Factors Associated with Early Referral to Palliative Care in Outpatients with Advanced Cancer

Abstract

Background:

Although timely palliative care is recommended for patients with advanced cancer, referrals to palliative care services are often late.

Objectives:

To identify factors associated with early referral to an oncology palliative care clinic and to describe symptom severity according to timing of referral.

Design:

We conducted a retrospective review of 337 patients with advanced cancer referred to outpatient palliative care at a comprehensive cancer center. We gathered data related to patient demographics, diagnosis, and referral. Timing of referral was categorized as early (>12 months before death), intermediate (6–12 months before death), or late (<6 months before death). Ordinal logistic regression was used to determine factors related to referral timing, and the Kruskal–Wallis test to determine symptom severity in each referral timing category.

Results:

Of the 337 patients, 232 (69%) referrals were late, 60 (18%) intermediate, and 45 (13%) early. On multivariable analysis, earlier referral was associated with earlier primary cancer diagnosis (p = 0.004), and referral for pain and symptom management (p = 0.001). Patients who were referred late had worse overall Edmonton Symptom Assessment System distress scores, as well as worse tiredness, nausea, drowsiness, appetite, and wellbeing (all p ≤ 0.001). Severity of pain, shortness of breath, anxiety, and depression did not differ based on time of referral.

Conclusions:

A longer disease course and referral for symptom management were associated with earlier referral, whereas overall symptom burden was higher for late referrals. Further research is required on combining symptom screening with timely referral to improve symptom management in advanced cancer.

Introduction

Timely referral to palliative care has been shown to improve patient outcomes, such as symptom management, quality of life, satisfaction with healthcare, and aggressiveness of care at the end of life.^1–4 Caregivers also benefit, with improved mood and increased satisfaction with care.^5–7 Since at least 2002, the definition of palliative care has emphasized early identification of problems to improve quality of life, and relevance for patients receiving treatments intended to prolong life.⁸ In light of recent evidence to support these assertions,^1–3,9 recent American Society of Clinical Oncology (ASCO) guidelines now recommend the involvement of palliative care services in conjunction with active treatment for all patients with advanced cancer.¹⁰ Despite this evidence and advocacy for early referral, many patients are still referred late or not at all.^11,12

To improve timely access to palliative care for patients with advanced cancer, it is necessary to understand referral practices. Although other studies have documented late referrals,^13,14 there is scant research describing characteristics of patients in relation to time of referral. In one study, patients referred early (defined as receiving/having received curative-intent treatment or expected survival >2 years) were more likely to have a reason for consultation of treatment-related side effects and to have head and neck cancer.¹⁵ In another study, older patients, inpatients, and patients with noncancer diagnoses were more likely to be referred to palliative care late in their disease course.¹⁶

Between December 2006 and February 2011, our center undertook a cluster randomized clinical trial of early palliative care.² As a starting point for our research on referral practices, we carried out the current study to examine patterns of palliative care referral before this trial was initiated and before other trials on early palliative care team interventions for outpatients had been published.^1–3,9 Our purpose was to examine characteristics associated with early referral to an outpatient oncology palliative care clinic and prevalence of specific symptoms according to referral time. We hypothesized that early palliative care referral would be associated with referral for symptom management, but that symptom burden would be worse among late referrals.

Methods

We reviewed medical records of 407 patients who were referred to the outpatient palliative care consultation service at Princess Margaret Cancer Centre in Toronto, Canada between June 1 and November 30, 2006. Data were abstracted from the electronic patient record and from the Palliative Care Clinical database. This study was approved by the Research Ethics Board of the University Health Network.

In addition to demographic information such as age, sex, cancer diagnosis, and date of diagnosis, we collected information on the reason for referral to the palliative care service (pain and symptom management, and/or palliative planning, or end-of-life care) and the referring physician (sex and specialty). We documented information related to the timing of referral to palliative care in relation to death, using the following classification^2,13: palliative care referrals made greater than 1 year before the patient's death were classified as “early”; referrals between 6 and 12 months before death were classified as “intermediate”; and referrals made less than 6 months before death were classified as “late.” In addition, we collected Edmonton Symptom Assessment System (ESAS) scores at the initial palliative care consultation as well as information pertaining to the Charlson Comorbidity Index.¹⁷

Descriptive statistics were used to characterize patients in the “early,” “intermediate,” and “late” groups. Ordinal logistic regression with three ordinal levels was carried out and univariable and multivariable analyses were performed to determine factors associated with timing of referral. The Kruskal–Wallis test was used to assess the difference in severity of ESAS symptoms in relation to timing of referral; for this analysis, a p-value of 0.005 was used to correct for multiple testing.

Results

Of the 407 patients, 70 were excluded due to incomplete data or because they were originally seen in consultation as inpatients, leaving 337 patients. Demographic characteristics are shown in Table 1.

Table 1.

Patient Characteristics, N = 337

	N (%)
Sex
Female	163 (48.4)
Male	174 (51.6)
Age at referral, in years
Mean ± SD	64.9 ± 14.5
Median (range)	66.2 (19.9–92.2)
Income quintile^a
1	64 (19.1)
2	64 (19.1)
3	60 (17.9)
4	61 (18.2)
5	86 (25.7)
Charlson Comorbidity Index
0	247 (73.3)
1	68 (20.2)
≥2	22 (6.5)
Time since cancer diagnosis, in years
<1 year	118 (35.1)
1–2 years	77 (22.9)
2–3 years	36 (10.7)
≥3 years	105 (31.3)
Primary tumor site
Gastrointestinal	87 (25.8)
Lung	49 (14.5)
Breast	37 (11.0)
Genitourinary	37 (11.0)
Gynecological	35 (10.4)
Head and neck	24 (7.1)
Hematological	22 (6.5)
Central nervous system	20 (5.9)
Other^b	26 (7.7)
Months from palliative care referral to death
Mean ± SD	6.8 ± 9.9
Median (range)	3.4 (0.1–63.6)
Received chemotherapy for advanced cancer diagnosis
Yes	240 (71.2)
No	97 (28.8)
Seen by a medical oncologist
Yes	300 (89.0)
No	37 (11.0)
Referring service
Medical oncology	206 (62.0)
Radiation oncology	80 (24.1)
Surgical oncology	25 (7.5)
Hematology	17 (5.1)
Other^c	4 (1.2)
Referring oncologist sex
Male	228 (68.7)
Female	104 (31.3)
Reason for referral
End-of-life care	6 (1.8)
Pain/symptom management	65 (19.3)
Palliative planning	85 (25.2)
Palliative planning and pain/symptom management	181 (53.7)

Average income after tax determined by postal code: 1, Low (average $15,400); 2, Low to Medium ($27,200); 3, Medium ($37,500); 4, Medium to High ($49,600); 5, High ($83,500).³¹

Other tumor sites include skin, sarcoma, neuroendocrine, or unknown primary.

Other referring services include Psychosocial Oncology and Anesthesia.

Data are missing for two patients for income quintile, for one patient for time since cancer diagnosis, for five patients for referring service, and for five patients for reason for referral.

SD, standard deviation.

Table 2 shows characteristics of the sample by referral time. Most patients were referred late (232 patients, 69%), 45 (13%) were referred early, and 60 (18%) were intermediate. Patients who were referred early to palliative care were more likely to have breast cancer (27% referred early vs. 10%–16% for other sites), to have had cancer for ≥2 years (21% referred early vs. 8% of those who had cancer <2 years), to have received chemotherapy for advanced disease (16% referred early vs. 7% of those who did not receive chemotherapy), and to have been referred for symptom management (25% referred early vs. 13% of those referred for palliative planning).

Table 2.

Patient Demographics and Characteristics by Time of Palliative Care Referral, N = 337

	Late referral (≤6 mo), N (%)	Intermediate (6 mo–1 yr), N (%)	Early referral (>1 yr), N (%)
Number of patients	232 (69)	60 (18)	45 (13)
Sex
Female	110 (67.5)	30 (18.4)	23 (14.1)
Male	122 (70.1)	30 (17.2)	22 (12.6)
Age at referral, in years
Mean ± SD	64.7 ± 15.3	64.8 ± 13.2	66.1 ± 12.0
Median (range)	66.9 (19.9–92.2)	65.6 (26.4–86.5)	64.6 (40.1–88.2)
Income quintile^a
1	41 (64.1)	14 (21.9)	9 (14.1)
2	43 (67.2)	9 (14.1)	12 (18.8)
3	46 (76.7)	10 (16.7)	4 (6.7)
4	43 (70.5)	12 (19.7)	6 (9.8)
5	57 (66.3)	15 (17.4)	14 (16.3)
Missing	2	0	0
Charlson Comorbidity Index
0	166 (67.2)	45 (18.2)	36 (14.6)
1	50 (73.5)	12 (17.6)	6 (8.8)
≥2	16 (72.7)	3 (13.6)	3 (13.6)
Time since cancer diagnosis, in years
<2 years	146 (74.9)	33 (16.9)	16 (8.2)
≥2 years	85 (60.3)	27 (19.2)	29 (20.6)
Missing	1	0	0
Primary tumor site
Breast	19 (51.4)	8 (21.6)	10 (27.0)
Central nervous system	14 (70.0)	4 (20.0)	2 (10.0)
Gastrointestinal	65 (74.7)	13 (14.9)	9 (10.3)
Genitourinary	25 (67.6)	6 (16.2)	6 (16.2)
Gynecological	27 (77.1)	5 (14.3)	3 (8.6)
Head and neck	16 (66.7)	6 (25.0)	2 (8.3)
Hematological	17 (77.3)	2 (9.1)	3 (13.6)
Lung	32 (65.3)	10 (20.4)	7 (14.3)
Other^b	17 (65.4)	6 (23.1)	3 (11.5)
Received chemotherapy for advanced cancer diagnosis
No	73 (75.3)	17 (17.5)	7 (7.2)
Yes	159 (66.3)	43 (17.9)	38 (15.8)
Seen by a medical oncologist
No	27 (73.0)	6 (16.2)	4 (10.8)
Yes	205 (68.3)	54 (18.0)	41 (13.7)
Referring service
Medical oncology	141 (68.4)	39 (18.9)	26 (12.6)
Radiation oncology	57 (71.3)	13 (16.3)	10 (12.5)
Surgical oncology	15 (60.0)	5 (20.0)	5 (20.0)
Hematology	14 (82.4)	2 (11.8)	1 (5.9)
Other^c	1 (25.0)	1 (25.0)	2 (50.0)
Missing	4	0	1
Referring oncologist sex
Male	155 (68.0)	44 (19.3)	29 (12.7)
Female	73 (70.2)	16 (15.4)	15 (14.4)
Missing	4	0	1
Reason for referral
End-of-life care	4 (66.7)	2 (33.3)	0 (0.0)
Pain/symptom management	31 (47.7)	18 (27.7)	16 (24.6)
Palliative planning	59 (69.4)	15 (17.6)	11 (12.9)
Palliative planning and pain/symptom management	138 (76.2)	25 (13.8)	18 (9.9)

Average income: 1, Low (average $15,400); 2, Low to Medium ($27,200); 3, Medium ($37,500); 4, Medium to High ($49,600); 5, High ($83,500).³¹

Other tumor sites include skin, sarcoma, neuroendocrine, or unknown.

Other referring services include Psychosocial Oncology and Anesthesia.

Results of the univariable and multivariable analyses are shown in Table 3. Factors significantly associated with earlier referral in the univariable analysis were a diagnosis of breast cancer (p = 0.05), cancer diagnosed ≥2 years previously (p = 0.002), and referral for pain and symptom management (p < 0.0001) (Table 3). On multivariable analysis, earlier referral was associated with a primary cancer diagnosis ≥2 years before the palliative care referral (p = 0.004), and referral for pain and symptom management (p = 0.001).

Table 3.

Univariable and Multivariable Analyses of Factors Associated with Early Palliative Care Referral Using 3-Level Ordinal Logistic Regression

	Univariable		Multivariable
	OR ^a (95% CI)	p	OR ^a (95% CI)	p
Age at referral, in years	1.00 (0.99–1.02)	0.63
Sex
Female	1.13 (0.72–1.78)	0.59
Male	—	—
Income quintile	0.98 (0.84–1.14)	0.76
Primary tumor site		0.27
Breast	3.20 (1.02–10.1)	0.047
Central nervous system	1.32 (0.34–5.15)	0.39
Gastrointestinal	1.09 (0.37–3.20)	0.88
Genitourinary	1.59 (0.49–5.18)	0.44
Gynecological	0.94 (0.27–3.28)	0.93
Head and neck	1.47 (0.41–5.34)	0.56
Hematological	—	—
Lung	1.68 (0.54–5.20)	0.37
Other^b	1.61 (0.46–5.67)	0.46
Charlson Comorbidity Index		0.51
0	1.27 (0.49–3.29)	0.63
1	0.91 (0.31–2.62)	0.85
≥2	—	—
Time since diagnosis, in years
≥2 years	2.10 (1.32–3.32)	0.002	2.00 (1.25–3.20)	0.004
<2 years	—	—	—	—
Chemotherapy received for advanced cancer diagnosis
Yes	1.63 (0.96–2.78)	0.07
No	—	—
Seen by a medical oncologist
Yes	1.26 (0.59–2.68)	0.55
No	—	—
Referring oncologist sex
Female	0.93 (0.57–1.54)	0.80
Male	—	—
Reason for referral		0.0002		0.004
Pain/symptom management	3.37 (1.90–5.96)	<0.0001	3.21 (1.80–5.71)	0.001
Palliative planning	1.41 (0.80–2.48)	0.23	1.40 (0.79–2.48)	0.17
Palliative planning and pain/symptom management	—	—	—	—
End-of-life care^c
Referring services		0.43
Hematology	—	—
Medical oncology	2.15 (0.60–7.73)	0.24
Radiation oncology	1.92 (0.51–7.28)	0.34
Surgical oncology	3.24 (0.75–14.0)	0.12
Other^{c d}

Proportional odds ratios with late referral as the base level, for early versus intermediate/late referral and early/intermediate referral versus late referral.

Other primary tumor sites include skin, sarcoma, neuroendocrine, or unknown.

Excluded from multivariable analysis due to small counts.

Other referring services include Psychosocial Oncology and Anesthesia.

Table 4 shows the symptom pattern of patients referred to palliative care at different times in their illness course. Patients who were referred late had worse ESAS distress scores as well as worse tiredness, nausea, drowsiness, appetite, and wellbeing. Severity of pain, shortness of breath, anxiety, and depression did not differ based on time of referral.

Table 4.

Edmonton Symptom Assessment System Scores Based on Time of Referral

ESAS symptom	Late referral, (N = 232)	Intermediate referral (N = 60)	Early referral, (N = 45)	p-value^a
Pain	n = 149	n = 47	n = 35	0.55
Mean ± SD	4.7 ± 3.2	4.1 ± 3.4	4.4 ± 3.1
Median (IQR)	5.0 (2.0–8.0)	3.0 (1.0–7.0)	5.0 (2.0–8.0)
Tiredness	n = 151	n = 46	n = 35	<0.001
Mean ± SD	6.9 ± 2.6	5.4 ± 2.9	5.4 ± 2.9
Median (IQR)	7.0 (5.0–9.0)	5.5 (4.0–7.0)	6.0 (3.0–8.0)
Nausea	n = 150	n = 47	n = 35	0.006
Mean ± SD	2.8 ± 3.0	1.8 ± 2.9	1.4 ± 2.2
Median (IQR)	2.0 (0.0–5.0)	0.0 (0.0–3.0)	0.0 (0.0–3.0)
Depression	n = 149	n = 47	n = 35	0.25
Mean ± SD	4.0 ± 3.3	3.2 ± 3.4	3.5 ± 3.0
Median (IQR)	4.0 (1.0–7.0)	1.0 (0.0–6.0)	4.0 (0.0–5.0)
Anxiety	n = 146	n = 45	n = 35	0.05
Mean ± SD	4.5 ± 3.2	3.4 ± 3.6	3.6 ± 3.2
Median (IQR)	4.0 (2.0–7.0)	2.0 (0.0–6.0)	3.0 (0.0–5.0)
Drowsiness	n = 145	n = 47	n = 35	<0.001
Mean ± SD	4.9 ± 3.2	3.7 ± 3.1	2.8 ± 2.8
Median (IQR)	6.0 (2.0–8.0)	3.0 (0.0–7.0)	3.0 (0.0–5.0)
Appetite	n = 150	n = 47	n = 35	0.006
Mean ± SD	5.5 ± 3.2	4.4 ± 3.0	3.8 ± 3.1
Median (IQR)	6.0 (3.0–8.0)	4.0 (2.0–6.0)	4.0 (1.0–6.0)
Wellbeing	n = 145	n = 44	n = 34	0.001
Mean ± SD	6.0 ± 2.7	4.4 ± 2.8	4.5 ± 2.9
Median (IQR)	6.04.0–8.0)	4.0 (2.0–6.5)	5.0 (2.0–6.0)
Shortness of breath	n = 149	n = 48	n = 35	0.62
Mean ± SD	3.6 ± 3.5	2.9 ± 3.2	3.2 ± 3.2
Median (IQR)	3.0 (0.0–6.0)	2.0 (0.0–5.5)	2.0 (0.0–6.0)
ESAS distress score	n = 151	n = 48	n = 35	0.001
Mean ± SD	43.1 ± 17.9	33.6 ± 19.4	32.7 ± 18.3
Median (IQR)	41.6 (31.0–57.0)	33.1 (16.5–50.3)	33.0 (15.0–48.0)

Based on Kruskal–Wallis test.

ESAS, Edmonton Symptom Assessment System.

Discussion

We have described factors associated with timing of referral to palliative care, and the symptom pattern relative to time of referral. Most patients were referred late in their disease course. On multivariable analysis, earlier referral was associated with having cancer for at least 2 years and with referral for pain and symptom management. As we hypothesized, overall symptom severity was worse for late referrals, although this was not the case for all individual symptoms.

A longer cancer history was associated with earlier referral to palliative care. This was also the case in a previous study¹⁵ and may be related to having a longer time for the gradual introduction of palliative care, or for patients to become aware of symptom control services and to request referral. Patients with breast cancer tend to have a longer survival at diagnosis than those with other cancers¹⁸ and this may in part explain the tendency for earlier referral in this group in the univariable analysis. Instituting referral guidelines that encourage early referral may standardize the referral process and ensure that patients receive timely access to palliative care.¹⁹ This would need to be done in concert with education and advocacy that palliative care is not only for end-of-life care.²⁰

Referral for pain and symptom management was also associated with earlier palliative care referral, which could have been for disease-related or treatment-related symptoms. Receiving chemotherapy tended to be associated with early referral in our study, and in a previous study, referrals for treatment-related toxicity were more common in those referred early.¹⁵ Nevertheless, early referrals for symptom management remain infrequent, perhaps because conventional history taking does not fully capture symptom burden.²¹ Routine screening for symptoms and distress at each oncology follow-up visit may identify symptoms proactively, and has been instituted at several cancer centers, including our own.^22–24 We are currently conducting a clinical trial of ESAS screening coupled with early palliative care referral for symptoms above a certain threshold.

Although referral for symptom management was associated with early referrals, overall symptom burden was worse in patients who were referred late. The latter was not the case in a previous study,¹⁵ but “late” referrals in that study had a clinical prognosis of up to 2 years. Specifically, in our study, tiredness, drowsiness, appetite, wellbeing, and nausea were worse in patients who were referred late, whereas there was no difference between early and late referrals in pain, shortness of breath, anxiety, or depression. Previous research has demonstrated that tiredness, drowsiness, appetite, wellbeing, and shortness of breath worsen as patients approach the end of life.^25,26 Nausea may have been more prevalent in our study among those referred late because nausea tends to be multifactorial at the end of life and more difficult to manage than earlier in the disease course.²⁷ Shortness of breath was not increased among late referrals in our study; this symptom may worsen closer to death, or patients might have been referred early specifically to control this symptom.

Our study has a number of limitations. The retrospective nature of the study prevents us from drawing firm conclusions. Data are from a single comprehensive cancer center and may not be generalizable. Data were limited to those available from our database, and ESAS scores were not available for all patients. It is possible that referral to palliative care may have improved survival, thus making some referrals appear earlier; however, since the majority of referrals occurred late, this is unlikely to have made a substantial impact on our conclusions. Since the time of this study, aggressiveness of care has continued to increase at the end of life²⁸; there have been advances in targeted treatments and immuno-oncology drugs with complex side-effect profiles²⁹; and several studies and reviews have been published on the benefits of early palliative care.^1–4,9 In the contemporary climate, there may be a reduction in the proportion of patients referred late. However, practice tends to be slow to change in response to guidelines,^10,30 and this study sheds light on factors that may determine early or late referral. Further research will examine whether referral practices and symptom patterns have changed.

In conclusion, most patients in this study were referred late in the disease course. Earlier referrals were associated with longer disease duration and referral for symptom control, whereas overall symptom burden was higher for late referrals. Further research is required on combining symptom screening with timely referral to improve symptom management in advanced cancer.

Footnotes

Acknowledgments

This study was funded by the Canadian Institutes for Health Research (grant number 152996, CZ) and the Ontario Ministry of Health and Long-Term Care. Dr. Zimmermann is supported by the Rose Family Chair in Supportive Care, Faculty of Medicine, University of Toronto. The views expressed do not necessarily reflect those of the funding agencies, which also had no role in the study design, data collection, analysis and interpretation, writing, or decision to submit for publication.

Results of this study were presented, in part, at the Multinational Association of Supportive Care in Cancer (MASCC) annual meeting, Copenhagen, Denmark; June 25, 2015.

Author Disclosure Statement

No competing financial interests exist.

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