We performed an observational study to examine the accuracy of survival prediction in both indicators of QLQ-C15-PAL scores and the inflammatory biomarkers CRP, Alb, and NLR in terminally ill patients with cancer hospitalized in a palliative care unit. Our study identified that dyspnea and fatigue symptom scores in the QLQ-C15-PAL and all inflammatory biomarkers could be independent prognostic factors of short-term survival for terminally ill patients with cancer. We further revealed the cut-off values for each of the dyspnea and fatigue symptom scores for predicting prognosis.
Although previous studies [7, 9, 10] have reported that several scores in the QLQ-C30 were associated with survival, there are few reports regarding the QLQ-C15-PAL. Lee et al. [8] reported that multiple QLQ-C15-PAL scores can be independent prognostic factors of survival in patients with far advanced cancer; however, our results indicate only dyspnea and fatigue symptoms as the independent prognostic factors in QLQ-C15-PAL scores. Our study included patients with terminally ill cancer, many of whom had low PPS (≤ 60, 103/130; 79.2%) and short survival times of 18 days (median). These results suggest that the dyspnea and fatigue symptoms among QLQ-C15-PAL scores are independent prognostic factors, particularly in terminally ill patients with cancer.
Many previous studies have identified PROs as prognostic factors for survival of patients with cancer [7–11], but few have examined the cut-off values for PRO measurements to predict survival. Therefore, we examined the cut-off values of dyspnea and fatigue in the QLQ-C15-PAL for detecting the risk of a short-term prognosis of < 3 weeks (21 days). Both dyspnea and fatigue showed cut-off values of 66.67 (transformed QLQ-C15-PAL scores). However, severe fatigue was indicated with transformed QLQ-C30 scores of ≥ 66.67 in a previous study [32]. Meanwhile, in our study, more than 50% of patients showed severe fatigue according to the QLQ-C15-PAL scores. These results suggest that the cut-off values of transformed QLQ-C15-PAL scores, which can lead to severe levels of dyspnea and fatigue symptoms experienced by many terminally ill patients, are a predictive indicator of short-term prognosis.
The levels of CRP, Alb, and NLR are known prognostic indicators for patients with cancer [18–24], which was confirmed in the Cox analysis (Table 2). We also identified cut-off values for these markers to predict 3-week survival (Table 3). Considering the criteria for an mGPS of 2 (CRP > 1.0 mg/dL and Alb < 3.5 g/dL), our results indicate that a high cut-off value for CRP (3.0 mg/dL) and a low cut-off value for Alb (2.5 g/dL) are estimates from advanced cancer patients near the end of life. Additionally, approximately 80% of patients had a CRP > 1.0 mg/dL, and over 70% had an mGPS of 2 in our study. This is consistent with previous reports in palliative care settings [18, 33]; therefore, terminally ill cancer patients might be at greater risk for chronic inflammation. Moreover, in cancer cachexia, inflammatory cytokines, such as IL-6 derived from cancer cells, act on hepatocytes to increase CRP production and increase protein catabolism [17]. The level of Alb, reflecting the visceral protein pool [34], is reduced in the presence of a systemic inflammatory response [34, 35].
NLRs have been reported as inflammatory biomarkers, based on neutrophil and lymphocyte counts [29]. A systematic review indicated that an NLR score of 4 was the best cut-off value for prognosis [24]. On the other hand, our study revealed that the cut-off value for the NLR was 8.2, and most patients had abnormally high NLR scores (> 4, 98/122; 80.3%). This is a similar finding to a previous study that reported scores of 9.21 in cancer patients who died within 4 weeks [23]. These findings also suggest increased inflammation in terminally ill patients with cancer. Although there are many biomarkers that can be influenced by systemic inflammatory responses, in our study, we chose only CRP, Alb, and NLR measurements because of strong evidence for their association with prognoses. In addition, it was impossible to measure all biomarkers related to inflammation. Therefore, we adopted the results of a univariate analysis and calculated cut-off values of each indicator. The current results suggest that the assessment of the systemic inflammatory response using these biomarkers is also useful in estimating prognoses for terminally ill patients with cancer.
Among the significant prognostic indicators, the sensitivity and specificity of patient-reported dyspnea and fatigue were comparable to that of the inflammatory biomarkers CRP, Alb, and NLR (Table 3). The measurements of PROs can be assessed directly by the patient themselves, even if no patients’ blood data were available. Near the end of life, the clinical prediction of survival requires simple, always-available prognostic indicators because the patient’s general condition rapidly deteriorates in the last month before death [3]. Therefore, the PRO score might be a more suitable prognostic indicator for short-term prognosis of 3 weeks as compared to laboratory values. The results of the present study suggest that monitoring QLQ-C15-PAL scores is necessary, along with measuring inflammatory biomarkers, in terminally ill patients with cancer.
This study had some limitations. First, it was conducted in a single hospital, and the sample size was not large enough to ensure generalizability. In addition, we could not evaluate the details of various factors that could affect inflammation status, such as use of concomitant drugs like anti-inflammatory medication, nutritional intake, cancer type, and coexisting infections.