The Relation between the Severity of Pain and Common Symptoms in Patients with Metastatic Cancer

Background: There is a relation between the severity of pain and common symptoms in patients with metastatic cancer. Aim: This study was done to explore this relation among Egyptian patients with advanced cancer. Methods: The study included 120 adult metastatic cancer patients with pain from two cancer centers in Cairo and Sharkia, Egypt. Pain and other common symptoms were assessed using the Arabic version of the Edmonton Symptom Assessment System (ESAS). The Eastern Cooperative Oncology Group (ECOG) performance scale was used to assess performance status. Results: The prevalence of ESAS symptoms was high among patients with cancer pain (tiredness, 94%; drowsiness, 63%; nausea, 60%; lack of appetite, 77%; shortness of breath, 53%; depression, 88%; anxiety, 83%; poor wellbeing, 96%). The ECOG performance scale was 1 in 21 (17.5%) patients, 2 in 57 (47.5%), 3 in 38 (31.7%) and 4 in 4 (3.3%). The average ESAS score was 33.9 ± 13.8, 48.9 ± 14.7, 58 ± 15.4 and 70 ± 5.5 among patients with ECOG score 1, 2, 3 and 4; respectively (p < 0.001). There was no significant difference in the average score of any of the ESAS items according to the site of metastases. There was a significant positive correlation between the pain score and the scores of tiredness (p<0.001), nausea (p=0.037), lack of appetite (p<0.001), shortness of breath (p=0.001), depression (p<0.001), anxiety (p<0.001) and poor wellbeing (p<0.001). Conclusion: Egyptian patients with cancer pain experience high symptom burden. The severity of pain strongly correlates with the presence and severity of other ESAS symptoms. Systematic assessment of other symptoms is indispensable in patients with cancer pain for proper control of symptoms and improving quality of life.


INTRODUCTION
The World Health Organization defines palliative care as "an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual" 1 .
Patients with advanced cancer usually suffer from multiple physical and psychological symptoms 2 .In a study from Egypt, >70% of newly diagnosed incurable cancer patients reported more than 10 symptoms and the average number of symptoms per patient was 16.8 in the same study 3 .Cancer patients near end of life report more severe symptoms than other cancer patients 4 .Hui et al found that patients in the last week of life still suffer from high symptom burden mainly dyspnea, fatigue and drowsiness; and according to them, these symptoms may be unavoidable in this group of patients in spite of high quality supportive care 5 .
The prevalence of pain in cancer patients varies significantly between studies.In a systematic review on the prevalence of pain in cancer patients at different stages of their disease, pain prevalence ranged from 33-64% 6 .The prevalence of pain varies between 50% at time of diagnosis to 75% in the advanced stages according to the International Association for the Study of Pain (IASP) files 2008-2009 7 .
Many assessment tools were developed to evaluate the symptom burden in advanced cancer patients including the Distress Thermometer (DT) 8 , the Memorial Symptom Assessment Scale (MSAS) 9 , the Edmonton Symptom Assessment System (ESAS) 10 , the European Organization for Research and Treatment of Cancer (EORTC) tools 11 , the Functional Assessment of Cancer Therapy (FACT) tools 12 , and McGill quality of life (QoL) questionnaire 13 .The ESAS is a simple tool to assess symptom burden.It was translated to many languages including Arabic and was validated in Egyptian patients where 65% of patients said the questionnaire was clear and 66% were able to answer it without help 14 .
Proper assessment of different symptoms and their relation to each other is important to control symptoms and to improve the QoL in palliative care patients 15  example, patients with depressive mood have higher symptom burden than other patients 16 .
The word symptom cluster is a relatively new concept and means that two or more symptoms are closely related and may have or not have a common cause.Once used in the clinical setting, it may have positive implications on diagnosis and treatment 17 .In the study done by Gift et al, the symptom cluster in a group of lung cancer patients was an independent predictor of patient death 18 .Chen et al identified 3 symptom clusters in cancer patients: sickness cluster (fatigue, sleep disturbance, lack of appetite and drowsiness), gastrointestinal symptom cluster (nausea and vomiting), and emotional symptom cluster (sadness and distress) 19 .The functional status of patients correlate negatively with sickness cluster, gastrointestinal symptoms are more common in patients under chemotherapy and patients with anxiety or depression had higher scores of emotional clusters.Different symptom clusters were described in other studies 20,21 .
In this study, we investigated the symptom burden in cancer patients with pain and the relation between pain and other symptoms in the ESAS.

METHODS
The study included adult patients with solid tumors and evidence of distant metastases.All included patients had pain and gave a verbal informed consent to participate in the study.Patients were recruited from two cancer centers in Cairo (Kasr Al-Ainy Center of Clinical Oncology and Nuclear Medicine [NEMROCK], Kasr Al-Ainy School of Medicine, Cairo University) and Sharkia (Department of Clinical Oncology, Faculty of Medicine, Zagazig University, Sharkia) governorates.The study was approved by the ethics committees in the two institutions where it took place.
A data collection sheet was constructed including age, sex, primary cancer, site of metastases and performance status which was assessed using the Eastern Cooperative Oncology Group (ECOG) performance scale 22 .The validated Arabic version of the ESAS was used to asses the severity of pain and other common symptoms including: tiredness, nausea, depression, anxiety, drowsiness, appetite, poor wellbeing and shortness of breath.The severity of each ESAS item is rated from 0 to 10 on a numerical scale, 0 meaning that the symptom is absent and 10 that it is of the worst possible severity.Due to the relatively high illiteracy rate, patients were interviewed by investigators NE and EN to complete the data collection sheets.
Data was expressed as percentage, mean ± standard deviation or median and range where appropriate.Independent sample t-test was used to test the significance of difference in the mean ESAS score between two groups and one-way ANOVA between > 2 groups.Pearson's correlation was used to test the relation between the severity of pain and that of other ESAS symptoms.Linear regression analysis was performed to identify symptoms that correlate with pain severity independently.A P value <.05 was considered significant.Statistical analysis was performed using SPSS, version 14.0.(SPSS Inc, Chicago, Illinois).

RESULTS
The study included 120 adult patients with metastatic cancer who were recruited from October 2016 to April 2017.The characteristics of patients are shown in Table 1.All included patients had cancer pain.The average severity of pain and other symptoms assessed by the ESAS are illustrated in Table 2.

ESAS: Edmonton Symptom Assessment System
There was no significant difference in the average score of any of the ESAS items according to presence of lymph nodes, liver or bone metastases.
Drowsiness was significantly higher (p = 0.007) in the presence of brain metastases and shortness of breath was significantly higher (p = 0.032) in the presence of lung metastases.

Figure 1. Box plot representation of the relation between ESAS (Edmonton Symptom Assessment System) and ECOG (Eastern Cooperative Oncology Group) performance scale
In univariate analysis, there was a significant positive association between the pain score and the scores of all other ESAS items except drowsiness (Table 3).In multivariate analysis, the only item that was associated significantly with pain was the "poor wellbeing" item (p = 0.018).

DISCUSSION
The current study showed that Egyptian metastatic cancer patients with pain experience high physical and psychological symptom burden.Most of the included patients suffered from tiredness (94%), anxiety (87.5%), and depression (83%).These results are much higher than those reported by Barbara et al 4 (tiredness 24%, 43% anxiety 43% and depression 55%) and Alsirafy et al 3 (tiredness 61%, anxiety 61%, depressed mood 57%).This might be related to the fact that all included patients suffered from pain.Also, both studies included patients earlier in the course of their disease.
In this study, there was a correlation between the severity of pain and that of tiredness, lack of appetite, depression, anxiety and poor wellbeing.This was previously reported by Tavoli et al, where higher score of cancer pain was associated with higher depression, and lower global QoL 23 .In an Italian study, there was a linear decrease in the mean global QoL from 64.9 in patients without pain to 36.4 in patients with severe pain (p<0.001) 24.The relation between pain, anxiety, and depression is complex and needs attention due to its implication on the proper assessment of patients and hence on the outcome of treatment of these symptoms.Pain increases the feeling of depression and anxiety 24 .At the same time, patients with depression and anxiety experience more severe pain 25 .
Lack of appetite occurred in 76% of our patients with an average ESAS score of 5.This is not far from that reported by Karabulut et al 26 , where 88% reported loss of appetite and Nayak et al who described loss of appetite in 89% of patients 27 .On the other hand, it is higher than that reported in a review by Teunissen et al where lack of appetite occurred in 53% of patients 28 .The lower rate reported by Teunissen et al may be related to the diversity of studies and different assessment methods in the studies included in their systematic review.
In our study, the total ESAS correlated significantly with the performance status.This is in accordance with a Japanese study where ESAS-r was significantly higher in patients with an ECOG performance status of 2-4 than in those with a performance status of 0 and 1 29 .Similarly, in the study done by Shalini et al, patients with lower performance status measured by both ECOG and Karnofsky performance scales had worse QoL scores in symptomatic pancreatic pain 30 .This can be explained by the fact that patients at the end of life are very sick and have high symptom burden which may contribute to the decline in performance status and QoL scores.However in an Italian study, there was a trend for the ESAS score to be higher in poor performance status but did not reach statistical significance 31 .
Our study has many limitations.First, the ESAS is a short instrument assessing only nine symptoms.Further studies are required with more comprehensive tools to properly assess the relation between different symptoms in cancer patients.Another limitation is the inclusion of only patients suffering from pain, which make our results different form other studies.The recruitment of patients was done by convenience method.More systematic recruitment methods can be used in future studies to avoid selection bias.Also, patients were interviewed only once and no follow up interviews were done after pain treatment to assess the difference in symptom burden and performance status after pain control.This may result in better understanding of the relation between pain and other symptoms.

Conclusion
Cancer pain in Egyptian patients with metastatic cancer is associated with high physical and psychological symptom burden.The severity of pain correlates with the severity of other symptoms present in the ESAS.Proper assessment of symptoms, physical and psychological, is indispensable for the proper control of cancer pain and other symptoms and improving QoL of advanced cancer patients.
. For

Table 3 . Correlation between pain score and other ESAS items scores. Other ESAS items Pain Pearson's correlation p value
ESAS: Edmonton Symptom Assessment System