (24 patients), and the target sample size increased to 285 participants to decrease erroneous results and improve the reliability of the research.
The pilot test was conducted first for 10% of the sample size (24 questionnaires).It was excluded from the study because sociodemographic data was edited after the content validity and the reliability of the internal consistency of the questionnaire were tested.The validity of the data was tested for their content only by triangulation, a panel that included hematologists, oncologists, three oncology nurses, and one statistician.The reliability was assessed for 11 patients (22 questionnaires) between two visits.Furthermore, after developing the questionnaire, the content and design were tested in a pilot in 11 patients, with modifications made as needed.Only some questions were modified to be clearer within categories and easier to respond to without writing, so the questionnaire was completed in less time, and some of the duplicate variables, prognostic factors, stages, and palliative care were removed.

Sampling procedure
The convenience sampling method consisted of 271 cancer patients.

Inclusion and exclusion criteria
Inclusion criteria: 1. Patients who agreed to participate 2. Individuals 18 years and older can read and write.3.Both sexes 4. Inpatients and outpatients with cancer and hematologic malignancies.

Data collection instrument
The palliative care symptoms ESAS-R is valid and reliable for assessing nine common symptoms common to cancer patients 16 .This tool assesses pain, fatigue, nausea, depression, anxiety, drowsiness, appetite, well-being, and SOB.Each patient was provided a blank carbon form with the ESAS-R questionnaire.Oncology nurses guided as needed to facilitate the completion of the forms.Patients can use a blank scale to assess "other problems" as needed.Furthermore, a numerical scale of 0 to 10 is used to rate the severity of each symptom, with 0 denoting the absence of the symptom and 10 being the worst possible severity 17 .The ESAS is a useful screening tool to assess psychological symptoms, including depression, which is easy to use by cancer care team professionals to provide the necessary palliative care and regular evaluation of the patient using the ESAS and a cutoff point > 3 18 .
The data was collected over five months, from April 2021 to August 2021.This data was collected through cross-sectional observations at various points during cancer treatment, encompassing the periods of diagnosis, chemotherapy, clinic visits, and autologous bone marrow transplantation (Auto-BMT).These observations were conducted for patients in advanced stages of cancer, both in outpatient and inpatient oncology settings.The researcher documented this information in separate papers.The Arabic version 19  www.nature.com/scientificreports/ to the patient directly by the delegated researcher or nurse (one nurse in outpatient oncology clinics and one nurse on the medical oncology ward), and all questionnaires were completed by the patients or read to them by the researcher or the two delegated nurses.If the patients had difficulty understanding the question's meaning, we explained it simply.All instruments were completed in paper forms and the questionnaires were saved in a special file in the targeted wards that receive adult patients with oncologic and/or hematologic malignancies: outpatient oncology clinics, medical oncology ward, vascular ward, surgical ward, bone marrow transplant and leukemia ward, and surgical cardiac care unit.Then, other medical-related information taken from patient files by the researcher was entered into an electronic database for analysis.Demographic data from patients and clinical factors were also collected.Approximately 15 patients refused to participate and ten incomplete questionnaires were excluded.

Statistical analysis
The Statistical Package for Social Sciences (SPSS) version 21 was used to enter and analyze the data.Descriptive statistics such as frequencies, percentages, means (standard deviations), and medians (interquartile ranges) were used to summarize basic demographic information.The Mann-Whitney U and Kruskal-Wallis tests were used to determine the association between independent variables and ESAS scores.All statistical tests were two-sided, with P values less than 0.05 considered statistically significant.In the bivariate analysis, all variables that showed a significant correlation with ESAS scores, including sociodemographic and clinical factors, were included in a multiple linear regression model.This model was used to identify the most important variables associated with each dimension of ESAS.

Ethics approval and consent to participate
Institutional Review Boards (IRBs) and local health authorities approved all components of the study protocol, including access to and use of patient clinical data, IRB approval no.(Mas.Feb. 2021/17), in which the human body is protected with no risk.This study was carried out following the Helsinki Declaration, and European guidelines for good clinical practice and approval were requested and obtained from the NNUH search center.We confirm that the information collected was used only for clinical research.All personal information provided by the patients is kept private and used only for this study.All participants received an informed consent form that confirmed data privacy, and all data were kept confidential and used specifically for research purposes.All information was stored in a locked cabinet for human body rights, and there was no access to anyone except the researcher.The IRB of An-Najah National University approved only verbal consent.The reason for verbal consent is that participants were only required for the interview and were not subjected to any harm as long as their privacy was kept confidential.The authors confirmed that all the methods were performed following the relevant guidelines and regulations.

The total ESAS score
The total score of the ESAS indicated the overall burden of symptoms, as shown in Table 3, which does not show a significant relationship between the total score of the ESAS and sociodemographic data.

Pain dimension
According to ESAS, the dimension of pain was significantly associated with many factors, as shown in Additional file 1: Table S1, including age (p = 0.003), sex (p = 0.007), marital status (p = 0.001), stage of work (p = 0.001), stage of treatment (p = 0.039), chemotherapy (p = 0.036), type of cancer (p < 0.001), and pancytopenia condition (p = 0.011).First, we found that cancer patients aged > 50 years had more pain.The median score [Q1-Q3] was 4.0 [2.0-7.0]compared to those aged < 50 years, with a median [Q1-Q3]: 3.0 [1.0-5.0].It was also found that women had a higher pain score than men.Furthermore, pain was higher in cancer patients in the treatment stage, with a score of 4.0 [1.0-6.0],than in cancer patients in the diagnosis stage, with a score of 3.0 [0.7-5.0].Cancer patients who underwent chemotherapy were reported to have significantly more pain, with a pain score of 4.0 [2.0-6.0],than those who did not actively receive chemotherapy.Furthermore, patients with solid tumors had significantly higher pain scores than patients with hematologic malignancies (p < 0.001).However, in the regression analysis, only work and type of cancer were significantly associated with the pain domain, as shown in Table 4.

Fatigue dimension
As indicated in Additional File 1: Table S2, fatigue among cancer patients was related to marital status (p = 0.006), and married patients experienced increased fatigue, which is associated with a high level of fatigue due to low income, as well as work (p = 0.042), which causes fatigue in non-workers and solid tumors (p = 0.021).We found work and type of cancer as predictors for the fatigue domain, as shown in Table 4.

Drowsiness dimension
As shown in Additional file 1: Table S3, drowsiness is significantly associated with socioeconomic status (p = 0.002), which is high at the low-income level, with a median score of 5 from 10.

Nausea dimension
Additional File: Table S4 shows that the nausea score was significantly higher in patients receiving active chemotherapy, with a score of 3.0 [1.0-5.0] and a p-value of 0.023, and was significantly associated with socioeconomic status (p = 0.007) and patients currently receiving chemotherapy for nausea, as predicted in the linear regression analysis in Table 4.

Lack of appetite dimension
As shown in Additional file 1: Table S5, lack of appetite was significantly associated with smokers (p = 0.016), hospitalized patients (p = 0.007) and AutoBMT (p = 0.037) and was associated with marital status (p = 0.002), work, and socioeconomic status (p = 0.004).In the multiple linear regression analysis, we reported that hospitalized patients, socioeconomic status, smoking, and work were substantially associated with a lack of appetite, as shown in Table 4.

Shortness of breath dimension
In Additional file 1: In Table S6 of the SOB domain, smoking was reported to be highly associated with this symptom (p = 0.021) and was the only predictor of SOB, as shown in Table 4, where the SOB score was 2.5 [0.0-5.0] for smokers and 1.0 [0.0-3.0] for non-smokers.Furthermore, SOB was significantly associated with family support (p = 0.021), indicating a lower severity of family support for SOB.

Depression dimension
As shown in Additional file 1: In Table S7, variables such as smoking (p = 0.004) and good or affordable socioeconomic status (p = 0.026) were significantly associated with depression, as shown in Table 4.

Anxiety dimension
As shown in Additional file 1: In Table S8, anxiety was found to be associated with educational level (p = 0.044) and treatment stage (p < 0.001).The anxiety score was 5.0 [3.8-9.3] for cancer patients in the diagnosis stage, while the score was 3.0 [1.0-6.0] for those in the treatment phase and was significantly associated with socioeconomic status (p = 0.012).However, two factors, socioeconomic status and treatment phase, were determinants of anxiety, as shown in the regression analysis in Table 4.

Wellbeing dimension
In the current analysis, as shown in Additional file 1: In Table S9, a poor feeling of well-being was identified in cancer patients with deformities (p = 0.026), with a score of 5.0 [3.5-9.5],compared to cancer patients without deformities, 4.0 [1.0-6.0], and well-being was significantly associated with socioeconomic status (p = 0.016) and smoking (p = 0.028).Socioeconomic status, deformities, smoking, and work status are predictive well-being factors, as shown in Table 4.

Discussion
This cross-sectional study carried out at NNUH in a developing country sheds light on the significant burden of symptoms experienced by cancer patients seeking palliative care.The current study used the ESAS to assess the intensity of various symptoms commonly encountered by cancer patients.
In our study sample, the male-to-female ratio was approximately 1:1, similar to Palestine's general distribution of malignancies.According to the Palestinian Ministry of Health Report 20 , in 2020, there were 49.3% male patients and 50.7% female patients.However, a similar study in Italy showed that 58% of the participants were women 18 .
In our study, the mean age of the participants was 47 years, while in other studies, the mean age was 49.12 years 21 and 61.9 years 18 .In our study, 88.9% of cancer patients were in the treatment stage and the others were in the diagnostic stage.This percentage is similar to a previous study that included patients recently on a chemotherapy protocol (82%) 18 .
The most common symptoms reported by our study were fatigue (62.7%), drowsiness (61.6%), poor health (56.5%), loss of appetite (55.0%), and pain (54.6%).In a study conducted in Egypt, the symptoms of advanced cancer were pain (93%), followed by fatigue (74%), poor well-being (67%), lack of appetite (62%), anxiety (60%), and drowsiness (56%) 11 .However, another study reported that pain was the most common symptom in the diagnosis stage of incurable cancers 22 .Furthermore, most of the patients included in the study were tired (94%), anxious (87.5%), and depressed (83%) 23 .Using the ESAS scale as a guide to identify and understand the main problems can help establish appropriate care for cancer patients 24 .
In a study analyzed, the median (range) score for depression was 2 (0-10) in the ESAS, with a cutoff of 2 out of 10 or more, having a sensitivity of 77% and 83%, respectively, with a specificity of 55% and 47% for depression and moderate/severe depression 25 .
Unfortunately, there is a lack of specialized centers or palliative care specialists in Palestine, which is essential to reduce the intensity of these symptoms 26 .In the United States of America (USA), research has examined the determinants of symptom improvement in 406 advanced cancer patients referred to palliative care.In this study, fatigue was more likely to improve in individuals with higher levels of other symptoms at baseline, such as dyspnea, sadness, and nausea.Pain relief was more prevalent in drowsy patients.Old age was associated with better health after 1-4 weeks of palliative care 27 .
Similarly, Canadian researchers looked at the factors influencing improvement in 150 cancer patients who participated in a palliative care team intervention.This study found that after one week of intervention, female sex was related to improved symptoms, with nausea, anxiety, dyspnea, and pain showing the greatest improvement 28 .Another study in the USA examined gastrointestinal symptoms in 202 advanced cancer patients referred for palliative surgical consultation.Again, surgical treatment patients had better symptoms than those who did not, and there was no link between improvement and sex, age, or current chemotherapy or biotherapy 29 .
In the current analysis, women with cancer and those aged > 50 years were found to have significantly higher pain scores.It seems that older individuals with depression may be more likely to show discomfort due to concurrent health conditions 30 .Additionally, those who worked had lower pain scores, possibly because work requires the body to move, which is excellent for circulation, prevents muscular tightness and joint stiffness, and raises the pain tolerance threshold 31 .The pain score was significantly higher in cancer patients in the treatment stage.This could be due to the adverse effects of anticancer medications, such as chemotherapy-induced peripheral neuropathy (Vince alkaloid) 32 .Pain was more severe in solid tumors (median pain score = 4) than in hematologic malignancies (median pain score = 3), which is supported by previous studies 33 .
As reported in the present study, the fatigue score was lower in workers than in non-workers.It should be noted that fatigue due to malignancy is not alleviated by rest.This symptom is multifactorial, either the primary disease or the side effects of cancer therapy.However, the specific underlying pathophysiology is unknown 34,35 .As expected, cancer patients actively on chemotherapy had significantly higher nausea scores than those who did not.Nausea and vomiting are distressing symptoms.Despite the availability of strong antiemetic and evidencebased recommendations, up to 40% of cancer patients receiving chemotherapy experience nausea and vomiting 36 .
Furthermore, the SOB score was significantly higher in smokers than in non-smokers, consistent with previous findings that identified increased dyspnea in cancer patients who smoke 37 .Furthermore, the depression score showed a statistically significant association between socioeconomic status and smoking, supported by other studies [38][39][40][41] .Regarding the anxiety score associated with educational level, the anxiety level was higher in cancer patients with an educational level of school and lower educational level, with a score of 4.0.The anxiety score in patients with a university or college educational level was 2.0, perhaps because a higher education level appears to have a protective impact against the accumulation of anxiety and sadness throughout life 42 .Our results showed that anxiety was higher in cancer patients in the diagnosis stage than in the treatment stage.A previous study concluded that chronic inflammatory conditions have been documented as risk factors for anxiety and depression among cancer patients.The diagnostic phase was found to be associated with a high level of anxiety 43 .Moderate anxiety or depression reported through the corresponding ESAS items (cutoff = 4) can be a useful screening tool for anxiety and depression in non-advanced patients with solid or hematologic malignancies 18 .
Cancer patients with deformities had worse well-being than cancer patients without deformities.Deformity due to malignant disease affects patients' appearance and quality of life, such as oral cancer 44 , Tel Hashomer syndrome, and Guillain-Barre syndrome in patients with lymphoma 45 .Additionally, poor well-being was reported in smokers, which was supported by other studies 46,47 .In particular, poor socioeconomic status was associated with an increase in almost all severities of the ESAS, which requires more attention to socioeconomic status.Poor quality of life has also been documented in Palestine due to low income 48 .
In terms of quality of life, Palestinian cancer patients face several challenges.For example, the high prevalence of depression in Palestine may be explained by the presence of life stressors, such as siege, occupation 49 , an increased level of anxiety 50 , and difficulties in accessing healthcare 51 .Therefore, palliative care should be included in the healthcare system to improve the quality of life and minimize suffering in these patients.Furthermore, policymakers must integrate specific services, such as palliative care for certain cancer patients, into the health system 52 .
Regarding the strengths of the scales, the ESAS is a practical, patient-centered symptom evaluation instrument that is simple to use, understand, and report.Simultaneous evaluation of ten symptoms enables the identification of symptom clusters and quick assessment.Many clinical and research organizations worldwide use it to benchmark their results.They have psychometrically confirmed their face validity and are available in over 20 languages.It has been determined that there are limited clinically significant differences and responsiveness.It is available in a variety of languages.It is freely available 53 .

Strengths and limitations
This study included cancer patients from all parts of Palestine, the West Bank, and the Gaza Strip with different socioeconomic statuses.It is also the first study in Palestine documenting depression and palliative care symptoms among oncology patients.However, the current study has several limitations.The major limitation is its cross-sectional design, which does not allow us to see how depression, for example, in cancer patients, changed over time between different treatment paths.Other limitations include the use of convenience sampling from a single tertiary hospital and the use of a small sample size.No stratified analysis was performed for different types of tumors and different treatments.
On the other hand, we have not fully defined all palliative care, as patients may receive care/support not defined in our research.Therefore, the current findings cannot be generalized.Additionally, we use only one scale for assessment, the ESAS, which is a short one-dimensional measure that assesses intensity and severity.Currently, several versions of the ESAS are used, each with a distinct time anchor and several elements, making it impossible to compare or combine the findings.Furthermore, some concepts (for example, well-being) are not clearly defined, and the tenth symptom is different and cannot be unified as headache, constipation, etc.

Conclusions
The study revealed that fatigue and drowsiness were the most commonly reported moderate to severe symptoms among the cancer patients included in the research.The presence of these symptoms can exert a substantial influence on the daily functioning and overall quality of life experienced by individuals affected by them.A number of sociodemographic and clinical factors were identified as being correlated with distinct symptoms.Factors such as age, gender, marital status, and type of cancer have been identified as influential variables affecting the severity of pain.Likewise, variables such as socioeconomic status, smoking habits, and stage of treatment exhibited associations with the intensity of additional symptoms, encompassing fatigue, somnolence, anxiety, and depression.The research underscores the significance of palliative care in effectively addressing the physical and psychological symptoms encountered by individuals diagnosed with cancer.Palliative care assumes a pivotal role in enhancing the overall quality of life and effectively addressing concurrent ailments such as depression.This study makes a valuable contribution to the expanding corpus of literature on cancer care, with a specific focus on the distinctive obstacles encountered by developing countries.This highlights the necessity for the implementation of comprehensive palliative care services and the development of strategies to effectively address symptom management within these particular contexts.

Table 1 .
Characteristics of the patients.

Table 2 .
Description of ESAS symptoms.

Table 4 .
Multiple linear regression analysis for variables associated with ESAS symptoms.Significant values are in bold.