Abstract
We examined the symptoms and referral rates to specialized palliative care and psychosocial oncology services of patients with acute leukemia. The Memorial Symptom Assessment Scale (MSAS) was completed by 249 adult patients with acute leukemia. Patients reported a median of 9 physical and 2 psychological symptoms, and those with intense lack of energy, difficulty sleeping and pain were more likely to report intense worrying/sadness (P < 0.001). No patients with moderate-severe pain were referred for specialized symptom control and only 13% of those with severe worrying/sadness were referred to psychiatry/psychology within one month of the assessment. Patients in this population have a substantial symptom burden; further research is needed to determine the benefit of early referral to specialized supportive care services.
Keywords: Leukemia, Symptom assessment, Pain, Palliative care, Supportive care, Psychosocial oncology
1. Introduction
The disease process in acute leukemia and the intensive treatment regimens that are typically employed can result in substantial symptom burden. However, while there has been extensive study of the symptom burden in patients with solid tumor cancers [1–3], there has been little systematic study of symptoms in patients with acute leukemia. Retrospective studies in patients with leukemia and other hematological malignancies have revealed that in the last month of life, pain is reported by 27–76% [4,5], shortness of breath by 44–50% [4–6], and fatigue by 88% [6]. However, these studies did not document symptoms earlier in the course of disease [5,6] and were not limited to patients with acute leukemia.
Few prospective studies have documented symptoms in patients with hematological diseases early in the disease course and even fewer specifically in patients with acute leukemia. In a prospective study of 180 patients with hematological malignancies, a mean of 8.8 symptoms was reported, with fatigue being most prominent. However, this study included only 19 patients with acute leukemia, with most patients having a diagnosis of myeloma or lymphoma [7]. Another prospective study examined symptoms using the EORTC-QLQ C-30 questionnaire during an outpatient management program for 60 patients with acute leukemia who were receiving intensive chemotherapy, and found that high infectious comorbidity significantly reduced physical functioning [8]. In a recent prospective study of 53 patients with newly-diagnosed acute leukemia, median scores of 0/10 for dyspnea and nausea, 1/10 for pain, depression, anxiety and appetite, and 3/10 for fatigue were reported on the Edmonton Symptom Assessment System (ESAS) [9]. However, the ESAS has severity ratings for only nine symptoms, and does not measure symptom distress or frequency.
There has been recent acknowledgment of the relevance of palliative care for patients with hematological malignancies [10], and accumulating evidence of the benefit of palliative care when provided concurrently with curative or life-prolonging treatment [11–15]. However, there have been no prospective studies assessing referral to palliative care and psychosocial services for patients with acute leukemia and correlating these data with symptom severity. Palliative care referral tends to occur late in the course of disease for patients with cancer [16], particularly for those with hematological malignancies [17–19]. Retrospective studies have found that for patients with hematological malignancies palliative care referral tends to occur within approximately 2 weeks of patient death, compared to approximately two months in patients with solid tumors, despite similar symptom severity [18,19]. However, these studies assessed symptoms at the time of referral to palliative care services, rather than at diagnosis or relapse, and did not specifically assess patients with acute leukemia.
In order to identify better the symptom control and psychosocial needs of patients with acute leukemia, we assessed comprehensively and systematically the symptom burden experienced by patients with newly-diagnosed or recently-relapsed disease, as well as their referral rates to palliative care, psychiatry/psychology and social work services.
2. Materials and methods
2.1. Setting and procedures
The study took place at the Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. Patients were recruited on a 35-bed specialized leukemia unit and in a hematology outpatient clinic. The unit and clinic represent a tertiary referral center for leukemia and are staffed by nurses, physicians and social workers with expertise in the care of patients with leukemia. Routine prophylactic and therapeutic medications are given for nausea, pain, sleeplessness and other symptoms, as required. On referral, specialized palliative care and psychiatry/psychology services offer pain and symptom management, advance care planning, counseling and treatment.
This study was approved by the University Health Network Research Ethics Board (REB); all participants provided informed written consent. Eligible participants were at least 18 years old, had a new diagnosis or relapse of acute leukemia within the past 8 weeks (at the time of completion of forms), had sufficient English literacy to provide informed consent and complete study questionnaires, and obtained a score of 20 or more on the Short Orientation-Memory-Concentration (SOMC) [20] test of cognitive functioning administered by research staff at the time of recruitment.
Patients were approached between January 30, 2008 and February 22, 2012 on the inpatient leukemia unit or in the hematology outpatient clinic, within one month of hospital admission for treatment. Patients were asked to fill out the questionnaire package and return it within 2 weeks. Outpatients mailed back the questionnaires in the stamped and addressed envelope that was provided; research staff collected inpatients’ questionnaires once they had been completed, and provided assistance, if required.
2.2. Measures
Participant and disease characteristics were obtained from patients and from their medical charts. These included: age, gender, marital status, living arrangements, country of birth, education, employment status, average family income, past psychiatric history, disease type, disease status, duration of illness, type and intensity of treatment received, number of days hospitalized until time of study assessment, and days since starting chemotherapy until time of study assessment.
Physical functioning was assessed using the Karnofsky Performance Status index (KPS) [21], a widely-used observer-rated measure of patient autonomy in carrying out normal activities and self-care [22,23]. Scores range from 100 (normal, no signs or symptoms of disease) downwards in decrements of 10 to 0 (death).
Symptom burden was assessed using the 32-item Memorial Symptom Assessment Scale (MSAS) [2], a well-validated multidimensional self-report scale that assesses, during the preceding week, the prevalence, frequency, severity, and distress associated with 26 physical and six psychological cancer symptoms [2]. The physical symptom subscale score (PHYS) is the average of the frequency, severity and distress associated with 12 prevalent physical symptoms (lack of appetite, lack of energy, pain, feeling drowsy, constipation, dry mouth, nausea, vomiting, change in taste, weight loss, feeling bloated, and dizziness). The psychological symptom sub-scale score (PSYCH) is the average of the frequency, severity and distress associated with six prevalent psychological symptoms (worrying, feeling sad, feeling nervous, difficulty sleeping, feeling irritable, and difficulty concentrating) [2].
The total MSAS score (TMSAS) is the average symptom score of all 32 MSAS symptoms; each symptom score is the average of its two or three associated dimensions. The global distress index (GDI) measures overall symptom distress, which is calculated from the average of the frequency of four psychological symptoms (worrying, feeling sad, feeling irritable, and feeling nervous), and the distress associated with six physical symptoms (lack of appetite, lack of energy, pain, feeling drowsy, constipation, and dry mouth) [24].
Treatment intensity was categorized into groups based on the chemotherapy regimens received by the participants: (1) none (not receiving or had not yet started chemotherapy at the time of assessment); (2) low (hydroxyurea, etoposide-only, clinical trial single agent or low-dose cytarabine); (3) moderate (daunorubicin + cytarabine 3 + 7 induction [+/− tretinoin, midostaurin or gemtuzumab], amsacrine + cytarabine induction [+/− tretinoin], A-NOVE, ALL DFCI [25] [+/− imatinib] or hyper-CVAD induction) [26]; and (4) High (NOVE-HiDAC [27] or MEC [28]).
Days since starting chemotherapy was categorized because toxicity generally peaks and then subsides. The following groups were used, based on the number of days from starting chemotherapy until the time of study assessment: no chemotherapy (not yet started or none given); 1–7 days; 8–14 days; 15–21 days; 22–28 days; 29–35 days; and >35 days. The chemotherapy regimens used were typically between 5 and 7 days in duration.
Incidence and reasons for referrals to palliative care, psychiatry/psychology and social work were determined from the Palliative Care and Psychosocial Oncology clinical databases for a period of 6 months from the symptom assessment.
Time to death was determined by calculating the time between completion of questionnaires and death. Death dates were collected from medical charts for all patients up to 6 months following the time of assessment.
2.3. Statistical analyses
Data were analyzed using the Statistical Package for the Social Sciences (SPSS), version 19.0 (IBM SPSS, Chicago, IL). An examination of missing data did not reveal any systematic or nonrandom patterns across all measures. For those with missing data, scores were pro-rated if 75% or more of the items in a given measure had been answered. Multivariable regression models were used to evaluate the relationship between validated MSAS subscales and study variables. Symptom intensity was defined as a combined ranking across frequency, severity and distress subscales, with symptoms that ranked highest on all subscales rated as the most intense. For the three most intense symptoms, the relative risks of having other associated intense symptoms (rated ≥2 in frequency, severity and distress) were calculated, similar to studies in other populations [24,29]. The Bonferroni correction was used to adjust for multiple comparisons, resulting in a level of significance of P < 0.0016. The GDI, PHYS and PSYCH subscale scores were compared using t-tests, between patients who died within 6 months and those who survived; and between patients referred, or not, to palliative care and psychosocial services within one month of the assessment.
3. Results
3.1. Sample
Of the 580 eligible patients approached for this study, 358 (62%) consented to participate and 272 (47%) returned completed assessments. Of the 222 (38%) who refused, 96 were not interested, 74 felt too unwell, and 27 cited the time required as the reason for declining. Of those who consented, 80 withdrew and 6 died before completing the questionnaires. Of the 272 who completed the assessment, 23 did so more than 8 weeks after their diagnosis/relapse and were therefore excluded. The present analyses included responses from a final sample of 249 participants.
Patients who refused to participate (n = 222) or who did not complete measures (n = 86) did not differ from those who completed measures, in terms of leukemia type, age, or gender (the only data available for comparison due to REB guidelines). Of 249 participants, 224 (90%) were in hospital at the time of assessment and 213 (86%) were receiving induction chemotherapy. The majority (78%; 193/249) had acute myeloid leukemia (AML) and the mean time since diagnosis or relapse was less than one month (Table 1).
Table 1.
Participant and disease characteristics.
| Variable | No. | % | Range |
|---|---|---|---|
| Age (years), mean (SD) | 49.8 | (16.0) | 18.3–86.1 |
| Male | 143 | 57.4 | |
| Married/common law | 174 | 69.9 | |
| Living alonea | 29 | 11.6 | |
| Canadian born | 148 | 59.4 | |
| Ethnicity (white) | 163 | 65.5 | |
| College/university educationb | 173 | 69.5 | |
| Employment statusc | |||
| Employed | 126 | 50.6 | |
| Student/retired | 83 | 33.3 | |
| Unemployed/on disability | 39 | 15.7 | |
| Mean family income | |||
| ≤$29,999 | 31 | 12.4 | |
| $30,000–$59,999 | 58 | 23.3 | |
| ≥$60,000 | 107 | 43.0 | |
| Not answered | 53 | 21.3 | |
| Past psychiatric history | 22 | 8.8 | |
| Karnofsky performance status, mean (SD) | 72.2 | (10.7) | 40–100 |
| Disease type | |||
| Acute myeloid leukemia | 193 | 77.5 | |
| Acute lymphocytic leukemia | 56 | 22.5 | |
| Time from diagnosis or relapse until assessment (months), mean (SD) | 0.9 | (0.4) | 0–2 |
| Disease status | |||
| New onset | 220 | 88.4 | |
| Recently-relapsed | 29 | 11.6 | |
| Treatment type | |||
| Induction | 213 | 85.5 | |
| Re-induction | 26 | 10.4 | |
| Clinical trial | 7 | 2.8 | |
| Supportive care | 3 | 1.2 | |
| Hospital status (at recruitment) | |||
| Inpatient | 231 | 92.8 | |
| Outpatient | 18 | 7.2 | |
| Hospital status (at time of assessment)d | |||
| Inpatient | 224 | 90.0 | |
| Outpatient | 25 | 10.0 | |
| Time from starting chemotherapy until assessmente (in days) | |||
| n = 239, mean (SD) | 17.1 | (10.9) | 0–55 |
| 0 (not yet started) | 11 | 4.6 | |
| 1–7 | 36 | 15.1 | |
| 8–14 | 60 | 25.1 | |
| 15–21 | 66 | 27.6 | |
| 22–28 | 34 | 14.2 | |
| 29–35 | 14 | 5.9 | |
| >35 | 18 | 7.5 | |
| Treatment intensity | |||
| Not yet started at time of assessment | 11 | 4.4 | |
| No treatment | 1 | 0.4 | |
| Low | 10 | 4.0 | |
| Moderate | 207 | 83.1 | |
| High | 20 | 8.0 | |
Living situation: missing data for one study participant.
Education: missing data for one study participant.
Employment status: missing data for one study participant.
Hospital status: 17 patients were recruited as inpatients but completed questionnaires as outpatients (after being discharged after treatment), 7 patients were never admitted and 10 were recruited as outpatients but completed questionnaires as inpatients (after being admitted for treatment).
Time from starting chemotherapy until assessment: 10 patients who were receiving supportive care or were participating in clinical trials were not included as dates were not available. Usual duration of induction/re-induction chemotherapy regimens was 5–7 days.
3.2. Symptom burden
Participants reported a median of 9 physical (range 0–22) and 2 psychological (range 0–6) symptoms (Table 2). Two hundred and twenty-six participants (91%) reported >5 concurrent physical and psychological symptoms and 151 (61%) reported >10 concurrent symptoms. The most prevalent physical symptoms were lack of energy (79%), drowsiness (56%), dry mouth (54%) and weight loss (54%); pain was present in 49% (Table 3). The most prevalent psychological symptoms were difficulty sleeping (55%), worrying (43%), difficulty concentrating (39%), and feeling sad (36%). Lack of energy, difficulty sleeping and pain were the most intense symptoms, with the highest combined ratings of severity, frequency and distress. Regarding symptom severity, the numbers of patients reporting slight, moderate, or severe symptoms were as follows: lack of energy, slight, 46 (18%); moderate, 94 (38%); severe, 48 (19%); difficulty sleeping, slight, 20 (8%); moderate, 66 (27%); severe, 43 (17%); and pain, slight, 20 (8%); moderate, 61 (25%); severe, 41 (16%).
Table 2.
Memorial Symptom Assessment Scale subscale scores.
| Mean | Standard deviation | Range | Scale range | |
|---|---|---|---|---|
| Number of physical symptoms | ||||
| Mean | 8.8 | 3.9 | 0–22 | 0–26 |
| Median | 9.0 | |||
| Number of psychological symptoms | ||||
| Mean | 2.2 | 1.9 | 0–6 | 0–6 |
| Median | 2.0 | |||
| Physical symptom frequency, n = 239 | 2.4 | 0.5 | 1–4 | 1–4 |
| Physical symptom severity, n = 247 | 2.0 | 0.5 | 1–4 | 1–4 |
| Physical symptom distress, n = 239 | 1.5 | 0.8 | 0–4 | 0–4 |
| PHYS, n = 246 | 1.9 | 0.6 | 0.5–3.3 | 0–4 |
| PSYCH, n = 188 | 2.0 | 0.6 | 0.7–3.7 | 0–4 |
| GDI, n = 244 | 1.5 | 0.9 | 0–4 | 0–4 |
| TMSAS, n = 248 | 1.9 | 0.5 | 0.5–3.2 | 0–4 |
Abbreviations: PHYS, physical symptom subscale (12 items); PSYCH, psychological symptom subscale (6 items); GDI, global distress index (10 items); TMSAS, total MSAS score (32 items).
Table 3.
Prevalence, frequency, severity and distress of symptoms reported by study participants (n = 249).
| Symptom | Overall prevalence (%) | Severity (%)a | Frequency (%)b | Distress (%)c |
|---|---|---|---|---|
| Psychological group | ||||
| Difficulty sleeping | 55.2 | 44.0** | 30.2** | 20.0** |
| Worrying | 43.2 | 28.0 | 15.3 | 8.4 |
| Difficulty concentrating | 39.2 | 20.0 | 11.1 | 7.2 |
| Feeling sad | 35.6 | 22.4 | 8.5 | 9.2 |
| Feeling nervous | 30.8 | 20.8 | 9.8 | 10.0 |
| Feeling irritable | 20.0 | 10.8 | 5.5 | 4.0 |
| Physical group | ||||
| Lack of energy* | 79.2 | 57.2** | 43.8** | 19.6** |
| Feeling drowsy* | 56.4 | 37.6** | 18.3 | 4.0 |
| Dry mouth* | 54.0 | 35.2 | 31.5** | 12.0** |
| Weight loss* | 53.6 | 31.6 | NE | 4.0 |
| Lack of appetite* | 52.0 | 39.2** | 31.9** | 9.2 |
| Change in taste of food* | 51.2 | 37.2 | NE | 12.4 |
| Pain* | 49.2 | 40.8** | 19.6** | 21.2** |
| Nausea* | 44.8 | 29.6 | 14.0 | 14.0** |
| Changes in skin | 42.2 | 31.2 | NE | 9.2 |
| Hair loss | 39.6 | 33.2 | NE | 6.8 |
| Sweats | 38.0 | 25.6 | 12.3 | 8.8 |
| Diarrhea | 32.0 | 22.8 | 16.2 | 9.6 |
| Mouth sores | 31.6 | 25.2 | NE | 10.8 |
| Constipation* | 26.4 | 20.4 | NE | 8.4 |
| Itching | 25.2 | 19.6 | 11.9 | 6.0 |
| Cough | 24.4 | 11.2 | 3.8 | 3.2 |
| Vomiting* | 24.0 | 16.8 | 3.0 | 7.6 |
| ‘I don’t look like myself’ | 22.4 | 14.4 | NE | 6.8 |
| Feeling bloated* | 20.4 | 12.8 | 6.0 | 3.2 |
| Shortness of breath | 20.4 | 13.2 | 4.3 | 5.6 |
| Dizziness* | 20.0 | 11.2 | 3.8 | 3.2 |
| Numbness or tingling in hands/feet | 18.0 | 9.2 | 8.9 | 2.0 |
| Swelling of arms and legs | 16.4 | 12.0 | NE | 4.8 |
| Difficulty swallowing | 16.0 | 12.0 | 8.1 | 6.0 |
| Problems with sexual interest/activity | 12.8 | 10.0 | 10.6 | 3.6 |
| Problems with urination | 7.6 | 6.4 | 5.5 | 4.0 |
Symptoms are derived from the 32-item Memorial Symptom Assessment Scale (MSAS); NE, MSAS does not evaluate this dimension for these symptoms.
Items included in the 12-item PHYS subscale. All 6 psychological symptoms listed make up the PSYCH subscale.
Items ranking in the top 5 of ratings for frequency, severity and distress, respectively.
Severity: percentage rated moderate to very severe.
Frequency: percentage rated frequently to almost constantly.
Distress: percentage rated quite a bit to very much.
Multivariable regression analyses revealed that PHYS was associated with poorer functional status (P < 0.0001; β = −0.247); PSYCH was associated with past psychiatric history (P = 0.007; β = 0.194) and acute lymphocytic leukemia (ALL) disease type (P = 0.013; β = −0.177); GDI was associated with worse functional status (P = 0.005; β = −0.178) and past psychiatric history (P = 0.028; β = .139); and TMSAS was associated with female gender (P = .046; β = 0.123), past psychiatric history (P = 0.033; β = 0.132) and worse functional status (P < 0.0001; β = −0.226). Of note, disease status, days since starting chemotherapy, relapsed versus newly diagnosed disease, and intensity of the chemotherapy regimen were not significant predictors of the TMSAS score or the MSAS subscale scores.
3.3. Relative risk of experiencing simultaneous intense symptoms
Patients with intense pain had an increased relative risk of having other intense physical symptoms, including lack of energy, nausea, mouth sores and lack of appetite (Table 4). They also had greater difficulty sleeping and more than a three-fold relative risk of sadness, worrying and difficulty concentrating. Intense lack of energy was associated with intense pain, nausea, weight loss and lack of appetite, and with all six MSAS psychological symptoms. Intense difficulty sleeping was associated with pain, sweats, lack of energy, drowsiness, lack of sexual interest/activity, sadness, worrying and nervousness.
Table 4.
Relative risks of intense symptoms associated with intense pain, lack of energy or difficulty sleeping.
| Symptoms rated moderately to severely intense | Pain | Lack of energy | Difficulty sleeping |
|---|---|---|---|
|
| |||
| Relative risk (95% CI) | Relative risk (95% CI) | Relative risk (95% CI) | |
| Psychological symptoms | |||
| Difficulty sleeping | 1.8 (1.3–2.6)a | 2.4 (1.7–3.4)a | – |
| Worrying | 3.3 (2.0–5.6)a | 4.5 (2.6–8.0)a | 3.5 (2.0–6.0)a |
| Difficulty concentrating | 4.7 (2.2–9.9)a | 15.8 (4.9–51.0)a | 2.6 (1.3–5.2) |
| Feeling sad | 3.4 (1.9–6.2)a | 3.7 (2.0–6.8)a | 2.7 (1.5–4.9)a |
| Feeling nervous | 1.7 (0.9–3.1) | 4.0 (2.1–7.5)a | 4.7 (2.4–9.0)a |
| Feeling irritable | 3.8 (1.6–8.8) | 8.4 (2.9–24.2)a | 3.3 (1.4–7.7) |
| Physical symptoms | |||
| Lack of energy | 2.6 (1.8–3.6)a | – | 2.4 (1.7–3.3)a |
| Feeling drowsy | 2.3(1.34.1) | 6.4 (3.1–12.8)a | 2.8 (1.6–5.1)a |
| Dry mouth | 1.9 (1.2–3.1) | 2.2 (1.4–3.7) | 2.0 (1.2–3.2) |
| Weight loss | 3.0 (1.4–6.6) | 4.5 (1.9–10.6)a | 1.9 (0.9–4.1) |
| Lack of appetite | 3.8 (2.2–6.4)a | 6.5 (3.5–12.1)a | 2.3 (1.4–3.8) |
| Change in taste of food | 2.7 (1.7–4.2)a | 2.5 (1.6–3.9)a | 1.4 (0.9–2.3) |
| Pain | – | 2.8 (1.9–4.1)a | 1.9 (1.3–2.7)a |
| Nausea | 3.4 (2.1–5.6)a | 2.5 (1.5–4.0)a | 1.8 (1.1–2.8) |
| Changes in skin | 1.6 (1.0–2.7) | 2.2 (1.3–3.7) | 2.1 (1.2–3.5) |
| Hair loss | 2.8 (1.5–5.3) | 3.0 (1.6–5.8)a | 2.2 (1.2–4.1) |
| Sweats | 3.1 (1.5–6.3) | 2.0 (1.0–4.0) | 3.7 (1.8–7.6)a |
| Diarrhea | 2.5 (1.3–4.8) | 2.7 (1.4–5.3) | 1.9 (1.0–3.7) |
| Mouth sores | 2.9 (1.7–4.8)a | 1.1 (0.7–1.9) | 1.2 (0.7–2.0) |
| Constipation | 1.6 (0.8–3.1) | 2.3 (1.2–4.4) | 2.3 (1.2–4.6) |
| Itching | 1.5 (0.8–2.9) | 1.4 (0.7–2.8) | 2.2 (1.1–4.2) |
| Cough | 2.3 (0.9–6.4) | 3.6 (1.2–10.3) | 1.5 (0.6–4.3) |
| Vomiting | 3.7 (1.5–9.1) | 3.1 (1.3–7.7) | 2.6 (1.1–6.3) |
| ‘I don’t look like myself’ | 1.8 (0.7–4.0) | 4.9 (2.0–12.3)a | 5.1 (2.1–12.7)a |
| Feeling bloated | 3.5 (1.5–8.2) | 3.0 (1.3–7.0) | 1.1 (0.5–2.7) |
| Shortness of breath | 1.3 (0.5–3.0) | 3.7 (1.5–8.9) | 1.7 (0.7–3.9) |
| Dizziness | 1.5 (0.5–4.3) | 4.5 (1.4–14.0) | 1.8 (0.6–5.1) |
| Numbness or tingling in hands/feet | 1.2 (0.4–3.8) | 1.4 (0.5–4.3) | 1.0 (0.3–3.3) |
| Swelling of arms and legs | 1.7 (0.7–4.0) | 1.4 (0.6–3.4) | 1.5 (0.6–3.6) |
| Difficulty swallowing | 2.3 (1.0–5.4) | 1.1 (0.4–2.6) | 1.4 (0.6–3.2) |
| Problems with sexual interest/activity | 1.0 (0.4–3.0) | 2.5 (1.0–6.6) | 6.1 (2.0–18.5)a |
| Problems with urination | 0.6 (0.2–2.2) | 2.6 (0.9–7.3) | 1.5 (0.6–4.3) |
Intense symptoms (rated ≥2 in severity, frequency and distress) with a significant relative risk of association with intense pain, lack of energy or difficulty sleeping (P < 0.001).
3.4. Referral to palliative care/psychosocial oncology services
Within one month of the symptom assessment, 0.8% (2/249) of patients were referred to palliative care and 8% (19/249) were referred to psychiatry or psychology; 2% (5/249) and 14% (34/249), respectively, were referred within 6 months of the assessment. There was no difference in GDI, PHYS or PSYCH subscale scores between those who were or were not referred to palliative care or psychiatry/psychology within one month of the assessment. Of those with moderate-severe pain, none (0/102) were referred to palliative care for symptom control within one month of the assessment; 13% (11/82) of those with severe worrying or sadness were referred to psychiatry/psychology services. Most patients (78%; 193/249) had contact with a social worker on the leukemia team, with discharge planning, transportation, accommodation, community resources, drug coverage, and/or financial difficulties as the reasons documented for this referral.
3.5. Subsample of deceased patients
Of the 249 patients, 35 (14%) died within the 6-month follow-up period, with a mean time to death of 3 ± 1.4 months from the assessment (Table 5). Almost all had AML (97%), and 83% were newly-diagnosed. All patients receiving supportive care, 71% of those participating in clinical trials, 19% undergoing re-induction, and 10% undergoing induction died within 6 months.
Table 5.
Disease characteristics at time of assessment and referral rates of deceased patients.
| Death/total deceaseda
|
Death/total categoryb
|
|||
|---|---|---|---|---|
| f/n | % | f/n | % | |
| Disease type | ||||
| AML | 34/35 | 97.1 | 34/193 | 17.6 |
| ALL | 1/35 | 2.9 | 1/56 | 1.8 |
| Disease status | ||||
| New onset | 29/35 | 82.9 | 29/220 | 13.2 |
| Recently-relapsed | 6/35 | 17.1 | 6/29 | 20.7 |
| Treatment type | ||||
| Induction | 22/35 | 62.9 | 22/213 | 10.3 |
| Re-induction | 5/35 | 14.3 | 5/26 | 19.2 |
| Clinical trials | 5/35 | 14.3 | 5/7 | 71.4 |
| Supportive care | 3/35 | 8.6 | 3/3 | 100.0 |
| Hospital admission status (at assessment) | ||||
| Inpatient | 27/35 | 77.0 | 27/224 | 12.1 |
| Outpatient | 8/35 | 23.0 | 8/25 | 32.0 |
| Treatment intensity | ||||
| Not yet started at time of assessment | 1/35 | 2.9 | 1/11 | 9.1 |
| No treatment (supportive care only) | 1/35 | 2.9 | 1/1 | 100.0 |
| Low | 7/35 | 20.0 | 7/10 | 70.0 |
| Moderate | 20/35 | 57.1 | 20/207 | 9.7 |
| High | 6/35 | 17.1 | 6/20 | 30.0 |
| Referrals | ||||
| Palliative care | 2/35 | 5.7 | 2/5 | 40.0 |
| Psychiatry/psychology | 0/35 | 0.0 | 0/34 | 0.0 |
| Social work | 24/35 | 68.6 | 24/193 | 12.4 |
All disease characteristics were collected at the time of assessment; the evaluation period for dates of death was 6 months (180 days) after completion of measures, as 6-month follow-up was available for all participants. Abbreviations: f/n, frequency/number.
Death/total deceased: proportion is based on the number of deaths in a given category over the total number of deaths in the sample (n = 35).
Death/total category: proportion is based on the number of deaths in a given category over the total sample in each category.
Of the 35 patients who died, 2 (6%) were referred to palliative care, with a mean time of 6 days from referral to death. Of these patients, one was receiving induction treatment at the time of the assessment and one was participating in a clinical trial. There was no significant difference in GDI, PSYCH and PHYS subscale scores between patients who died within 6 months and those who survived beyond the 6-month period.
4. Discussion
We investigated systematically the prevalence of physical and psychological symptoms in patients with newly-diagnosed or recently-relapsed acute leukemia and the referral of such patients for specialized psychosocial and palliative care services. Most of these patients were hospitalized with recently-diagnosed acute leukemia, and were receiving intensive treatment. The symptom burden was high, with patients reporting a median of 9 physical and 2 psychological symptoms, and 61% reporting 10 or more concurrent symptoms. The mean scores on measures of physical, psychological and global distress were even higher than those reported in two studies of inpatients and outpatients with solid tumors [1,24]. Most patients received social work assistance, as is routine for newly-diagnosed patients at the study center. Referral for specialized palliative care was rare, even in those who died, and only a small minority of those with severe worrying or sadness were referred to psychiatry or psychology for psychological treatment and/or medication.
The most problematic symptoms, as reflected in combined rankings of severity, frequency, and distress, were lack of energy, difficulty sleeping and pain. Lack of energy and difficulty sleeping were particularly prominent, both reported in more than half of the study sample. Although fatigue may eventually improve in patients with AML who live longer than 6 months [30,31], it may be associated with considerable distress. Difficulty sleeping might have been accentuated by the inpatient environment, and by the psychological distress associated with a recent diagnosis of acute leukemia. Both fatigue and difficulty sleeping were correlated with a number of other physical and psychological symptoms. In addition to screening for and treating such associated symptoms, exercise programs are being evaluated to ameliorate fatigue in hospitalized patients and outpatients with acute leukemia, including those receiving chemotherapy [32–35].
Forty-one percent of patients rated their pain as moderate to severe despite the frequent use of opioid analgesics at the study center; none of these were referred to the palliative care service within one month of the assessment. Intense pain was associated with lack of appetite, fatigue, nausea and psychological distress, as in patients with solid tumors [3,24,29,36]. The additional association of pain with mouth sores and changes in taste may be due either to gum disease from the leukemia itself or to mucositis from its treatment. Longitudinal studies are necessary to understand better the nature and course of the pain experienced by patients with acute leukemia and its response to treatment, with or without involvement of a specialized pain management/palliative care team.
Severe sadness and worrying were reported by more than 20% of the sample, which is consistent with our recent observation that full syndrome or subsyndromal acute stress disorder is present in approximately one third of patients with newly-diagnosed acute leukemia [37]. These patients received support from the treatment team, and the majority also had social work consultations. However, only 13% of patients with severe sadness or worrying were referred to psychology or psychiatry services within one month of the assessment. Routine distress screening may help to identify symptoms that are clinically significant and that may benefit from timely referral to specialized psychosocial services [38].
The rate of referral to palliative care was extremely low, even for those who died, and did not correlate with symptom severity. Previous retrospective studies have found similarly low rates of referral to palliative care in patients with hematological malignancies [6,17,39]. The interval of 6 days between referral and death in this sample of patients with acute leukemia is similar to that reported in retrospective studies of patients with hematological malignancies, which have reported intervals between referral and death of 2 weeks or less [18,19]. There is increasing evidence of the benefit of early palliative care in patients with metastatic cancer [11–15]. Models of palliative and supportive care, designed specifically for patients with acute leukemia, may be useful to support patients through the symptoms and distress associated with intensive treatment, and potentially to the end of life. Further research in this area is needed.
Limitations of this study include its cross-sectional nature, the exclusion of patients who were not fluent in English, and the possibility that participants may differ in undetected ways from nonparticipants. Incidence of referrals to palliative care and psychosocial services did not take into account those who were offered referral but refused. Patients diagnosed with acute leukemia are treated as soon as possible, and for most patients it was therefore not possible to obtain symptom assessments before treatment. However, neither time from start of chemotherapy nor regimen intensity was a significant predictor of symptom severity.
The results of this prospective study in patients with acute leukemia reveal a high burden of physical and psychological symptoms, with a low rate of referral to psychiatry/psychology or palliative care services. Further research is needed to examine longitudinal symptom trends and to determine the benefit of early referral to specialized supportive care services.
Acknowledgments
We thank our research and clinical staff who contributed to this project, especially Andrea Chan for her assistance with study management and recruitment, and our study participants who kindly gave their time and effort to help us better understand the experience of living with acute leukemia.
Role of the funding source
This work was supported by the Canadian Institutes of Health Research (grant number MOP-84317, GR and CZ, Co-Principal Investigators), and in part by the Ontario Ministry of Health and Long Term Care. The views expressed do not necessarily reflect those of the funding sources. Dr. Zimmermann is supported by the Rose Family Chair in Supportive Care, Faculty of Medicine, University of Toronto, and Dr. Rodin by the University of Toronto/University Health Network Harold and Shirley Lederman Chair in Psychosocial Oncology and Palliative Care.
The sponsors of this study had no role in study design, data collection, data analysis, interpretation of findings, writing of the manuscript; and in the decision to submit the manuscript for publication.
Footnotes
Authors’ contributions: All authors made substantial contributions. The conception and design of the study (CZ, GR), or acquisition of data (DY, AM), or analysis and interpretation of data (CZ, GR, AM, DY, AR, CL, LG, MM, JB, AS). Drafting the article or revising it critically for important intellectual content (CZ, DY, AM, MM, JB, AS, LG, CL, AR, GR). Final approval of the version to be submitted (CZ, DY, AM, MM, JB, AS, LG, CL, AR, GR).
Conflict of interest
The authors have declared no conflicts of interest. The authors have no financial or personal relationship with individuals, organizations or companies that might be perceived to bias the work.
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