Palliative Care Outpatients in a German Comprehensive Cancer Center - Identifying Indicators for Early and Late Referral

doi:10.21203/rs.3.rs-1449220/v2

Download PDF

Research Article

Palliative Care Outpatients in a German Comprehensive Cancer Center - Identifying Indicators for Early and Late Referral

https://doi.org/10.21203/rs.3.rs-1449220/v2

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Background.

Despite that early integration of palliative care is recommended in advanced cancer patients, referrals to specialisedana palliative care (SPC) frequently occur late. Well-defined referral criteria are still missing. We analyzed indicators associated with early (ERs) and late referral (LRs) to SPC of a high volume outpatient unit of a German comprehensive cancer center.

Methods.

Characteristics, laboratory parameters and symptom burden of 281 patients at first SPC referral were analyzed. Timing of referral was categorized as early, intermediate and late (> 12, 3–12 and < 3 months before death). Ordinal logistic regression analyze was used to find factors related to referral timing. Kruskal-Wallis test was used to determine symptom severity and laboratory parameter in each referral category.

Results.

LRs (50.7%) had worse scores of weakness, loss of appetite, drowsiness, assistance of daily living (all p < 0.001) and organisation of care (p < 0.01) in contrast to ERs. The mean symptom sum score was significantly higher in LRs than ERs (13.03 vs. 16.08; p < 0.01). Parameters indicative of poor prognosis, such as elevated LDH, CRP and neutrophil-to-lymphocyte ratio (NLR) (p < 0.01) as well as the presence of ascites (p < 0.05), were significantly higher (all p < 0.001) in LRs. In univariable analyzes, psychological distress (p < 0.05) and female gender (p < 0.05) were independently associated with an ER.

Conclusion.

A symptom sum score and parameters of poor prognosis like NLR or LDH might be useful to integrate into palliative care screening tools.

Outpatient

Palliative Care

Advanced Cancer

Timing of Referral

Symptom Burden

Referral Indicators

Advanced cancer patients should be offered palliative care treatment timely in combination with oncological cancer therapy (1, 2). Multiple studies have shown that integration of palliative care improves various modalities of patients’ environment, such as quality of life, patient experience, patient and family satisfaction, symptom burden and in the form of less aggressive care at the end of life (3–5).

Various conceptual frameworks have been proposed including a recent Delphi study from Hui et al. (6) involving 60 international experts supporting a combination of trigger-based and clinician-based approaches to timely offer palliative care referral, but not all of them are consistently used (7–9). A large retrospective cohort study with more than 22,500 patients could demonstrate that outpatients had high scores in the Edmonton Symptom Assessment System (ESAS) for tiredness, lack of appetite and impaired wellbeing (10). Another study also mentioned symptoms like lack of appetite, drowsiness, dyspnoea and fatigue as significant factors that tend to intensify in outpatients at the end of life (11). Additionally, differences in gender and cancer subtypes were observed regarding palliative care consultations (12).

Due to the ongoing process of improving treatment options for advanced cancer patients, cancer is increasingly becoming a kind of "chronic disease" with a prolonged survival time (13). In this context, outpatient care and treatment options such as specialised palliative care are increasingly coming to the fore (14). Therefore, many oncological comprehensive cancer centres (CCC) integrate nowadays a specialised palliative care consultation (SPCC) for outpatients into their routine care (15, 16).

One of these CCC in Germany established a SPCC in a high volume outpatient clinic for cancer patients (17). In a former study, we used a patient reported outcome measurement called MInimal DOcumentation System (MIDOS) in the oncological outpatient setting. We showed that the symptoms “weakness”, “depression” and “anxiety” were predictive factors for patient's request of receiving a SPCC (18).

Additionally, laboratory parameter are nowadays not integrated in PC routine screening tools, which are frequently used (6, 19). Therefore, we wanted to explore the contribution of laboratory parameters as indicators in cancer patients regarding SPCC. Our study analyzes the symptom burden as well as laboratory data at first referral to an outpatient SPCC. Our objective is to analyzes common clinical and laboratory indicators in early and late referrals to an SPCC. Secondary, we describe symptom burden using the validated Hospice and Palliative Care Evaluation (HOPE) Symptoms and Problem Checklist, which is a common tool used in German specialized palliative care units (20).

Although many referral criteria and clinical indicators have been already described, the role of laboratory parameters as indicators of early referral remains unexamined. Furthermore, current studies of different cancer types showed that the neutrophil-to-lymphocyte ratio (NLR) is a predictor for reduced overall survival in cancer patients. Therefore, we wanted to analyze symptom burden, clinical indicators and timing of referral to a SPCC in our patient population and explore the role of NLR as a laboratory indicator. Moreover, we hypothesized that the symptom burden would be lower in early referrals and patients who were female and had gynaecological cancer types would be referred earlier to a SPCC, similar to other studies.

2.1 Study Design

In this retrospective, non-interventional study based on medical records, we reviewed 310 patients who were referred to the SPCC of a German CCC between November 2013 and December 2020. Documentation at first referral to a SPCC and patients’ characteristics in the medical charts were evaluated. All referring physicians had completed the German hematology and oncology medical specialty. The time of death was obtained from the local residents' registration office.

2.2 Demographics

Participants in our study had to meet the following inclusion criteria: age above 18 years and a histologically confirmed solid cancer type according to the Union for International Cancer Control (UICC) stage IV at the time of first referral to a SPCC.

In addition to demographic information such as sex, age, cancer diagnosis, date of first diagnosis and date of metastasis, we collected information with the HOPE Symptoms and Problem Checklist such as chemotherapy treatment, location of metastasis, the reason for referral to the SPCC listed by the attending physician, the existence of a level of care and the patient's physical condition.

2.2.1 Timing of Referral. We also documented information related to the timing of referral to palliative care in relation to death as follows: first palliative care referrals more than one year before the patient‘s death were classified as „early“ (ER); referrals between 3 and 12 months before death were classified as „intermediate“; and referrals made less than 3 months before death were classified as „late“ (LR) (21).

2.2.2. HOPE. The German Hospice and Palliative Care Evaluation (HOPE) Symptoms and Problem Checklist is used for standard documentation in German inpatient and outpatient hospice and palliative care services since 1999 (22, 23). The checklist includes 16 different items, eight for physical symptoms (pain, nausea, vomiting, dyspnoea, constipation, weakness, loss of appetite, tiredness), two special nursing problems (wound care, assistance with activities of daily living [ADLs]), four psychological issues (depression, anxiety, confusion, tension) and two social topics (organization of care, overburdening of family). Symptoms are documented in a 4-point-Likert-Scale (0 = none, 1 = mild, 2 = moderate and 3 = strong) by a palliative care nurse (24). The global sum score for each patient is calculated ranking from minimum 0 to maximum 51 (22). A low score means no complains, a high score corresponds to a high symptom burden.

2.2.3. ECOG. The Performance status scale from the Eastern Cooperative Oncology Group (ECOG) is a simple and validated tool commonly used in patients with cancer to quantify general wellbeing, physical status and estimate survival (25, 26). The graduation is according to a 0 to 5 scale, where 0 indicates optimal health and 5 indicates death. A palliative care nurse documented the ECOG status at the time of first palliative care consultation.

2.2.4. Laboratory parameters. We abstracted commonly used laboratory parameters, which includes leucocytes [per nl], neutrophil granulocytes [per nl], neutrophil-to-lymphocyte ratio (NLR), haemoglobin [g/dL], total protein [g/dL], albumin [g/dL], CRP [mg/dL] and LDH [U/l], from the routine database of the hospital information system at the time of initial presentation. We defined laboratory data as valid if they were documented within a time interval of 4 weeks from the initial presentation.

2.3 Statistical analyzes

Data management and analyzes were conducted using the program Statistical Program for Social Sciences SPSS version 26.0 (IBM, New York). To characterize the patients at first referral and in context of time of referral we used descriptive statistics. We used univariable logistic regression analyzes to find indicators of early and late referral. One-way ANOVA was used for group-differences. To analyze the HOPE symptom burden (as a sum score and each item separately) and laboratory parameters related to the time of referral Kruskal-Wallis-tests were used. The significance level was set at p < 0.05 for all tests.

From November 2013 to December 2020, a total of 310 patients were referred to an outpatient SPCC. Of these, two patients died before the first presentation and 27 patients did not undergo a palliative care consultation for various reasons. Thus, 281 patients underwent a SPCC. Up to the evaluation period on 20 March 2021, 227 patients had died.

Table 1

**Baseline characteristics of outpatients referred at first referral**
Patient Characteristics	Total, N (%)	Late referral^a, n (%)	Intermediate referral^a, n (%)	Early referral^a, n (%)
Number of patients	281 (100)
Patients died	227 (80.1)	115 (50.7)	82 (36.1)	30 (13.2)
Gender	281	115	82	30
Male	116 (41.3)	54 (47.0)	35 (42.7)	6 (20.0)
Female	165 (58.7)	61 (53.0)	47 (57.3)	24 (80.0)
Age at first presentation, in years
Mean ± SD	61.54 (12.13)	62.65 (11.95)	60.55 (14.103)	60.33 (10.694)
Median (range)	62 (18–88)	63 (30–87)	62 (18–88)	59 (28–80)
Site of primary tumor	281	115	82	30
Gastrointestinal tract	72 (25.6)	35 (30.4)	22 (26.8)	4 (13.3)
Lung	62 (22.1)	31 (27.7)	18 (22.0)	6 (20.0)
Breast	49 (17.4)	15 (13.0)	14 (17.1)	12 (40.0)
Sarcoma	41 (14.6)	15 (13.0)	11 (13.4)	3 (10.0)
Genitourinary	16 (5.7)	7 (6.3)	2 (2.4)	0
Head and neck	15 (5.3)	4 (3.6)	6 (7.3)	2 (6.7)
Other gynaecologic	8 (2.8)	3 (2.7)	2 (2.4)	1 (3.3)
Others^b	18 (6.4)	5 (4.5)	7 (8.5)	2 (6.7)
Months after first metastasis
Mean ± SD	29.16 (37.27)	24.98 (31.285)	25.09 (28.515)	39.76 (55.912)
Median (range)	15.5 (-48-222)	15 (-2-222)	15 (-9-143)	16 (-48-200)
Chemotherapy at time of first referral	281	115	82	30
Yes	189 (67.3)	75 (65.2)	63 (76.8)	23 (76.7)
No	92 (32.7)	40 (34.8)	19 (23.2)	7 (23.3)
Chemotherapy line	281	115	82	30
1st	74 (26.3)	19 (16.5)	24 (29.3)	12 (40.0)
2nd	73 (26.0)	28 (24.3)	27 (32.9)	6 (20.0)
3rd	46 (16.4)	32 (27.8)	8 (9.8)	1 (3.3)
> 3rd	45 (16.0)	23 (20.0)	13 (15.9)	6 (20.0)
None	43 (15.3)	13 (11.3)	10 (12.2)	5 (16.7)
^a Timing of Referral: early, intermediate and late (> 12, 3–12 and < 3 months before death)
^b Others: includes hematologic, central nervous system, malignant melanoma, cancer unknown primary (CUP)

The median age of all patients at first presentation in the SPCC was 62 (18–88) years. Gastrointestinal (N = 72; 25.6%), lung (N = 62; 22.1%), breast cancer (N = 49; 17.4%) and sarcomas (N = 41; 14.6%) were the most common tumour entities among our cohort. At first referral, 189 patients (67.3%) were receiving chemotherapy at the time. The majority of patients were in the first (N = 74; 26.3%) and second (N = 73; 26%) palliative chemotherapy line. The median time from first referral to death was 6.38 months (± 9.02). Cumulatively, 95.2% of patients died within two years after the initial presentation. Detailed demographic information is shown in Table 1.

Table 2

**Outpatient’s characteristics referred at first referral**
Patient Characteristics	Total, N (%)	Late referral^a, n (%)	Intermediate referral^a, n (%)	Early referral^a, n (%)
Reason for Referral	281	115	82	30
Pain	95 (33.8)	37 (32.2)	27 (33.0)	8 (26.7)
Social care planning (SCP)	58 (20.6)	27 (23.5)	17 (10.7)	6 (20.0)
Dyspnoea	18 (6.4)	9 (7.8)	7 (8.5)	2 (6.7)
Nutritional advice	17 (6.0)	6 (5.2)	6 (7.3)	1 (3.3)
Psychological distress	16 (5.7)	0	5 (6.1)	6 (20.0)
Fatigue	6 (2.1)	5 (4.3)	1 (1.2)	0
Pain and dyspnoea	10 (3.6)	3 (2.6)	5 (6.1)	1 (3.3)
Pain and SCP	9 (3.2)	4 (3.5)	2 (2.4)	2 (6.7)
Pain and fatigue	9 (3.2)	3 (2.6)	3 (3.6)	2 (6.7)
Others^b	24 (8.5)	7 (6.1)	6 (7.3)	0
More than two reasons	25 (8.9)	14 (12.2)	3 (3.6)	2 (6.7)
ECOG^c	280	115	81	30
0	36 (12.9)	8 (7.0)	13 (16.0)	7 (23.3)
1	141 (50.4)	44 (38.3)	47 (58.0)	20 (66.7)
2	64 (22.9)	38 (33.0)	14 (17.3)	3 (10.0)
3	34 (12.1)	21 (18.3)	7 (8.6)	0
4	5 (1.8)	4 (3.5)	0	0
Qualified social care planning	276	111	81	29
no level of care	161 (58.3)	61 (55.0)	47 (58.0)	19 (65.5)
existing level of care	115 (41.7)	50 (45.0)	34 (42.0)	10 (34.5)
Pain premedication	279	115	82	29
NSAID	193 (69.2)	80 (69.6)	60 (73.2)	16 (53.3)
Opioid analgesic WHO II	32 (11.5)	13 (11.3)	7 (8.5)	4 (13.3)
Opioid analgesic WHO III	128 (45.9)	60 (52.2)	35 (42.7)	11 (36.7)
Use of coanalgesics^d	115 (41.2)	44 (42.6)	31 (37.8)	13 (44.8)
No medication	51 (18.3)	14 (12.2)	17 (20.4)	10 (33.3)
^a Timing of Referral: early, intermediate and late (> 12, 3–12 and < 3 months before death)
^b Others: includes physiotherapy, fatigue, edema treatment, itching, incontinence, wound management
^c ECOG: Eastern Cooperative Oncology Group
^d Includes antidepressants, antiepileptics and benzodiazepines

As shown in Table 2, almost 60 percent of patients did not have a qualified social care planning at time of referral. Before initial presentation, 81.7 percent of patients already received pain medication. Most patients were referred late (n = 115; 50.7%), 82 (36.1%) patients were referred intermediate and 30 (13.2%) patients were referred early. Patients who were referred early to palliative care were more likely to have breast cancer (40.0% referred early vs. 3.3–20.0% for other cancer sites) and the reason of referral was mostly related to social care planning (n = 6; 20.0%) and psychological distress (n = 6; 20.0%). Patients with a late referral presented worse physical condition in terms of ECOG performance status (H = 30.054, p < 0.001, n = 226).

Table 3

**Univariable analyzes of factors associated with early and late palliative care referral**
Subjects
	[95% CI]	Wald	p-value
Gender	0.554 [0.041; 1.067]	3.638	0.034
NLR^a	0.105 [0.038; 0.173]	9.295	0.002
ECOG^b	0.804 [0.409; 1.2]	15.872	< 0.001
Ascites	0.982 [0.126; 1.839]	5.057	0.025
Type of metastasis
Hepatic	-0.666 [-1.307; -0.026]	4.154	0.042
Pulmonary	-0.758 [-1.394; -0.121]	5.446	0.020
Other visceral^c	-0.850 [-1.6; -0.1]	4.936	0.026
Cerebral	0.332 [-0.463; 1.127]	0.671	0.413
Bone	0.399 [-0.232; 1.03]	1.537	0.215
Reason of referral^d
Pain	0.445 [-0.396; 1.285]	1.074	0.300
Social care planning	0.458 [-0.409; 1.326]	1.072	0.301
Dyspnoea	0.649 [-0.52; 1.818]	1.183	0.277
Psychological Distress	-1.691 [-3.156; -0.226]	5.118	0.024
Nutritional advice	0.159 [-1.171; 1.489]	0.055	0.815
Others	-	-	-
^a NLR: neutrophil-to-lymphocyte ratio
^b ECOG: Eastern Cooperative Oncology Group
^c All locations except hepatic metastasis
^d Only categories with more than 10 patients were considered. Reason of referral was given by the referring attending physician

The single factor variance analyzes showed that most of patients who were referred early to a SPCC were female (F = 3.638; p < 0.05; N = 226). In addition, patients who were referred early were on average younger than in the group of late referrals (60.33 years vs. 62.65 years). Using univariable logistic regression analyzes (see Table 3), early referral was associated with pulmonary (95% CI, -1.394 to -0.121; p < 0.05), hepatic (95% CI, -1.307 to -0.026; p < 0.05) or other visceral metastasis (95% CI, -1.6 to -0.1; p < 0.05). Psychological distress (95% CI, -3.156 to -0.226; p < 0.05) was another indicator for an early referral. Moreover, late referrals were associated with suffering from ascites (95% CI, 0.126 to 1.839; p < 0.05), with a higher NLR (95% CI, 0.038 to 0.173; p < 0.01) and a higher ECOG performance status (95% CI, 0.409 to 1.2; p < 0.001).

3.1 Analyzes to Timing of Referral

Symptom burden differed in subgroups of early, intermediate and late referral as shown in Table 4. Patients who were referred late had higher HOPE global sum scores (16.1 ± 6.4 vs. 13.0 ± 5.4; p < 0.01) as well as worsening pain (1.6 ± 1.0 vs. 1.4 ± 1.1; p < 0.05), weakness (2.1 ± 0.8 vs. 1.4 ± 0.8; p < 0.001), loss of appetite (1.5 ± 1.1 vs. 0.8 ± 0.8; p < 0.001), tiredness (1.9 ± 0.9 vs. 1.4 ± 0.7; p < 0.001), assistance with activities of daily living (1.4 ± 0.98 vs. 0.8 ± 0.7; p < 0.001) and organisation of care (0.9 ± 0.9 vs. 0.5 ± 0.6; p < 0.01). Other symptoms did not differ regarding time of referral.

Table 4

**Hospice and palliative care evaluation (HOPE) based on time of referral according to Wadhwa, D et al.**^a [21]
HOPE-SP-CL^b	Early referral^c, (N = 30)	Intermediate referral^c, (N = 82)	Late referral^c, (N = 115)	Kruskal-Wallis H	p-value
Pain	n = 30	n = 79	n = 104	6.187	< 0.05
Mean ± SD	1.37 ± 1.066	1.22 ± 0.929	1.59 ± 1.03
Nausea	n = 29	n = 80	n = 106	0.756	0.685
Mean ± SD	0.69 ± 0.806	0.65 ± 0.781	0.78 ± 0.894
Vomiting	n = 29	n = 79	n = 104	1.760	0.415
Mean ± SD	0.34 ± 0.553	0.35 ± 0.680	0.51 ± 0.812
Dyspnoea	n = 29	n = 78	n = 106	5.410	0.067
Mean ± SD	1.0 ± 0.964	0.86 ± 0.817	1.16 ± 0.906
Constipation	n = 28	n = 78	n = 102	0.879	0.644
Mean ± SD	0.75 ± 0.844	0.72 ± 0.82	0.63 ± 0.783
Weakness	n = 28	n = 78	n = 105	19.082	< 0.001
Mean ± SD	1.39 ± 0.786	1.64 ± 0.821	2.05 ± 0.825
Loss of appetite	n = 29	n = 81	n = 105	19.705	< 0.001
Mean ± SD	0.76 ± 0.786	0.9 ± 0.903	1.50 ± 1.084
Tiredness	n = 26	n = 80	n = 105	17.662	< 0.001
Mean ± SD	1.35 ± 0.689	1.39 ± 0.803	1.87 ± 0.889
Depression	n = 29	n = 79	n = 98	1.172	0.557
Mean ± SD	1.03 ± 0.865	0.87 ± 0.939	0.96 ± 0.919
Anxiety	n = 28	n = 81	n = 101	0.328	0.849
Mean ± SD	1.07 ± 0.858	0.99 ± 0.942	1.01 ± 0.933
Tension	n = 29	n = 78	n = 98	0.854	0.652
Mean ± SD	0.93 ± 0.842	0.9 ± 0.934	0.8 ± 0.849
Wound care	n = 29	n = 79	n = 99	2.575	0.276
Mean ± SD	0.31 ± 0.660	0.42 ± 0.778	0.24 ± 0.591
ADLs^d	n = 29	n = 81	n = 101	17.791	< 0.001
Mean ± SD	0.79 ± 0.675	0.93 ± 0.863	1.44 ± 0.984
Confusion	n = 28	n = 77	n = 97	1.738	0.419
Mean ± SD	0.11 ± 0.315	0.08 ± 0.315	0.16 ± 0.472
Organisation of care	n = 29	n = 75	n = 95	9.691	< 0.01
Mean ± SD	0.45 ± 0.572	0.56 ± 0.663	0.89 ± 0.856
Overburdening of family	n = 29	n = 76	n = 90	7.575	0.023
Mean ± SD	1.34 ± 0.857	1.03 ± 0.748	1.33 ± 0.793
Global sum score	n = 30	n = 81	n = 107	12.669	< 0.01
Mean ± SD	13.03 ± 5.404	13.14 ± 5.616	16.08 ± 6.433
Median (IQR)	11.0 (17.25-9.0)	12.0 (17.0–9.0)	16.0 (20.0–12.0)
^a Based on Kruskal-Wallis test. Evaluation from 20 march 2021
^b HOPE: Hospice and Palliative Care Evaluation Symptom and Problem Checklist
^c Timing of Referral: early, intermediate and late (> 12, 3–12 and < 3 months before death)
^dADLs: assistance with activities of daily living

3.2 Analyzes of the laboratory parameters

The laboratory parameters analyzed differed significantly when comparing referral groups. As illustrated in Table 5, the leukocytes (9.1 ± 5.4 vs. 6.8 ± 4.7; p < 0.01), the neutrophil granulocytes (7.4 ± 5.2 vs. 4.8 ± 4.1; p < 0.001), the CRP (7.8 ± 7.7 vs. 1.2 ± 1.8; p < 0.001), the NLR (10.1 ± 13.9 vs. 4.9 ± 3.4; p < 0.001) and the LDH (479.9 ± 508.9 vs. 277.7 ± 182.6; p < 0.001) were significant higher in the group of late referral. Other objective parameters like haemoglobin (10.3 ± 1.9 vs. 11.8 ± 1.4; p < 0.001), total protein (6.1 ± 0.8 vs. 6.6 ± 0.4; p < 0.01) and albumin (3.5 ± 0.5 vs. 4.2 ± 0.4; p < 0.001) were significant lower in the group of late referrals.

Table 5

**Laboratory parameters based on time of referral**^a
Value	Early referral, (N = 30)	Intermediate referral, (N = 82)	Late referral, (N = 115)	Kruskal-Wallis H	p-value
Leukocytes^b	n = 29	n = 79	n = 113	11.932	< 0.01
Mean ± SD	6.834 ± 4.648	6.687 ± 3.547	9.118 ± 5.426
Neutrophil granulocytes^b	n = 29	n = 73	n = 105	18.068	< 0.001
Mean ± SD	4.767 ± 4.081	4.799 ± 3.304	7.362 ± 5.219
NLR^c	n = 29	n = 73	n = 105	15.746	< 0.001
Mean ± SD	4.999 ± 3.391	5.662 ± 4.582	10.124 ± 13.877
Haemoglobin^d	n = 29	n = 79	n = 113	20.854	< 0.001
Mean ± SD	11.817 ± 1.421	10.981 ± 1.692	10.287 ± 1.857
Total protein^d	n = 29	n = 78	n = 109	11.849	0.003
Mean ± SD	6.582 ± 0.439	6.357 ± 0.720	6.137 ± 0.813
Albumin^d	n = 17	n = 46	n = 66	23.330	< 0.001
Mean ± SD	4.15 ± 0.364	3.815 ± 0.452	3.533 ± 0.520
CRP [mg/dL]	n = 29	n = 78	n = 112	62.976	< 0.001
Mean ± SD	1.217 ± 1.761	2.976 ± 5.293	7.812 ± 7.741
LDH [U/l]	n = 29	n = 79	n = 112	27.294	< 0.001
Mean ± SD	277.72 ± 182.602	267 ± 100.048	479.94 ± 508.880
^a Based on Kruskal-Wallis test. Evaluation from 20 march 2021
^b Quantity per nanoliter
^c Neutrophil-to-lymphocyte ratio
^d in g/dL

Although a clear recommendation of early integration of palliative care has already been described, the optimal time point of referral remains unclear (27). Therefore, we conducted a retrospective analyze to identify factors associated with an “early”, “intermediate” and “late” referral to a SPCC. Our study showed that still most of advanced cancer patients were referred late (< 3 months before death) in their course of disease. This is in line with the study of Wentlandt et al., who described referral practices of Canadian oncologists to specialized palliative care and defined characteristics associated with these referrals. Hereby they showed that 83.3% of advanced cancer patients were referred less than 6 months before death (28). Likewise the study of Scibetta et al. (29) showed that from 297 palliative patients 204 (68%) were referred less than 90 days prior to death (late referral). A current study from 2020 from Hausner et al. (8) compared timing of referral before and after the publication of ASCO recommendation supporting early palliative care referral (30). They showed that late referrals (less than 6 months to death) decreased from 68.8–44.8%. However, late referrals were still the majority in both groups. Therefore, further attempts should be made to reach out an early referral that might benefit our patients and their families.

Our analyze clearly showed that pain, social care planning problems and psychological distress were indicators for referring to a SPCC among outpatients with advanced cancer. This data show again the importance of a proper assessment of palliative care needs, where physical symptoms might not be the main burden of our patients and their families. This is in line with a systematic review showing that psychological distress is a common recurrent referral criteria for outpatient palliative cancer care (31). Additionally, a low ECOG Performance Status is an indicator for early referral likewise to the study from Carrasco-Zafra et al. (32). Furthermore, the quantity of assistance with activities of daily living changed significantly from early to late referral. Both indicators show once more the impact of lost of autonomy in our patients.

Moreover, we detected a significant higher intensity of symptoms like “pain”, “weakness”, “tiredness”, “loss of appetite” in patients who were referred late to specialised palliative care. Social problems like “restriction of daily life“, „overburdening of family” and a higher HOPE global sum score were also frequently associated with late referrals. In a previous study from our CCC, we examined needs and requests of cancer patients in the oncology outpatient clinic for palliative care using a patient reported outcome measurement with MIDOS 2 (20). Symptoms like “depression”, “anxiety” and “weakness” were indicators for outpatient’s wish for referral to a SPCC (18). In our study, symptoms like depression or anxiety did not result in an early referral similar to the study of Whadhwa et al. (21). These results might show the difference between the wish of patient and the reasons for a referrer to actually refer a patient to a specialized palliative care unit. Second, a palliative care nurse rated the questionnaire at first referral to the SPCC. Therefore, further analyzes comparing results between self-reported and external assessments would contribute to a better understanding and improvement of patient-centred outcomes. The difference in symptom intensity by early and late referrals are in line with Cheung et al. (33) and Whadwa et al. (21). Cheung et al. analyzed 1366 outpatients with advanced cancer. In their study, gastrointestinal, lung and breast cancer were the most common primary cancer sites of patients referred to a palliative care cancer center. The most distressful symptoms were “poor general wellbeing”, “decreased appetite” and “fatigue”, similar to our study. In addition, Whadwa et al. (21) used the Edmonton Symptom Assessment System (ESAS) to compare early (> 12 months before death) with late referrals (< 6 months before death). Patients who were referred late showed a significant worse overall symptom score as well as the symptoms “tiredness”, “nausea”, “drowsiness”, “loss of appetite” and “overall wellbeing”, similar to most of our results. Therefore, an increasing intensity of these symptoms could be an indicator for a timely referral to specialised palliative care.

Furthermore, our study showed that early referrals were associated with the female gender. This is in line with a previous study from the authors Kwon et al. (34). They compared early referrals (expected survival greater than two years) with late referrals and showed that for example younger patients, female gender and head and neck cancer are indicators for an early referral. Also, a recently study showed that younger age and gynaecologic cancer were more likely to receive a PC referral (31). The Robert Koch Institute (RKI) documented, that women attend cancer screenings more regularly than men (35). This might be one reason for the association between the female gender and earlier referral to palliative care. In addition, it was shown that female gender is more frequently associated with suffering from depression and fear. This could be an explanation for the mentioned psychological distress and younger age as indicator for a timely referral.

The presence of ascites in cancer patients is an indicator for a late referral. Many studies documented that malignant ascites correlates with a poor overall prognosis and a deteriorating in quality of life (36, 37). For example, a retrospective review of 76 patients with malignant ascites by Mackey et al. (37) from 1996, showed that the median survival was 11 weeks from time of diagnosis. Additionally they showed that the presence of low serum albumin and hepatic metastases were significant indicators of poor prognosis.

Some laboratory parameters like NLR, LDH and CRP have been described as indicators of poor prognosis in oncologic patients (38, 39). The NLR is described as a factor related to systemic inflammation, which is associated with cancer growth. Current studies from 2020 and 2021 have suggested that a high baseline NLR is an indicator of lower rates of progression-free and overall survival in various tumour entities like breast, lung and gastrointestinal cancers (40–42). In our study we show that leukocytes, neutrophils, NLR, LDH and CRP are significantly higher in cancer patients who were referred late to a SPCC. The recommendation of these laboratory parameters, some of them well known as prognostic factors, might be further explored in the oncologic palliative care setting as a measure for identifying appropriate candidates for a specialist palliative care referral. There are currently many examples of tools that include both laboratory and clinical or other parameters to assess prognosis (43, 44).

In sum, our data convincingly show that patients with late referrals could have received PC earlier. We propose that not only symptom monitoring, but also other physical (for example the presence of ascites) and laboratory parameters associated with a poor prognosis (like NLR, low serum albumin) might provide useful information for a timely palliative care consultation and therefore its use in the palliative care screening process might be further explored.

Our study has several limitations. First, the retrospective approach of this study may allow us to miss confounders and generates a sampling bias. Additionally, an adjustment for confounders likewise to the national retrospective cohort study from Allsop et al. (45) is not established, this could leads to different results. Secondly, the results of our monocentric study may not be generalizable. Third, our sample included cancer patients. Factors of patient with non-oncological diseases associated with early and late referral might be further explored in additional studies. Fourth, the implications of these indicators in the clinical practice and future research must be analyzed and discussed in additional studies. Fifth, the characteristics of the referrer were not collected, this might influence early or late referrals given that clinicians who has some palliative care skills or training are more aware of the benefits of palliative care for their patients and families. Sixth, the terms “early” and “late referral” differ between publications, therefore a carefully comparison should be made while comparing results from other publications.

Most patients in an outpatient setting are referred late in their course of disease. We showed that female gender, having visceral metastasis and psychological distress are mainly reasons and indicators of an early referral. As a new aspect, laboratory parameters and well known prognostic factors like CRP or NLR could be integrated in existing screening tools for oncologist involved in the decision-making about when to refer to a specialized palliative care unit. Further research is required on combining symptoms and laboratory parameters with timely referral to improve the quality of life in advanced cancer.

7.1 Ethics approval and consent to participate

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and local ethical review committee of the University of Essen and approved the data analyze (16-6800-BO) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

7.2 Consent for publication

Not applicable.

7.3 Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

7.4 Competing interests

The authors declare that they have no competing interests.

7.5 Funding

Not applicable.

7.6 Authors' contributions

SM collected, analyzed and interpreted the patient data regarding to find indicators for early and late referral. MTew and MCS interpreted and reviewed previous versions of the paper. MTew was a major contributor in writing the manuscript. MF helps by visualisation of results and find the right statistical mean. MS enabled the general conditions. JH helps by acquisition of data. MTeu proofed developed design of survey. All authors read and approved the final manuscript.

7.7 Acknowledgements

Not applicable.

Kaasa S, Loge JH, Aapro M, Albreht T, Anderson R, Bruera E, et al. Integration of oncology and palliative care: a Lancet Oncology Commission. Lancet Oncol. 2018;19(11):e588–653.
Ferrell BR, Temel JS, Temin S, Smith TJ. Integration of Palliative Care Into Standard Oncology Care: ASCO Clinical Practice Guideline Update Summary. J Oncol Pract. 2017;13(2):119–21.
Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733–42.
Greer JA, Jackson VA, Meier DE, Temel JS. Early integration of palliative care services with standard oncology care for patients with advanced cancer. CA Cancer J Clin. 2013;63(5):349–63.
Vanbutsele G, Pardon K, Van Belle S, Surmont V, De Laat M, Colman R, et al. Effect of early and systematic integration of palliative care in patients with advanced cancer: a randomised controlled trial. Lancet Oncol. 2018;19(3):394–404.
Hui D, Mori M, Watanabe SM, Caraceni A, Strasser F, Saarto T, et al. Referral criteria for outpatient specialty palliative cancer care: an international consensus. Lancet Oncol. 2016;17(12):e552-e9.
Hui D, Anderson L, Tang M, Park M, Liu D, Bruera E. Examination of referral criteria for outpatient palliative care among patients with advanced cancer. Support Care Cancer. 2020;28(1):295–301.
Hausner D, Tricou C, Mathews J, Wadhwa D, Pope A, Swami N, et al. Timing of Palliative Care Referral Before and After Evidence from Trials Supporting Early Palliative Care. Oncologist. 2020:332–40.
Gemmell R, Yousaf N, Droney J. "Triggers" for early palliative care referral in patients with cancer: a review of urgent unplanned admissions and outcomes. Support Care Cancer. 2020;28(7):3441–9.
Bubis LD, Davis LE, Coburn NG, Mahar AL. Authors' Reply to the Response to "Patient-Reported Symptom Severity Among 22,650 Cancer Outpatients in the Last 6 Months of Life''. J Pain Symptom Manag. 2020;59(1):E3–4.
Cheung WY, Barmala N, Zarinehbaf S, Rodin G, Le LW, Zimmermann C. The association of physical and psychological symptom burden with time to death among palliative cancer outpatients. J Pain Symptom Manage. 2009;37(3):297–304.
de Oliveira Valentino TC, Paiva BSR, de Oliveira MA, Hui D, Paiva CE. Factors associated with palliative care referral among patients with advanced cancers: a retrospective analysis of a large Brazilian cohort. Support Care Cancer. 2018;26(6):1933–41.
Hoerger M, Greer JA, Jackson VA, Park ER, Pirl WF, El-Jawahri A, et al. Defining the Elements of Early Palliative Care That Are Associated With Patient-Reported Outcomes and the Delivery of End-of-Life Care. J Clin Oncol. 2018;36(11):1096–102.
Barton MK. Early outpatient referral to palliative care services improves end-of-life care. CA Cancer J Clin. 2014;64(4):223–4.
Berendt J, Stiel S, Simon ST, Schmitz A, van Oorschot B, Stachura P, et al. Integrating Palliative Care Into Comprehensive Cancer Centers: Consensus-Based Development of Best Practice Recommendations. Oncologist. 2016;21(10):1241–9.
Muir JC, Daly F, Davis MS, Weinberg R, Heintz JS, Paivanas TA, et al. Integrating palliative care into the outpatient, private practice oncology setting. J Pain Symptom Manage. 2010;40(1):126–35.
Berendt J, Thomas M, Neukirchen M, Schwartz J, Hense J, Tewes M. [Integration of Palliative Care into the Comprehensive Cancer Center of Germany - Consultation Hours and Fellowship Rotations of the Specialized Palliative Care]. Dtsch Med Wochenschr. 2018;143(17):e139-e45.
Tewes M, Rettler T, Wolf N, Hense J, Schuler M, Teufel M, et al. Predictors of outpatients' request for palliative care service at a medical oncology clinic of a German comprehensive cancer center. Support Care Cancer. 2018;26(10):3641–7.
van Wijmen MPS, Schweitzer BPM, Pasman HR, Onwuteaka-Philipsen BD. Identifying patients who could benefit from palliative care by making use of the general practice information system: the Surprise Question versus the SPICT. Fam Pract. 2020;37(5):641–7.
Stiel S, Matthes MEB, Ostgathe L, Elsner C, Radbruch F. L. Validerung der neuen Fassung des Minimalen Dokumentationssystems (/MIDOS2) für Patienten in der Palliativmedizin. Der Schmerz. 2010;24:596–604.
Wadhwa D, Popovic G, Pope A, Swami N, Le LW, Zimmermann C. Factors Associated with Early Referral to Palliative Care in Outpatients with Advanced Cancer. J Palliat Med. 2018;21(9):1322–8.
Stiel S, Pollok A, Elsner F, Lindena G, Ostgathe C, Nauck F, et al. Validation of the Symptom and Problem Checklist of the German Hospice and Palliative Care Evaluation (HOPE). J Pain Symptom Manage. 2012;43(3):593–605.
Lindena G, Nauck F, Bausewein C, Neuwohner K, Heine O, Schulenberg D, et al. [Quality assurance in palliative medicine–results of the core documentation of 1999–2002]. Z Arztl Fortbild Qualitatssich. 2005;99(9):555–65.
Lindena G, Wellmann A, Ostgathe C, Radbruch L, Nauck F. HOPE K. Ambulante Palliativversorgung in Deutschland – in HOPE dokumentierte Erfahrungen. Z Palliativmed. 2011;12(1):27–32.
Conill C, Verger E, Salamero M. Performance status assessment in cancer patients. Cancer-Am Cancer Soc. 1990;65(8):1864–6.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649–55.
Jordan RI, Allsop MJ, ElMokhallalati Y, Jackson CE, Edwards HL, Chapman EJ, et al. Duration of palliative care before death in international routine practice: a systematic review and meta-analysis. BMC Med. 2020;18(1):368.
Wentlandt K, Krzyzanowska MK, Swami N, Rodin GM, Le LW, Zimmermann C. Referral practices of oncologists to specialized palliative care. J Clin Oncol. 2012;30(35):4380–6.
Scibetta C, Kerr K, McGuire J, Rabow MW. The Costs of Waiting: Implications of the Timing of Palliative Care Consultation among a Cohort of Decedents at a Comprehensive Cancer Center. J Palliat Med. 2016;19(1):69–75.
Schnipper LE, Smith TJ, Raghavan D, Blayney DW, Ganz PA, Mulvey TM, et al. American Society of Clinical Oncology identifies five key opportunities to improve care and reduce costs: the top five list for oncology. J Clin Oncol. 2012;30(14):1715–24.
Glare PA, Chow K. Validation of a Simple Screening Tool for Identifying Unmet Palliative Care Needs in Patients With Cancer. J Oncol Pract. 2015;11(1):e81-6.
Carrasco-Zafra MI, Gomez-Garcia R, Ocana-Riola R, Martin-Rosello ML, Blanco-Reina E. Level of Palliative Care Complexity in Advanced Cancer Patients: A Multinomial Logistic Analysis. J Clin Med. 2020;9(6).
Cheung WY, Le LW, Zimmermann C. Symptom clusters in patients with advanced cancers. Support Care Cancer. 2009;17(9):1223–30.
Kwon JH, Hui D, Chisholm G, Ha C, Yennurajalingam S, Kang JH, et al. Clinical characteristics of cancer patients referred early to supportive and palliative care. J Palliat Med. 2013;16(2):148–55.
Robert-Koch-Institut. Herausgeber 2012 Daten und Fakten: Ergebnisse der Studie »Gesundheit in Deutschland aktuell 2010«. Beiträge zur Gesundheitsberichterstattung des Bundes.: RKI; Berlin.
Runyon BA. Care of patients with ascites. N Engl J Med. 1994;330(5):337–42.
Mackey JR, Venner PM. Malignant ascites: demographics, therapeutic efficacy and predictors of survival. Can J Oncol. 1996;6(2):474–80.
Jurisic V, Radenkovic S, Konjevic G. The Actual Role of LDH as Tumor Marker, Biochemical and Clinical Aspects. Adv Exp Med Biol. 2015;867:115–24.
Amano K, Maeda I, Morita T, Miura T, Inoue S, Ikenaga M, et al. Clinical Implications of C-Reactive Protein as a Prognostic Marker in Advanced Cancer Patients in Palliative Care Settings. J Pain Symptom Manage. 2016;51(5):860–7.
Chen S, Li R, Zhang Z, Huang Z, Cui P, Jia W, et al. Prognostic value of baseline and change in neutrophil-to-lymphocyte ratio for survival in advanced non-small cell lung cancer patients with poor performance status receiving PD-1 inhibitors. Transl Lung Cancer Res. 2021;10(3):1397–407.
Nemoto T, Endo S, Isohata N, Takayanagi D, Nemoto D, Aizawa M, et al. Change in the neutrophil-to-lymphocyte ratio during chemotherapy may predict prognosis in patients with advanced or metastatic colorectal cancer. Mol Clin Oncol. 2021;14(5):107.
Duan J, Pan L, Yang M. Preoperative elevated neutrophil-to-lymphocyte ratio (NLR) and derived NLR are associated with poor prognosis in patients with breast cancer: A meta-analysis. Med (Baltim). 2018;97(49):e13340.
Raith EP, Udy AA, Bailey M, McGloughlin S, MacIsaac C, Bellomo R, et al. Prognostic Accuracy of the SOFA Score, SIRS Criteria, and qSOFA Score for In-Hospital Mortality Among Adults With Suspected Infection Admitted to the Intensive Care Unit. JAMA. 2017;317(3):290–300.
Mallik M, Singhai A, Khadanga S, Ingle V. The Significant Morbidity and Mortality Indicators in Patients of Cirrhosis. Cureus. 2022;14(1):e21226.
Allsop MJ, Ziegler LE, Mulvey MR, Russell S, Taylor R, Bennett MI. Duration and determinants of hospice-based specialist palliative care: A national retrospective cohort study. Palliat Med. 2018;32(8):1322–33.

Download PDF

Editorial decision: Major revision
28 Jul, 2022
Reviewers agreed at journal
22 Jun, 2022
Reviewers invited by journal
22 Jun, 2022
Editor invited by journal
31 May, 2022
Editor assigned by journal
27 May, 2022
First submitted to journal
27 May, 2022

You are reading this latest preprint version

Palliative Care Outpatients in a German Comprehensive Cancer Center - Identifying Indicators for Early and Late Referral

Status:

Version 2

Abstract

Background.

Methods.

Results.

Conclusion.

1. Background

2. Methods

2.1 Study Design

2.2 Demographics

2.3 Statistical analyzes

3. Results

3.1 Analyzes to Timing of Referral

3.2 Analyzes of the laboratory parameters

4. Discussion

5. Limitations

6. Conclusion

7. Declarations

References

Status:

Version 2