Cancer cachexia is defined as a multifactorial syndrome involving the ongoing loss of skeletal muscle mass that cannot be fully reversed and leads to progressive functional impairment.1 Cancer cachexia is characterized by a negative protein and energy balance driven by a combination of reduced food intake and abnormal metabolism.1,2 There is accumulating evidence to show that systemic inflammation and inflammation in the tumour microenvironment are involved in the mechanisms responsible for cancer cachexia.3–6 Physical disorders have been emphasized in the definition; however, the negative impact of pro-inflammatory cytokines on the central nervous system (CNS) appears to contribute to a number of psychological symptoms, e.g. sleep disturbance, depression, and cognitive dysfunction, as well as physical disorders in patients with cancer.7–16 Nevertheless, studies on CNS regulation in cancer cachexia have been limited to investigations on the systemic levels of neuromodulatory peptides, such as appetite-regulating hormones.2 Moreover, ‘sickness behaviour’ has been reported in infected mammals and recognized as a symptom cluster, including fatigue, sleep disturbance, depression, and cognitive dysfunction, which is associated with systemic inflammation and its impact on the CNS. Accordingly, infection and sickness behaviour have many overlapping features of cancer cachexia.2,7
Delirium is a neuropsychiatric condition that is characterized by the acute onset of changes in attention or awareness accompanied by altered cognition.17 Delirium is frequently observed in patients with advanced cancer with a prevalence of between 30% and 40% at admission to palliative care units and up to 90% at the end of life.18,19 Delirium may be a source of distress among not only patients themselves but also their families because attention or awareness deficits impede the ability to communicate within the family and affect decision making for end-of-life care planning.20,21 Previous studies reported that the causes of delirium are opioids, corticosteroids, psychotropic drugs, anticholinergic drugs, hypercalcaemia, hyponatremia, dehydration, hypoxia, infection, and organic damage to the CNS.22–26 Additionally, a recent study by our group suggested that hyponatremia, dehydration, hypoxia, and CNS damage correlate with irreversible delirium.27 Thus, CNS damage appears to be associated with the occurrence and severity of delirium in patients with advanced cancer. Furthermore, there is increasing evidence to show that delirium is frequently present under conditions in which a systemic inflammatory response occurs and also to support serum levels of C-reactive protein (CRP) being a surrogate of systemic inflammation related to delirium in a number of settings.28–35
However, to the best of our knowledge, it currently remains unclear whether a relationship exists between delirium and elevated CRP levels mainly due to cancer cachexia with or without infection. Therefore, the primary aim of the present study was to investigate the relationship between serum CRP levels and the incidence, type, and severity of delirium; and the secondary aim was to examine the prevalence of other psychological symptoms, i.e. drowsiness, sleep disturbance, anxiety, and depression, according to CRP levels in patients with advanced cancer admitted to palliative care units.
Materials and methods Sites and participantsThis study was a secondary analysis of a large prospective cohort study, which was conducted to investigate the dying process in terminally ill patients with advanced cancer in 23 palliative care units in Japan between January 2017 and June 2018. In brief, consecutive eligible patients who had been newly referred to the palliative care units were enrolled. All participating palliative care units obtained data up to the designated number of patients of 50, 60, 70, 80, 100, 150, and 250 according to the size of the institution. Inclusion criteria were as follows: (i) patients aged 18 years or older; (ii) patients with locally advanced or metastatic cancer, including haematological neoplasms; and (iii) patients admitted to palliative care units. Patients who planned to be discharged within 1 week or those who did not want to be enrolled were excluded. Patients discharged alive from palliative care units or those with missing data for essential variables, e.g. a baseline CRP value, were also excluded.
The present study was conducted in accordance with the ethical standards of the Helsinki Declaration and the ethical guidelines for medical and health research involving human subjects presented by the Ministry of Health, Labor, and Welfare in Japan. This study was also approved by the local Institutional Review Boards in participating institutions. We used an opt-out method because individual informed consent from participants is not required in a non-invasive observational trial by Japanese law.
MeasurementPatient characteristics, e.g. age, sex, primary cancer site, CNS metastasis, medical history, psychotropic drugs, opioids, and the Eastern Cooperative Oncology Group Performance Status (ECOG PS),36 were obtained on the day of admission to palliative care units (baseline). Additionally, drowsiness was estimated on the Integrated Palliative care Outcome Scale (IPOS)37 ranging between 0 (not at all) and 4 (overwhelming) by the palliative care physicians at baseline. Laboratory data, e.g. CRP, haemoglobin, sodium, calcium, and albumin, measured within 7 days before admission or 3 days after admission, were also recorded. For the analysis, we calculated calcium level corrected with low serum albumin levels using the formula: measured calcium (mEq/L) + 0.8 × [4.0 − serum albumin (g/dL)].
At baseline, the palliative care physicians diagnosed delirium with the Diagnostic and Statistical Manual of Mental Disorders 5th edition17 and also categorized delirious patients into four types, i.e. hypoactive, hyperactive (mild), hyperactive (moderate), and hyperactive (severe), with the item 9 (decreased or increased psychomotor activity) in the Memorial Delirium Assessment Scale.38 On the seventh day after enrolment, the palliative care physicians evaluated whether new delirium had occurred within 1 week and categorized patients who had been delirious in the same manner. Other psychological symptoms, i.e. sleep disturbance, anxiety, and depression, were also estimated with the IPOS ranging between 0 (not at all) and 4 (overwhelming) by the palliative care physicians at 1 week. Survival was observed from baseline to death.
Statistical analysesAll subjects were divided into two groups as follows: patients without and with delirium. Patient characteristics were compared between the two groups and presented as means ± standard deviations (SDs) or numbers (%) where appropriate. Subjects were also divided into four groups according to CRP levels: (i) low (CRP < 1 mg/dl), (ii) moderate (1 ≤ CRP < 5 mg/dl), (iii) high (5 ≤ CRP < 10 mg/dl), and (iv) very high (10 mg/dl ≤ CRP). We used approximate figures to quartile points, as described in our previous studies,10,11 which indicated that CRP may be useful for predicting outcomes, symptoms, and activities of daily living disabilities in patients with advanced cancer. We assessed the associations between CRP levels and proportions of psychological symptoms, including delirium, drowsiness, sleep disturbance, anxiety, and depression. Comparisons among the groups were made using chi-squared test. To evaluate the relationship between CRP levels and the incidence of delirium, adjusted odd ratios (ORs) and 95% confidence intervals (CIs) were calculated after adjustments for independent variables known as potential risk factors for developing delirium in cancer patients, such as age, sex, CNS metastasis, cerebrovascular disease, dementia, ECOG PS, calcium corrected with albumin, and the opioid oral morphine milligram equivalent.18–27 We entered them into the logistic model. We sequentially introduced variables into the model, first demographic and biological variables and then dose of opioid to understand the effect of opioid as confounding factors to the effects of other factors for developing delirium in patients with advanced cancer. All results were considered to be significant if the P value was less than 0.05. All analyses were performed using SPSS software version 24.0 and R software version 3.6.1.
ResultsAmong the original cohort of 1896 patients, 230 were excluded because they were discharged alive, and 312 were also excluded due to missing data. Thus, 1354 patients (71.4%) were considered to be eligible for analyses. We divided patients into two groups: patients without delirium (n = 732) and those with delirium (n = 622). Subject characteristics are summarized in Table 1. Mean age was 72.5 ± 12.2 years old, the proportion of patients aged 70 years or older was 60.5%, and 50.5% were male patients. The top three primary cancer sites were the upper and lower gastrointestinal tract, liver/biliary system/pancreas, and lung. The proportion of patients with ECOG PS 0–2, 3, and 4 were 6.1%, 42.5%, and 51.4%, respectively. Mean survival time was 26.0 ± 29.5 days. Significant differences were observed in age, sex, cerebrovascular disease, dementia, opioid oral morphine milligram equivalent, ECOG PS, CRP, sodium, calcium, albumin, calcium corrected with albumin, saturation of percutaneous oxygen, and survival time between the two groups.
Table 1 Patient characteristics.
| Total ( |
Patients without delirium ( |
Patients with delirium ( |
|||||
| Age, years (SD) | 72.5 (25–100) | (12.2) | 71.7 | (12.5) | 73.5 | (11.9) | <0.01 |
| Age, n (%) | 0.01 | ||||||
| <70 | 535 | (39.5) | 312 | (42.6) | 223 | (35.9) | |
| 70≤ | 819 | (60.5) | 420 | (57.4) | 399 | (64.1) | |
| Sex, n (%) | < 0.01 | ||||||
| Male | 684 | (50.5) | 343 | (46.9) | 341 | (54.8) | |
| Female | 670 | (49.5) | 389 | (53.1) | 281 | (45.2) | |
| Primary cancer site, n (%) | 0.16 | ||||||
| Lung | 230 | (17.0) | 114 | (15.6) | 116 | (18.6) | |
| Upper and lower gastrointestinal tract | 385 | (28.4) | 218 | (29.8) | 167 | (26.8) | |
| Liver, biliary system, and pancreas | 265 | (19.6) | 148 | (20.2) | 117 | (18.8) | |
| Gynaecological | 81 | (6.0) | 54 | (7.4) | 27 | (4.3) | |
| Urological | 93 | (6.9) | 43 | (5.9) | 50 | (8.0) | |
| Breast | 93 | (6.9) | 50 | (6.8) | 43 | (6.9) | |
| Head and neck | 52 | (3.8) | 24 | (3.3) | 28 | (4.5) | |
| Brain | 21 | (1.6) | 9 | (1.2) | 12 | (1.9) | |
| Haematological | 37 | (2.7) | 20 | (2.7) | 17 | (2.7) | |
| Others | 97 | (7.2) | 52 | (7.1) | 45 | (7.2) | |
| CNS metastasis, yes, n (%) | 180 | (13.3) | 86 | (11.8) | 94 | (15.1) | 0.07 |
| Cerebrovascular disease, yes, n (%) | 88 | (6.5) | 38 | (5.2) | 50 | (8.0) | 0.03 |
| Dementia, yes, n (%) | 108 | (8.0) | 44 | (6.0) | 64 | (10.3) | < 0.01 |
| Mental illness, yes, n (%) | 124 | (9.2) | 65 | (8.9) | 59 | (9.5) | 0.70 |
| Psychotropic drug, yes, n (%) | 386 | (28.5) | 211 | (28.8) | 175 | (28.1) | 0.78 |
| Opioid oral morphine milligram equivalent, mg/day (SD) | 45.3 (0–1,200) | (88.2) | 42.0 | (80.2) | 49.0 | (96.8) | 0.15 |
| Opioid oral morphine milligram equivalent, n (%) | 0.04 | ||||||
| 0 | 477 | (35.2) | 277 | (37.8) | 200 | (32.2) | |
| 1–60 | 616 | (45.5) | 329 | (44.9) | 287 | (46.1) | |
| 60≤ | 261 | (19.3) | 126 | (17.2) | 135 | (21.7) | |
| ECOG performance status, n (%) | < 0.01 | ||||||
| 0–2 | 83 | (6.1) | 67 | (9.2) | 16 | (2.6) | |
| 3 | 575 | (42.5) | 348 | (47.5) | 227 | (36.5) | |
| 4 | 696 | (51.4) | 317 | (45.4) | 379 | (60.9) | |
| CRP, mg/dl (SD) | 8.0 | (7.4) | 7.3 | (7.2) | 8.8 | (7.7) | < 0.01 |
| CRP, n (%) | < 0.01 | ||||||
| CRP < 1 | 170 | (12.6) | 105 | (14.3) | 65 | (10.5) | |
| 1 ≤ CRP < 5 | 453 | (33.5) | 264 | (36.1) | 189 | (30.4) | |
| 5 ≤ CRP <10 | 334 | (24.7) | 174 | (23.8) | 160 | (25.7) | |
| 10 ≤ CRP | 397 | (29.3) | 189 | (25.8) | 208 | (33.4) | |
| Haemoglobin, g/dl (SD) | 10.03 | (2.27) | 10.05 | (2.26) | 10.01 | (2.30) | 0.73 |
| Sodium, mEq/L (SD) | 135.4 | (6.58) | 135.0 | (6.47) | 135.8 | (6.68) | 0.04 |
| Calcium, mEq/L (SD) | 8.65 | (1.16) | 8.58 | (1.01) | 8.72 | (1.29) | 0.04 |
| Albumin, g/dl (SD) | 2.42 | (0.63) | 2.46 | (0.63) | 2.37 | (0.63) | 0.01 |
| Calcium corrected with albumin, mEq/L (SD) | 9.89 | (1.12) | 9.78 | (1.00) | 10.0 | (1.23) | < 0.01 |
| Saturation of percutaneous oxygen, % (SD) | 95.7 | (3.2) | 96.0 | (2.7) | 95.4 | (3.7) | < 0.01 |
| Survival time, days (SD) | 26.0 | (29.5) | 30.9 | (32.0) | 20.3 | (25.0) | < 0.01 |
SD, standard deviation; CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; CRP, C-reactive protein.
Values are the mean ± SD or n (%).
We also classified patients into four groups according to CRP levels: (i) low (CRP < 1 mg/dl) (n = 170), (ii) moderate (1 ≤ CRP < 5 mg/dl) (n = 453), (iii) high (5 ≤ CRP < 10 mg/dl) (n = 334), and (iv) very high (10 mg/dl ≤ CRP) (n = 397) (Table 2). The incidence of delirium significantly increased with increasing CRP levels (P = 0.02), while there was no relationship between the type and severity of delirium and CRP (P = 0.82). Drowsiness at baseline was significantly worse in the very high CRP group (P = 0.05). In addition, there were no relationships between other psychological symptoms at 1 week, i.e. sleep disturbance, anxiety, and depression, and CRP (P = 0.68, 0.44, and 0.57, respectively).
Table 2 Relationships between C-reactive protein levels, delirium, and psychological symptoms
| Total ( |
CRP < 1 ( |
1 ≤ CRP < 5 ( |
5 ≤ CRP < 10 ( |
10 ≤ CRP ( |
||
| Delirium, yes n (%) | 622 (45.9) | 65 (38.2) | 189 (47.9) | 160 (46.3) | 208 (52.4) | 0.02 |
| Type and severity of delirium, n (%) | 0.82 | |||||
| Hypoactive | 240 (38.6) | 27 (41.5) | 79 (41.8) | 56 (35.0) | 78 (37.5) | |
| Hyperactive, mild | 236 (37.9) | 24 (36.9) | 70 (37.0) | 66 (41.3) | 76 (36.5) | |
| Hyperactive, moderate | 122 (19.6) | 12 (18.5) | 35 (18.5) | 33 (20.6) | 42 (20.2) | |
| Hyperactive, severe | 24 (3.9) | 2 (3.1) | 5 (2.6) | 5 (3.1) | 12 (5.8) | |
| Drowsiness at baseline, n (%) | 0.05 | |||||
| Not at all, mild (IPOS 0, 1) | 956 (70.6) | 126 (74.1) | 343 (75.7) | 226 (67.7) | 261 (65.7) | |
| Moderate, severe, overwhelming (IPOS 2, 3, 4) | 318 (23.5) | 34 (20.0) | 88 (19.4) | 87 (26.0) | 109 (27.5) | |
| Impossible to assess owing to coma | 80 (5.9) | 10 (5.9) | 22 (4.9) | 21 (6.3) | 27 (6.8) | |
| Sleep disturbance at 1 week, n (%)a | 0.68 | |||||
| Not at all, mild (IPOS 0, 1) | 706 (69.5) | 114 (75.5) | 250 (68.7) | 169 (69.5) | 173 (67.1) | |
| Moderate, severe, overwhelming (IPOS 2, 3, 4) | 209 (20.6) | 27 (17.9) | 77 (21.2) | 49 (20.2) | 56 (21.7) | |
| Impossible to assess owing to coma | 101 (9.9) | 10 (6.6) | 37 (10.2) | 25 (10.3) | 29 (11.2) | |
| Anxiety at 1 week, n (%)b | 0.44 | |||||
| Not at all, mild (IPOS 0, 1) | 712 (70.0) | 117 (77.5) | 254 (69.6) | 169 (69.5) | 172 (66.7) | |
| Moderate, severe, overwhelming (IPOS 2, 3, 4) | 199 (19.6) | 24 (15.9) | 71 (19.5) | 48 (19.8) | 56 (21.7) | |
| Impossible to assess owing to coma | 106 (10.4) | 10 (6.6) | 40 (11.0) | 26 (10.7) | 30 (11.6) | |
| Depression at 1 week, n (%)a | 0.57 | |||||
| Not at all, mild (IPOS 0, 1) | 839 (82.6) | 134 (88.7) | 298 (81.6) | 198 (81.8) | 209 (81.0) | |
| Moderate, severe, overwhelming (IPOS 2, 3, 4) | 71 (7.0) | 7 (4.6) | 27 (7.4) | 18 (7.4) | 19 (7.4) | |
| Impossible to assess owing to coma | 106 (10.4) | 10 (6.6) | 40 (11.0) | 26 (10.7) | 30 (11.6) |
CRP, C-reactive protein; IPOS, Integrated Palliative care Outcome Scale.
Values are n (%).
aData on 1016 sleep disturbance and depression symptoms assessed at 1 week were analysed.
bData on 1017 anxiety symptoms assessed at 1 week were analysed.
Crude and adjusted ORs for CRP and other variables associated with delirium are shown in Table 3. In model 1, which included eight variables other than the opioid oral morphine milligram equivalent, significantly higher adjusted ORs than in the low CRP group were observed in the high CRP and very high CRP groups (1.63 [95% CI 1.06–2.50], P = 0.03; 1.72 [95% CI 1.13–2.62], P = 0.01, respectively). In model 2, which included nine variables, a significantly higher adjusted OR than in the low CRP group was observed in the very high CRP group (1.61 [95% CI 1.05–2.45], P = 0.03).
Table 3 Crude and adjusted odd ratios for C-reactive protein and other variables associated with delirium (
| Crude OR (95% CI) | Adjusted OR (95% CI) Model 1 | Adjusted OR (95% CI) Model 2 | ||||
| Age, years | ||||||
| <70 | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | |||
| 70 ≤ | 1.40 (1.10–1.77) | 0.01 | 1.27 (0.99–1.64) | 0.06 | 1.44 (1.10–1.87) | 0.01 |
| Sex | ||||||
| Male | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | |||
| Female | 0.78 (0.62–0.98) | 0.03 | 0.81 (0.64–1.04) | 0.09 | 0.81 (0.64–1.04) | 0.10 |
| CNS metastasis | ||||||
| No | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | |||
| Yes | 1.25 (0.89–1.74) | 0.19 | 1.31 (0.92–1.86) | 0.14 | 1.39 (0.97–1.99) | 0.07 |
| Cerebrovascular disease | ||||||
| No | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | |||
| Yes | 1.59 (0.97–2.61) | 0.06 | 1.35 (0.81–2.27) | 0.25 | 1.36 (0.81–2.28) | 0.25 |
| Dementia | ||||||
| No | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | |||
| Yes | 2.17 (1.36–3.46) | < 0.01 | 2.00 (1.22–3.29) | 0.01 | 2.06 (1.26–3.39) | < 0.01 |
| ECOG performance status | ||||||
| 0–2 | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | |||
| 3 | 2.43 (1.36–4.35) | < 0.01 | 2.30 (1.27–4.17) | 0.01 | 2.21 (1.22–4.01) | < 0.01 |
| 4 | 4.51 (2.53–8.03) | < 0.01 | 3.93 (2.17–7.10) | < 0.01 | 3.93 (2.17–7.10) | < 0.01 |
| CRP, mg/dl | ||||||
| CRP < 1 | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) | |||
| 1 ≤ CRP < 5 | 1.24 (0.84–1.84) | 0.27 | 1.19 (0.79–1.78) | 0.41 | 1.16 (0.77–1.74) | 0.48 |
| 5 ≤ CRP < 10 | 1.70 (1.13–2.55) | 0.01 | 1.63 (1.06–2.50) | 0.03 | 1.53 (0.99–2.36) | 0.06 |
| 10 ≤ CRP | 1.93 (1.30–2.87) | < 0.01 | 1.72 (1.13–2.62) | 0.01 | 1.61 (1.05–2.45) | 0.03 |
| Calcium corrected with albumin, mEq/L | ||||||
| 1.22 (1.09–1.36) | < 0.01 | 1.18 (1.05–1.32) | < 0.01 | 1.19 (1.07–1.33) | < 0.01 | |
| Opioid oral morphine milligram equivalent, mg/day | ||||||
| 0 | 1.00 (reference) | - | - | 1.00 (reference) | ||
| 0–60 | 1.18 (0.91–1.53) | 0.22 | - | - | 1.29 (0.98–1.71) | 0.07 |
| 60 ≤ | 1.36 (0.98–1.87) | 0.06 | - | - | 1.79 (1.25–2.57) | < 0.01 |
CRP, C-reactive protein; CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; OR, odds ratio; CI, confidence interval.
DiscussionTo the best of our knowledge, there has been no large prospective study that investigated the clinical implications of CRP as a biomarker in psychological symptoms, particularly delirium, among patients with advanced cancer admitted to palliative care units. We demonstrated that CRP levels were associated with delirium in this population. Almost all of the patients included in this study seemed to be cachexia or refractory cachexia because the top three primary cancer sites were the upper and lower gastrointestinal tract, liver/biliary system/pancreas, and lung; and the mean survival time was 3 and 4 weeks. Therefore, the present results have revealed that a relationship existed between delirium and elevated CRP levels mainly due to cancer cachexia.
Systemic inflammation plays an important role in the mechanisms responsible for cancer cachexia. In systemic inflammation, pro-inflammatory cytokines are generated from tumour-immune system crosstalk and are also secreted by tumour cells. Pro-inflammatory cytokines act not only in skeletal muscle and adipose tissue as intercellular messengers, but also through alternations in the CNS, particularly the hypothalamic–pituitary–adrenal (HPA) axis. Exposure to pro-inflammatory cytokines in the CNS induces the abnormal metabolism of proteins and lipids, i.e. hypercatabolism in proteolytic and lipolytic pathways, as well as anorexia and a reduced food intake. Thus, CNS inflammation evokes catabolism in muscle and adipose tissue and rapidly induces muscle atrophy. This effect is dependent on the production of glucocorticoids, which is a type of corticosteroid and may be a cause of delirium and other psychological symptoms in addition to other outcomes of systemic inflammation, by the adrenal gland through the activation of the HPA axis.2
A randomized trial reported that a low skeletal muscle mass (sarcopenia) due to cachexia was associated with depression and quality of life in patients with advanced cancer.16 Other studies on cancer patients revealed that systemic inflammation or elevated CRP levels were related to pain, anorexia, dyspnoea, fatigue, sleep disturbance, activities of daily living disabilities, and survival,8–15 that these symptoms rarely existed in isolation,11,13,39 and that pain, fatigue, and sleep disturbance were the basis of a symptom cluster in combination with reduced physical function.14 A cross-sectional study showed a higher physical and psychological symptom burden (including pain, fatigue, sleep disturbance, distress, and anxiety) in patients with cancer cachexia, which increased with the stages of cachexia, and these findings emphasized the importance of screening for multiple co-occurring symptoms in cachexia patients.13 A meta-analysis revealed that interleukin-6 (IL-6), tumour necrosis factor, and CRP were elevated in non-cancer patients with depression.40 Other studies demonstrated that depression and cognitive dysfunction were associated with systemic inflammation due to the breakdown of the serotonergic system in cancer patients. Patients with depression had increased levels of IL-6.41,42 Conversely, patients who were treated with immunotherapy for chronic myeloid leukaemia had more severe cognitive dysfunction.43 Additionally, pro-inflammatory cytokines, i.e. interferon-α and IL-2, which are used in cancer treatments, caused depression, cognitive dysfunction, and fatigue.44,45 According to previous studies that investigated cancer cachexia, systemic inflammation, and symptoms, the first step in the mechanisms responsible for cancer cachexia is considered to be the negative impact of systemic inflammation on the CNS, which may lead via a complex process to not only physical disorders but also delirium and other psychological symptoms in patients with cancer cachexia.
On the other hand, pro-inflammatory cytokines change the metabolism of relevant neurotransmitters in the CNS, including serotonin, norepinephrine, and dopamine, the roles of which are very important in the regulation of mental activity. The impaired metabolism of these neurotransmitters leads to psychological symptoms, such as depression and anxiety, in patients with advanced cancer.7 Moreover, physical disorders and psychological symptoms may induce changes in the lifestyles of patients, such as eating habits and sleep–wake cycles, which may cause sleep disturbance and reversely disrupt CNS function. Furthermore, sleep disturbance, the disarrangement of sleep–wake cycles, and circadian rhythm disorders are predictors of fatigue and mortality in patients with advanced cancer.46–50 Ultimately, changes in the lifestyles of patients may cause social isolation and psychosocial distress,51 which may activate the HPA axis, thereby inducing the secretion of glucocorticoids, norepinephrine, and epinephrine.52 Psychosocial distress may reversely deteriorate physical and psychological status and quality of life. Hence, psychosocial distress due to the impact of systemic inflammation on the CNS may also be a cause of delirium and other psychological symptoms in patients with cancer cachexia.
In summary, systemic inflammation has a negative impact on the CNS/HPA axis and deteriorates its function. Physical disorders and psychological symptoms may be directly affected through alternations in the CNS/HPA axis and correlate with systemic inflammation. Physical disorders and psychological symptoms may in turn cause psychosocial distress, which may reversely promote systemic inflammation and alter the CNS/HPA axis. Physical disorders, psychological symptoms, and psychosocial distress generally co-exist and amplify one another in advanced cancer patients with cachexia (Figure 1).
Enlarge this image.Figure 1. Negative impact of systemic inflammation on the CNS/HPA axis, physical disorders, psychological symptoms, and psychosocial distress in advanced cancer patients with cachexia. Systemic inflammation has a negative impact on the CNS/HPA axis and deteriorates its function. Physical disorders and psychological symptoms may be directly affected through alternations in the CNS/HPA axis and correlate with systemic inflammation. Physical disorders and psychological symptoms in turn cause psychosocial distress, which may reversely promote systemic inflammation and alter the CNS/HPA axis. Physical disorders, psychological symptoms, and psychosocial distress generally co-exist and amplify one another in advanced cancer patients with cachexia. CNS, central nervous system; HPA, hypothalamic–pituitary–adrenal; ADL, activities in daily living.
The present study had several limitations. The causal relationship between CRP levels and delirium remains unclear due to the characteristics of an observational study. There may be unmeasured confounding factors and reverse causality (elevated CRP levels as a consequence of delirium). Furthermore, the very high CRP group (10 mg/dl ≤ CRP) may have been affected by coexisting acute infections, acute medical conditions, or other factors. However, we consider the clinical implications of CRP to remain unchanged because these factors also deteriorate psychological symptoms as well as physical disorders. In addition, the present results were not influenced by cancer treatments, such as chemotherapy and radiotherapy, which cause systemic inflammation, because all subjects were admitted to palliative care units after the cessation of aggressive cancer treatments. Another limitation is that the effects of medical agents suppressing systemic inflammation, e.g. steroids and non-steroidal anti-inflammatory drugs, were not considered. In addition, the majority of patients were receiving strong opioids, which may have had an impact on CNS function. Furthermore, although drowsiness at baseline was significantly worse in the very high CRP group, no relationships were observed between CRP at baseline and sleep disturbance, anxiety, and depression at 1 week. This may have been because these symptoms had been alleviated after admission to palliative care units. Moreover, physical disorders, psychological symptoms, and psychosocial distress were considered in the same dimension; however, the relationships between them were not investigated. Although a deteriorated physical and psychological status may adversely affect psychosocial distress and vice versa, the clinical implications of CRP are the same because the negative impacts of systemic inflammation on physical disorders, psychological symptoms, and psychosocial distress are commonly expected in patients with advanced cancer.
ConclusionsThe present study is the first to demonstrate that a relationship exists between systemic inflammation and delirium in patients with advanced cancer. Although there are several possible causes of delirium, the impact of systemic inflammation on the CNS may be one of the most strongly contributing factors to this process. There is currently insufficient evidence to show that systemic inflammation acts through alternations in the CNS in the genesis of a number of psychological symptoms in this population. However, it is clinically true that long-term physical disorders severely affect psychological symptoms, and it is inevitable that these physical disorders and psychological symptoms markedly amplify psychosocial distress in patients with advanced cancer. Hence, the relationships between systemic inflammation, physical disorders, psychological symptoms, and psychosocial distress have to be studied in a longitudinal design in order to understand how they are related and how they change in the disease trajectory. Further research in this field is warranted.
AcknowledgementsThe authors of this manuscript certify that they comply with the ethical guidelines for editorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle.53
This study was performed in the East-Asian collaborative cross-cultural Study to Elucidate the Dying process (EASED). The participating study sites and site investigators in Japan were as follows: Satoshi Inoue, MD (Seirei Hospice, Seirei Mikatahara General Hospital), Naosuke Yokomichi, MD, PhD (Department of Palliative and Supportive Care, Seirei Mikatahara General Hospital), Hiroaki Tsukuura, MD, PhD (Department of Palliative Care, TUMS Urayasu Hospital), Toshihiro Yamauchi, MD (Seirei Hospice, Seirei Mikatahara General Hospital), Akemi Shirado Naito, MD (Department of palliative care Miyazaki Medical Association Hospital), Yu Uneno, MD (Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University), Akira Yoshioka, MD, PhD (Department of Oncology and Palliative Medicine, Mitsubishi Kyoto Hospital), Shuji Hiramoto, MD (Department of Oncology and Palliative Medicine, Mitsubishi Kyoto Hospital), Ayako Kikuchi, MD (Department of Oncology and Palliative Medicine, Mitsubishi Kyoto Hospital), Hiroyuki Kohara, MD, PhD (Hiroshima Prefectural Hospital), Hiromi Fanaki, MD (Hiroshima Prefectural Hospital), Keiko Tanaka, MD, PhD (Department of Palliative Care Tokyo Metropolitan Cancer & Infectious Diseases Center Komagome Hospital), Tina Kamei, MD (Department of Palliative Care, NTT Medical Center Tokyo), Yukari Azuma, MD (Home Care Clinic Aozora Shin-Matsudo), Teruaki Uno, MD (Department of Palliative Medicine, Osaka City General Hospital), Jiro Miyamoto, MD (Department of Palliative Medicine, Osaka City General Hospital), Hirofumi Katayama, MD (Department of Palliative Medicine, Osaka City General Hospital), Hideyuki Kashiwagi, MD, MBA. (Aso Iizuka Hospital / Transitional and Palliative Care), Eri Matsumoto, MD (Aso Iizuka Hospital / Transitional and Palliative Care), Kiyofumi Oya, MD (Aso Iizuka Hospital / Transitional and Palliative Care), Takeya Yamaguchi, MD (Japan Community Health care Organization Kyushu Hospital /Palliative Care), Tomonao Okamura, MD, MBA. (Aso Iizuka Hospital /Transitional and Palliative Care), Hoshu Hashimoto, MD, MBA. (Inoue Hospital/Internal Medicine), Shunsuke Kosugi, MD (Department of General Internal Medicine, Aso Iizuka Hospital), Nao Ikuta, MD (Department of Emergency Medicine, Osaka Red Cross Hospital), Yaichiro Matsumoto, MD (Department of Transitional and Palliative Care, Aso Iizuka Hospital), Takashi Ohmori, MD (Department of Transitional and Palliative Care, Aso Iizuka Hospital), Takehiro Nakai, MD (Immuno-Rheumatology Center, St Luke's International Hospital), Takashi Ikee, MD (Department of Cardiorogy, Aso Iizuka Hospital), Yuto Unoki, MD (Department of General Internal Medicine, Aso Iizuka Hospital), Kazuki Kitade, MD (Department of Orthopaedic Surgery, Saga-Ken Medical Centre Koseikan), Shu Koito, MD (Department of General Internal Medicine, Aso Iizuka Hospital), Nanao Ishibashi, MD (Environmental Health and Safety Division, Environmental Health Department, Ministry of the Environment), Masaya Ehara, MD (TOSHIBA), Kosuke Kuwahara, MD (Department of General Internal Medicine, Aso Iizuka Hospital), Shohei Ueno, MD (Department of Haematology/ Oncology, Japan Community Healthcare Organization Kyushu Hospital), Shunsuke Nakashima, MD (Oshima Clinic), Yuta Ishiyama, MD (Department of Transitional and Palliative Care, Aso Iizuka Hospital), Akihiro Sakashita, MD, PhD (Department of Palliative Medicine, Kobe University School of Medicine), Ryo Matsunuma, MD (Department of Palliative Medicine, Kobe University Graduate School of Medicine), Hana Takatsu, MD (Division of Palliative Care, Konan Medical Center), Takashi Yamaguchi, MD, PhD (Division of Palliative Care, Konan Medical Center), Satoko Ito, MD (Hospice, The Japan Baptist Hospital), Toru Terabayashi, MD (Hospice, The Japan Baptist Hospital), Jun Nakagawa, MD (Hospice, The Japan Baptist Hospital), Tetsuya Yamagiwa, MD, PhD (Hospice, The Japan Baptist Hospital), Akira Inoue, MD, PhD (Department of Palliative Medicine Tohoku University School of Medicine), Takuhiro Yamaguchi, PhD (Professor of Biostatistics, Tohoku University Graduate School of Medicine), Mitsunori Miyashita, R.N., PhD (Department of Palliative Nursing, Health Sciences, Tohoku University Graduate School of Medicine), Saran Yoshida, PhD (Graduate School of Education, Tohoku University), Yusuke Hiratsuka, MD, PhD (Department of Palliative Medicine Tohoku University School of Medicine), Keita Tagami, MD, PhD (Department of Palliative Medicine Tohoku University School of Medicine), Watanabe Hiroaki, MD (Department of Palliative Care, Komaki City Hospital), Odagiri Takuya, MD (Department of Palliative Care, Komaki City Hospital), Tetsuya Ito, MD,PhD (Department of Palliative Care, Japanese Red Cross Medical Center), Masayuki Ikenaga, MD (Hospice, Yodogawa Christian Hospital), Keiji Shimizu, MD, PhD (Department of Palliative Care Internal Medicine, Osaka General Hospital of West Japan Railway Company), Akira Hayakawa, MD, PhD (Hospice, Yodogawa Christian Hospital), Lena Kamura, MD (Hospice, Yodogawa Christian Hospital), Takeru Okoshi, MD, PhD (Okoshi Nagominomori Clinic), Tomohiro Nishi, MD (Kawasaki Municipal Ida Hospital, Kawasaki Comprehensive Care Center), Kazuhiro Kosugi, MD (Department of Palliative Medicine, National Cancer Center Hospital East), Yasuhiro Shibata, MD (Kawasaki Municipal Ida Hospital, Kawasaki Comprehensive Care Center), Takayuki Hisanaga, MD (Department of Palliative Medicine, Tsukuba Medical Center Hospital), Takahiro Higashibata, MD, PhD (Department of General Medicine and Primary Care, Palliative Care Team, University of Tsukuba Hospital), Ritsuko Yabuki, MD (Department of Palliative Medicine, Tsukuba Medical Center Hospital), Shingo Hagiwara, MD (Department of Palliative Medicine, Tsukuba Medical Center Hospital), Miho Shimokawa, MD (Department of Palliative Medicine, Tsukuba Medical Center Hospital), Satoshi Miyake, MD, PhD (Professor, Department of Clinical Oncology Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University (TMDU)), Junko Nozato, MD (Specially Appointed Assistant Professor, Department of Internal Medicine, Palliative Care, Medical Hospital, Tokyo Medical and Dental University), Tetsuji Iriyama, MD (Specially Appointed Assistant Professor, Department of Internal Medicine, Palliative Care, Medical Hospital, Tokyo Medical and Dental University), Keisuke Kaneishi, MD, PhD (Department of Palliative Care Unit, JCHO Tokyo Shinjuku Medical Center), Mika Baba, MD, PhD (Department of Palliative medicine Suita Tokushukai Hospital), Yoshihisa Matsumoto, MD, PhD (Department of Palliative Medicine, National Cancer Center Hospital East), Ayumi Okizaki, PhD (Department of Palliative Medicine, National Cancer Center Hospital East), Yuki Sumazaki Watanabe, MD (Department of Palliative Medicine, National Cancer Center Hospital East), Kazuhiro Kosugi, MD (Department of Palliative Medicine, National Cancer Center Hospital East), Yuko uehara, MD (Department of Palliative Medicine, National Cancer Center Hospital East), Eriko Satomi, MD (Department of palliative medicine, National Cancer Center Hospital), Kaoru Nishijima, MD (Department of Palliative Medicine, Kobe University Graduate School of Medicine), Junichi Shimoinaba, MD (Department of Hospice Palliative Care, Eikoh Hospital), Ryoichi Nakahori, MD (Department of Palliative Care, Fukuoka Minato Home Medical Care Clinic), Takeshi Hirohashi, MD (Eiju General Hospital), Jun Hamano, MD, PhD (Assistant Professor, Faculty of Medicine, University of Tsukuba), Natsuki Kawashima, MD (Department of Palliative Medicine, Tsukuba Medical Center Hospital), Takashi Kawaguchi, PhD (Tokyo University of Pharmacy and Life Sciences Department of Practical Pharmacy), Megumi Uchida, MD, PhD (Dept. of Psychiatry and Cognitive-Behavioural Medicine, Nagoya City University Graduate School of Medical Sciences), Ko Sato, MD, PhD (Hospice, Ise Municipal General Hospital), Yoichi Matsuda, MD, PhD (Department of Anesthesiology & Intensive Care Medicine/Osaka University Graduate School of Medicine), Satoru Tsuneto, MD, PhD (Professor, Department of Human Health Sciences, Graduate School of Medicine, Kyoto University Department of Palliative Medicine, Kyoto University Hospital), Sayaka Maeda, MD (Department of Palliative Medicine, Kyoto University Hospital), Yoshiyuki Kizawa MD, PhD, FJSIM, DSBPMJ. (Designated Professor and Chair, Department of Palliative Medicine, Kobe University School of Medicine), Hiroyuki Otani, MD (Palliative Care Team, and Palliative and Supportive Care, National Kyushu Cancer Center).
Conflict of interestThe authors have read and understood the journal's policy on the declaration of interest and declare that there are no conflict of interest.
FundingThis study was supported in part by a Grant-in-Aid from the Japan Hospice Palliative Care Foundation.
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