ABSTRACT
Objective
Although symptom assessment is fundamental to palliative care, its independent impact on survival remains unclear. This study addresses survival time differences between high and low symptom burden, assessed using the Edmonton Symptom Assessment System (ESAS), among terminal cancer patients (PPS ≤ 30) at Naresuan University Hospital.
Material and Methods
A bidirectional observational cohort study was conducted from October 1, 2019, to January 31, 2024. Patients were categorized into high or low symptom distress groups based on ESAS physical, emotional, and total symptom scores. Multivariable models adjusted for age, sex, BMI, Charlson Comorbidity Index, and metastatic sites. Survival impact was quantified using restricted mean survival time (RMST) and hazard ratios (HR).
Results
A total of 143 terminal cancer patients were included; 76 were males (53.15%) and the average age was 66.17 ± 12.11 years. HRs for high physical, emotional, and total symptom distress scores (TSDS) were 1.50 (95% CI: 1.02–2.20), 1.02 (95% CI: 0.64–1.63), and 1.34 (95% CI: 0.91–1.97), respectively. Only the physical domain remained significant after adjustment. RMST demonstrated that patients with high physical burden experienced a significant survival reduction of 3.70 days (95% CI: −7.17 to −0.23) within a 28‐day follow‐up period.
Conclusions
High physical symptom burden is significantly associated with shorter survival in terminal cancer patients. These findings highlight the prognostic importance of physical symptoms, emphasizing the need for effective symptom management to optimize remaining survival time.
Keywords: palliative care, survival time, symptom burden
1. Introduction
Palliative care is fundamental to managing the multidimensional symptom burden and enhancing the quality of life for patients with life‐limiting illnesses [1, 2]. In terminal cancer care, accurate prognostication is essential for effective treatment decision‐making and care planning. While clinician‐rated tools like the Palliative Performance Scale (PPS) and Palliative Prognostic Index (PPI) are widely used for survival estimation [3, 4, 5], they primarily focus on functional status and clinical signs, which are often irreversible in terminal stages.
However, these functional‐based tools may overlook subjective symptom distress, a significant independent prognostic factor. While symptom burden assessed via the Edmonton Symptom Assessment System (ESAS) is central to palliative care [6], its impact on survival remains equivocal [7, 8, 9, 21]. Furthermore, current literature relies predominantly on Hazard Ratios (HR), which often lack intuitive clinical interpretation of survival duration.
To address these gaps, this study investigates survival disparities based on ESAS‐defined symptom severity among terminal cancer patients. By integrating patient‐reported symptom burden with standard functional assessments, we aim to highlight the prognostic significance of severe symptom distress. Through the application of Restricted Mean Survival Time (RMST) alongside Hazard Ratio (HR) methodologies, we provide a more robust and clinically meaningful quantification of how symptom distress influences life expectancy. These findings may underscore the necessity of intensified symptom management, recognizing that high symptom burden is not only a matter of comfort but also a critical indicator of shortened survival.
2. Material and Methods
A bidirectional observational cohort study (retrospective and prospective data collection) was conducted from October 1, 2019, to January 31, 2024, involving terminal cancer patients who consulted the palliative care team at Naresuan University Hospital (NUH), Phitsanulok, Thailand, a tertiary referral hospital with a total of 494 beds as of 2024. Terminal cancer patients were defined as those with PPS ≤ 30, utilizing the validated Thai PPS with an intraclass correlation coefficient (ICC) of 0.911 (95% CI 0.86–0.96) [10].
A total of 442 patients followed this IPD consultation pathway, with 143 patients or main caregivers who completed the ESAS included in the study. IPD cancer patients were admitted by primary doctors such as oncologists, surgeons, and hematologists. Afterwards, they consulted the palliative care team, which consisted of palliative care nurses, family medicine residents, family physicians, and palliative care physicians. The palliative care team has at least 10 years of clinical experience. The team assesses patients within 24 h according to urgency.
ESAS is one of the tools used for every patient as part of routine care for symptom management, psychosocial, and spiritual support. We conduct ward rounds every day and do home visits or telephone calls at least every week after hospital discharge until death. The last day of follow‐up in this cohort was 27 February 2024.
The requirement for informed consent was waived by the Institutional Review Board (IRB) because symptom assessment and follow‐up visits are part of routine palliative care at NUH, and data were de‐identified for analysis.
2.1. Variables, Data Sources/Measurement, Quantitative Variables
Ethical approval was obtained from the institutional review board of Naresuan University Hospital on August 23, 2023 (IRB No. P3–0068/2566). We collected the consultation. This date was defined as information from patients' paper and electronic medical records: potential confounders such as age (< 60, ≥ 60 according to Thai elderly people cut‐off), sex (male, female), BMI (< 18.5, 18.5–22.9, ≥ 23 kg/m2 according to Asia‐Pacific people cut‐off), CCI (0, 1, ≥ 2), and number of metastases sites (0, 1, 2, ≥ 3) [8, 11, 12, 13, 14, 15, 16, 17]. We collected as continuous data first and then classified as quantitative data. We also noted cancer types as one of the baseline characteristics.
2.2. Measurement Symptom Burden
The ESAS assessment was conducted during the initial palliative care consultation, which served as the index date for survival analysis. The ESAS scores assessed the nine main cancer‐associated symptoms: pain, fatigue, nausea, depression, anxiety, drowsiness, anorexia, feeling of well‐being, and shortness of breath. The scale ranged from 0 to 10, with 0 being the least and 10 the most severe symptom burden. We utilized the validated Thai ESAS (Cronbach's alpha = 0.79) to calculate the Total Symptom Distress Score (TSDS) and its components: the Physical Symptom Subscale (PSS) (pain, fatigue, nausea, drowsiness, anorexia, and shortness of breath) and the Emotional Symptom Subscale (ESS) (depression and anxiety) [18, 19, 20]. These scores were stratified into two levels of symptom burden: high and low. According to a previous study, a moderate to severe symptom burden (ESAS score ≥ 4 per symptom) has significant clinical significance and should be promptly managed. This is defined as a high symptom burden level [21].
2.3. Study Size
Based on the Hazard Ratio (HR) of 1.5 from a previous study [21], we calculated the study size using the survival analysis formula in Stata ver. 17, with a two‐sided p‐value of 0.05 and power of 0.8.
2.4. Statistical Methods
Baseline patient characteristics were summarized using descriptive statistics including means, medians, frequencies (compared by the Exact probability test), and percentages (compared by the independent t‐test). Missing data were detected in potential confounders ranging from 0%–7.69% for each variable, so we didn't perform imputation since we accounted for sample size calculation. Survival rates between high and low symptom burden levels were compared using the Kaplan–Meier Survival Curve. The effect of the level of symptom burden on survival time was analyzed using Cox proportional‐hazards regression.
The proportional hazards assumption was verified using Schoenfeld residuals, with no violations detected. Furthermore, Restricted Mean Survival Time (RMST) with 95% confidence intervals (CI) was applied to provide a more robust and clinically meaningful quantification of how symptom burden influences survival. Confounders were adjusted across 4 models using the forward selection method and the likelihood ratio test.
3. Results
In this study, we enrolled 143 terminal cancer patients, 30 of whom were censored. The cohort consisted of patients with various cancer types, with the most prevalent being gastrointestinal (GI) cancer (37 patients; 25.87%), followed by lung and hepatobiliary cancer (29 patients; 20.28%, and 18 patients; 12.59%, respectively). Males were the predominant gender in the cohort, comprising 53.15% of the participants. The mean age of the cohort was 66.17 ± 12.11 years. Notably, approximately 40.91% of patients had a BMI below 18.5 kg/m2. Regarding comorbidities, 59.86% of participants had a Charlson Comorbidity Index by Deyo of 0, indicating a relatively low comorbidity burden. Conversely, nearly half (45.77%) presented with three or more metastatic sites, reflecting an advanced stage of cancer in many cases. The clinical course was rapid; 75.5% of patients died within 1 month of consultation, with a median survival of 11 days.
Importantly, no significant differences were observed in baseline clinical characteristics between the studied groups, except for the mean age in the TSDS group and BMI categories in the ESS group (Table 1). Patients with a high symptom burden according to TSDS tended to be younger.
TABLE 1.
Baseline characteristics of terminal cancer patients classified by symptom scores.
| Characteristics | Total | Symptom scores | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Total symptom distress scores (TSDS) n (%) | p | Physical symptom scores n (%) | p | Emotional symptom scores n (%) | p | |||||
| High (36–90) | Low (0–35) | High (24–60) | Low (0–23) | High (8–20) | Low (0–7) | |||||
| Age (Mean ± SD) | 66.17 ± 12.11 | 63.44 ± 12.03 | 67.88 ± 11.91 | 0.032 | 65.91 ± 12.65 | 66.49 ± 11.47 | 0.777 | 62.66 ± 10.17 | 67.18 ± 12.47 | 0.062 |
| < 60 | 37 (25.87) | 15 (27.27) | 22 (25.00) | 0.845 | 20 (25.00) | 17 (26.98) | 0.849 | 10 (31.25) | 27 (24.32) | 0.493 |
| ≥ 60 | 106 (74.13) | 40 (72.73) | 66 (75.00) | 60 (75.00) | 46 (73.02) | 22 (68.75) | 84 (75.68) | |||
| Sex | ||||||||||
| Female | 67 (46.85) | 24 (43.64) | 43 (48.86) | 0.607 | 37 (46.25) | 30 (47.62) | 1.000 | 16 (50.00) | 51 (45.95) | 0.693 |
| Male | 76 (53.15) | 31 (56.36) | 45 (51.14) | 43 (53.75) | 33 (52.38) | 16 (50.00) | 60 (54.05) | |||
| BMI | 20.05 ± 3.70 | 19.49 ± 2.97 | 20.42 ± 4.08 | 0.158 | 19.74 ± 3.32 | 20.48 ± 4.15 | 0.257 | 19.08 ± 3.84 | 20.34 ± 3.62 | 0.103 |
| < 18.5 | 54 (40.91) | 25 (48.08) | 29 (36.25) | 0.314 | 33 (43.42) | 2 1 (37.50) | 0.438 | 18 (60.00) | 36 (35.29) | 0.043 |
| 18.5–22.9 | 53 (40.15) | 17 (32.69) | 36 (45.00) | 27 (35.53) | 26 (46.43) | 7 (23.33) | 46 (45.10) | |||
| ≥ 23 | 25 (18.94) | 10 (19.23) | 15 (18.75) | 16 (21.05) | 9 (16.07) | 5 (16.67) | 20 (19.61) | |||
| Charlson comorbidity index | ||||||||||
| 0 | 85 (59.86) | 36 (66.67) | 49 (55.68) | 0.337 | 50 (63.29) | 35 (55.56) | 0.650 | 23 (74.19) | 62 (55.86) | 0.170 |
| 1 | 27 (19.01) | 10 (18.52) | 17 (19.32) | 14 (17.72) | 13 (20.63) | 3 (9.68) | 24 (21.62) | |||
| ≥ 2 | 30 (21.13) | 8 (14.81) | 22 (25.00) | 15 (18.99) | 15 (23.81) | 5 (16.13) | 25 (22.52) | |||
| Number of metastasis | ||||||||||
| 0 | 10 (7.04) | 3 (5.56) | 7 (7.95) | 0.539 | 7 (8.86) | 3 (4.76) | 0.312 | 2 (6.45) | 8 (7.21) | 0.944 |
| 1 | 26 (18.31) | 8 (14.81) | 18 (20.45) | 15 (18.99) | 11 (17.46) | 5 (16.13) | 21 (18.92) | |||
| 2 | 4 1 (28.87) | 14 (25.93) | 27 (30.68) | 18 (22.78) | 23 (36.51) | 8 (25.81) | 33 (29.73) | |||
| ≥ 3 | 65 (45.77) | 29 (53.70) | 36 (40.91) | 39 (49.37) | 26 (41.27) | 16 (51.61) | 49 (44.14) | |||
Kaplan–Meier survival curves (Figures 1, 2) demonstrated consistent patterns where individuals in the high symptom burden group tended to exhibit shorter survival times across all measured scores. This association was statistically significant for the physical symptom burden (log‐rank p = 0.04). Presents crude Hazard Ratios (HR) for TSDS, PSS, and ESS, which were 1.34 (95% CI 0.91–1.97), 1.50 (95% CI 1.02–2.20), and 1.02 (95% CI 0.64–1.63), respectively. Notably, the prognostic significance of high PSS remained robust after adjusting for potential confounders (Table 2).
FIGURE 1.
Total symptom distress score (TSDS).
FIGURE 2.
Physical symptom distress score (PSS).
TABLE 2.
Multivariable Cox proportional hazard ratio estimates adjusting for ESAS symptom burden.
| model1 a HR (95% CI) | model2 b HR (95% CI) | model3 c HR (95% CI) | model4 d HR (95% CI) | |
|---|---|---|---|---|
| Total symptom distress scores | ||||
| High vs. low | 1.46 (0.97–2.20) | 1.50 (0.97–2.20) | 1.46 (0.97–2.20) | 1.47 (0.98–2.20) |
| Physical symptom scores* | ||||
| High vs. low | 1.60 (1.06–2.43) | 1.58 (1.05–2.39) | 1.61 (1.06–2.44) | 1.60 (1.06–2.41) |
| Emotional symptom scores | ||||
| High vs. low | 1.11 (0.68–1.81) | 1.09 (0.67–1.77) | 1.12 (0.69–1.82) | 1.11 (0.68–1.80) |
Model adjusted for Age, Sex, BMI, Charlson Comorbidity Index, Number of metastasis.
Model adjusted for Age, Sex, BMI, Charlson Comorbidity Index.
Model adjusted for Age, Sex, BMI, Number of metastases.
Model adjusted for Age, Sex, BMI.
p < 0.05.
Finally, RMST analysis (Table 3) indicated that patients in the high physical symptom burden group were estimated to experience a reduction in survival time of 3.70 days (95% CI −7.17 to −0.23) up to day 28 compared to the low symptom burden group. This reduction is statistically significant and highlights the impact of physical symptom distress on survival outcomes in terminal cancer care.
TABLE 3.
Restricted mean survival time (RMST) differences between groups at four pre‐specified landmarks (t*).
| Landmark (t*) (days) | Physical high symptom burden (n = 80) | Physical low symptom burden (n = 63) | Physical symptom burden effect RMST difference (95% CI) | p | ||
|---|---|---|---|---|---|---|
| Number at risk | RMST (95% CI) | Number at risk | RMST (95% CI) | |||
| 7 | 42 | 5.50 (5.01–5.99) | 43 | 5.98 (5.52–6.44) | −0.49 (−1.14 to 0.17) | 0.144 |
| 14 | 31 | 9.08 (7.92–10.24) | 31 | 10.54 (9.37–11.72) | −1.46 (−3.07 to 0.14) | 0.075 |
| 21 | 21 | 11.78 (10.00–13.55) | 20 | 14.34 (12.44–16.24) | −2.56 (−5.14 to 0.01) | 0.051 |
| 28 | 17 | 13.86 (11.52–16.20) | 18 | 17.56 (14.93–20.19) | −3.70 (−7.17 to −0.23) | 0.037* |
p < 0.05.
4. Discussion
This study demonstrates that a high symptom burden, particularly within the physical domain, is independently associated with shortened survival among terminal cancer patients. Even after adjusting for potential confounders—including age, sex, BMI, comorbidity index, and metastatic burden—physical symptom distress remained a significant predictor of early mortality. Notably, our RMST analysis quantified this association, revealing a significant loss of approximately 3.7 survival days within a 28‐day horizon for patients with high physical distress compared to those with lower burden. However, the decreasing number of patients at risk by day 28 led to wider confidence intervals; thus, RMST estimates at later landmarks should be interpreted with caution. This quantifiable reduction in survival underscores the critical prognostic value of patient‐reported physical distress during the terminal phase.
While the prognostic utility of functional‐based instruments, such as the PPS and PPI, is well‐established, these tools primarily reflect the irreversible physiological decline characteristic of terminal illness. Our findings add a crucial dimension by demonstrating that subjective symptom distress also carries substantial prognostic weight. Unlike irreversible functional decline, severe physical symptoms—such as pain and dyspnea—are often amenable to targeted palliative interventions. By identifying high physical burden as a significant risk factor for shortened survival, our study emphasizes that aggressive symptom management serves a dual purpose: it addresses immediate suffering and recognizes that uncontrolled distress is a potent indicator of accelerated mortality.
Interestingly, while the Total Symptom Distress Score (TSDS) and Emotional Symptom Subscale (ESS) showed trends toward shorter survival, only the physical domain remained a statistically significant independent predictor in multivariable models. This distinction may help clarify conflicting findings in existing literature. For instance, while a previous study in South Korea demonstrated that higher ESAS scores correlated with poor outcomes in acute care settings [14], other studies focusing on composite scores have yielded inconsistent results. Specifically, Nieder et al. observed comparable survival regardless of TSDS levels in patients undergoing radiotherapy [7], and Bandieri et al. found no significant survival disparities based on TSDS in the context of early palliative care [8].
Our findings suggest that relying solely on TSDS may dilute the critical prognostic signal specifically driven by physical distress. By differentiating between symptom domains, this study highlights that physical burden is the primary driver of the observed survival association during the terminal phase. This nuanced understanding underscores the importance of domain‐specific assessment rather than aggregate scoring when evaluating prognosis.
Similar trends were observed in other studies. For instance, in advanced pancreatic cancer, higher TSDS scores have been significantly correlated with diminished overall survival (HR = 1.34) [21]. Similarly, McGee et al. demonstrated that patients with advanced non‐small‐cell lung cancer (NSCLC) and elevated symptom burden experienced a substantial reduction in median survival 5.5 months compared to 9.9 months in those with lower distress (p < 0.0001) [9]. While our results are concordant with these established observations, this study provides a more granular and clinically intuitive insight by utilizing RMST to quantify the precise impact of symptom distress on life expectancy.
A primary strength of this study is the application of RMST analysis, which offers a more clinically intuitive measure of survival disparities specifically (i.e., “days lost”) than traditional Hazard Ratios. This tangible reduction of nearly 4 days over a 28‐day period carries significant weight for terminal patients and their families, particularly concerning end‐of‐life preparation and the preservation of quality time.
However, the clinical significance of this four‐day difference is inherently individualized and value‐sensitive. In the final stages of life, the perception of survival time is inextricably linked to the quality of that time; for patients enduring refractory symptom distress, a longer survival period may be perceived as prolonged suffering rather than a clinical benefit. This nuance underscores that while our study identifies a statistical link between distress and shortened survival, the goal of palliative intervention remains the alignment of care with the patient's values, ensuring that “time remaining” is defined by comfort rather than distress.
This study has certain limitations that warrant consideration. First, the observational and non‐randomized design precludes definitive causal inferences; thus, we can only report a significant association between high symptom burden and shortened survival. Second, the potential for residual confounding remains, as symptom distress may be influenced by unmeasured factors—such as specific disease trajectories, medication use, and complex psychosocial contexts—that independently affect both ESAS scores and mortality. Third, ESAS scores were treated as baseline measures during the initial consultation. Given that symptoms often fluctuate rapidly during the terminal phase, the lack of time‐updated or longitudinal assessments may not fully capture the dynamic nature of symptom distress. Finally, as a single‐center study, the generalizability of our findings may be limited, although our cohort reflects the typical clinical presentations of terminal cancer in Thailand.
For future research, we recommend multicenter longitudinal studies to enhance generalizability and capture temporal changes in symptom burden. Furthermore, subgroup analyses are warranted to explore whether the prognostic impact of symptom distress varies across different cancer types or specific stages of the disease trajectory.
5. Conclusion
This study demonstrates that a high physical symptom burden, assessed by ESAS, is significantly associated with shortened survival in terminal cancer patients. Unlike functional markers which are often irreversible, physical symptoms represent modifiable factors. Therefore, comprehensive assessment and intensified management of physical distress are paramount not only for improving quality of life but also to address a critical driver of survival outcomes in the terminal phase. The application of RMST provides a clearer, clinically relevant quantification of this survival difference, aiding clinicians in more accurate prognostication and patient‐centered care planning.
Author Contributions
Phitchaya Bussaba: conceptualization, validation, writing – original draft. Non Sowanna: conceptualization, supervision, project administration, writing – original draft, writing – review and editing. Sukrit Kanchanasurakit: formal analysis, validation, supervision, writing – review and editing. Nitiya Lamkham: investigation, data curation. Nuchjaree Srivichaiwong: investigation, data curation. Theerapat Limsakul: investigation, data curation.
Funding
The authors have nothing to report.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
We thank the Continuity of Care team Naresuan University hospital for providing data acquisition and cleaning. We used Gemini Pro in manuscript revision for checking logical flow, coherence, and correcting grammatical errors. We confirmed that the authors take responsibility for the integrity of the content generated.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.