The impact of acute myeloid leukemia and its treatment on quality of life and functional status in older adults

The impact of acute myeloid leukemia and its treatment on quality of life and functional status in older adults

Critical Reviews in Oncology/Hematology 64 (2007) 19–30 The impact of acute myeloid leukemia and its treatment on quality of life and functional stat...

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Critical Reviews in Oncology/Hematology 64 (2007) 19–30

The impact of acute myeloid leukemia and its treatment on quality of life and functional status in older adults Shabbir M.H. Alibhai a,b,c,d,∗ , Marc Leach a , Husnain Kermalli a , Vikas Gupta a,c , Matthew E. Kowgier a , George A. Tomlinson a,e , Joseph Brandwein a,c , Rena Buckstein c,f , Mark D. Minden a,c a

Department of Medicine, University Health Network, Toronto, Canada Geriatric Program, Toronto Rehabilitation Institute, Toronto, Canada c Department of Medicine, University of Toronto, Toronto, Canada Department of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada e Department of Public Health Sciences, University of Toronto, Toronto, Canada f Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Canada b

d

Accepted 4 July 2007

Contents 1. 2.

3.

4.

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Data collection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Quality of life measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Functional status measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Sample size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Baseline characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Changes in QOL over time and by treatment group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Changes in functional status over time and by treatment group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Clinically important changes in QOL over time. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Impact of missing data among patients who withdrew . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Impact of achieving CR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20 20 20 20 21 21 21 21 21 22 22 23 23 23 25 25 25 29 29 29 30

Abstract Although intensive chemotherapy (IC) may modestly improve survival compared to supportive care in older people with acute myeloid leukemia (AML), treatment may worsen quality of life (QOL) and functional status. We assessed QOL and functional status at baseline, 1 month, 4 months, and 6 months in 65 consecutive, English-speaking, patients age 60 or older with newly diagnosed AML. At baseline, functional status was high but QOL was negatively affected in global health and most QOL domains. Over time, QOL remained stable or ∗ Corresponding author at: University Health Network, Room EN 14-214, 200 Elizabeth Street, Toronto, Ont. M5G 2C4, Canada. Tel.: +1 416 340 5125; fax: +1 416 595 5826. E-mail address: [email protected] (S.M.H. Alibhai).

1040-8428/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2007.07.003

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improved in most patients and was generally similar between IC and non-IC groups. Basic activities of daily living (ADL) scores did not change over time, whereas instrumental ADL scores declined slightly regardless of treatment. Receiving IC does not appear to lead to worse QOL or functional status than more palliative approaches. This information may aid treatment discussions in older patients with AML. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Aged; Acute myeloid leukemia; Quality of life; Functional status; Treatment

1. Introduction Acute myeloid leukemia (AML) primarily affects adults over age 60 [1,2], in whom the median overall survival is under 6 months [3,4]. Even in selected series, 3-year survival is about 10% [5,6]. Two major strategies are typically used to manage AML—intensive chemotherapy (IC) and best supportive care. IC, the standard treatment for AML in younger adults, is both less effective and less tolerated in seniors, even with optimal supportive care [7–10]. Few older adults with AML receive IC [3]. This may be due in large part to a perception that IC is only associated with modest survival benefits but significantly worse quality of life (QOL). Indeed, in one randomized trial of patients age 65 or older with AML, IC was associated with a higher rate of complete remission (CR) but more early deaths led to similar overall survival compared to best supportive care [11]. However, the sample size was small (87 patients) and QOL was not formally assessed. There have been significant advances in risk stratification and supportive management in the last decade, with 50–60% CR rates and improved three-year survival among older AML patients without adverse cytogenetics who underwent IC in recent studies [12–16]. Although IC may be associated with improved survival in selected patients, it is associated with significant treatmentrelated toxicity [13]. In such a scenario, understanding the effects of treatment on QOL becomes important [17,18]. To date, however, few studies have examined QOL in patients with AML [19–21], and only one study has focused on older adults with AML [22]. In that study [22], 43 patients age 60 or older with either AML or advanced myelodysplastic syndrome were followed over the course of 1 year. Patients were treated with either IC or best supportive care. At baseline, QOL was affected primarily in the domain of physical function and declined at 2 weeks. However, general QOL recovered by 4–6 weeks and improved after hospital discharge [22]. Although type of treatment did not appear to have an impact on QOL beyond hospital discharge, quantitative analyses were not performed and the sample size was small. IC also requires a 4–6-week period of hospitalization for induction chemotherapy and a further period of hospitalization for consolidation chemotherapy. During IC, patients experience prolonged periods of neutropenia, associated with increased susceptibility of infection. The majority of patients with AML also experience significant fatigue [22]. Prolonged periods of bed rest as a consequence of hospitalization, fatigue, and infection may lead to functional declines [23].

Most older adults value highly their functional independence [24,25]. To date, however, there is no information on the functional status of older adults with AML over time. If QOL and functional status are not significantly worse in older patients undergoing IC compared with best supportive care, this may lead to greater consideration of IC and, ultimately, improved survival. Detailed information on QOL and functional outcomes can also focus intervention studies designed to improve these outcomes in this population regardless of the primary treatment that is chosen. We therefore prospectively examined QOL and self-reported functional status over a 6 month period in older adults with newly diagnosed AML who were being managed with either IC or less aggressive approaches. This was an observational study; the decision to use IC or less aggressive approaches was made on clinical grounds.

2. Materials and methods 2.1. Patients Consecutive English-speaking patients aged 60 years or older with newly diagnosed AML were approached prior to starting chemotherapy. The diagnosis of AML was based on morphologic examination of a bone marrow specimen, using World Health Organization (WHO) criteria, and classified according to the French–American–British (FAB) classification system. Patients with another active malignancy or life expectancy of less than 1 month were excluded. Patients were approached regardless of treatment intent and were recruited primarily from the leukemia Service at the Princess Margaret Hospital (PMH). PMH is a tertiary care cancer center and the major referral center for approximately 85% of patients with acute leukemia who live in the Greater Toronto Area (catchment area of 4.5 million). All patients provided written, informed consent. The study was approved by the PMH Research Ethics Board. 2.2. Data collection Baseline socio-demographic and disease information (including age, education, comorbidity, routine hematology and biochemistry, and bone marrow results, including cytogenetics) were obtained from the patients or their clinical records. Patients were classified into risk groups by karyotype according to the Medical Research Council (MRC) schema [26]. Comorbidity was assessed with the Charlson

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Index [27], and performance status was assessed with the Karnofsky performance status and the Eastern Cooperative Oncology Group (ECOG) score. Patients were excluded if they had at least moderate cognitive impairment, as reflected by a score of 21/30 or less on the Folstein mini-mental status examination [28]. Follow-up visits were conducted at 1 month, 4 months, and 6 months to coincide with the completion of induction therapy, consolidation chemotherapy, and anticipated median survival time points, respectively. Patients filled in questionnaires at the same time points regardless of treatment intent. 2.3. Treatment Three main treatment strategies were available for older patients—IC, investigational agents, and best supportive care. At our center, treatment decisions are made for patients age 60 or older on the basis of karyotype, performance status, and patient preference; age is not viewed as a contraindication to IC but IC is not encouraged outside of a clinical trial in older patients with an adverse karyotype (as defined by the MRC schema) given the poor prognosis and treatment-related toxicity associated with IC [12,26]). IC consisted of one or two courses of induction chemotherapy, followed by two courses of consolidation chemotherapy. Induction chemotherapy consisted of daunorubicin 60 mg/m2 /day for 3 days plus cytosine arabinoside (Ara-C) 100 mg/m2 /day as a continuous infusion for 7 days. For individuals with significant left ventricular dysfunction, amsacrine was substituted for daunorubicin. The first cycle of consolidation chemotherapy consisted of the same regimen as induction (daunorubicin and Ara-C) using identical doses. Most patients received a second cycle of consolidation chemotherapy with mitoxantrone (10 mg/m2 /day) and etoposide (100 mg/m2 /day) each for 5 days. Some patients did not receive consolidation chemotherapy either because of active serious infection, severe toxicity from induction chemotherapy, or personal choice. However, we did not record these reasons during the study. For patients who opted not to receive IC, two main investigational agents were available at PMH during the enrollment period—decitabine and temozolomide. Both agents were used singly instead of IC. These agents are not considered equivalent to IC in terms of toxicity because they do not require prolonged hospitalization, do not lead to prolonged immunosuppression, and have much lower treatment-related toxicity than traditional IC regimens. Decitabine was administered intravenously in doses ranging from 7.5 to 22 mg/m2 every 12 h for 5 days [29,30]. Temozolomide was given orally at a dose of 200 mg/m2 for 7 days [31]. Best supportive care included antibiotic and antifungal prophylaxis, blood product support as necessary, and antibiotics to treat infections. 2.4. Quality of life measures We measured cancer-specific QOL at each time point with the EORTC QLQ-C30. The QLQ-C30 is a widely used,

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multidimensional, psychometrically sound QOL instrument [32–34]. It features five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea/vomiting), and a global health measure. All scores are scaled from 0 to 100, with higher scores representing better QOL and fewer symptoms [21,32]. A 10-point difference in QOL domain scores is considered clinically important [35]. The QLQ-C30 has been shown to be sensitive to change in patients undergoing cancer treatment (chemotherapy and/or radiotherapy) (e.g. [32,34,36,37]). Given the significant role of fatigue in patients with AML [19,38], we used the Functional Assessment of Cancer Therapy (FACT) Fatigue (FACT-F) subscale [39] to explore symptoms of fatigue. Analyses of fatigue outcomes have been reported elsewhere [40]. Mood was assessed with the 15-item Geriatric Depression Scale (GDS) [41]. The GDS is self-administered and has been validated in various groups of older adults [23,42,43]. 2.5. Functional status measures Basic activities of daily living (ADL) were assessed with the Barthel Index [44]. The Barthel Index is a self-report measure that covers 10 areas, including bathing, dressing, toileting, transfers, and use of stairs. It is scored from 0 to 100, with higher scores representing greater independence. Instrumental ADL were assessed with the scale developed by Lawton and Brody [45]. The scale covers eight items, including shopping, housekeeping, and medication management. It is scored from 0 to 17, with higher scores representing greater independence. Both measures have been employed in previous cancer studies in older populations [23,46]. ADL/IADL measures are sensitive to the impact of cancer (particularly lung, breast, cervical/uterine, prostate, and ovarian) [47] and are beginning to be used to modify cancer treatment (e.g. chemotherapy) among older patients with functional impairment at baseline [48]. Although these published studies have measured similar functional items as the Barthel Index and the Lawton–Brody scale, neither of the latter two have specifically been studied in this regard. 2.6. Sample size As this was primarily a descriptive study, our sample size was determined by feasibility considerations. The planned recruitment was 60 patients. 2.7. Statistical analysis A log was maintained of all patients who declined participation or were ineligible. Patients were stratified into two treatment groups—those who received IC and those who received non-IC treatment (including investigational agents and best supportive care). Differences in baseline characteristics between the two groups were compared using Student’s t-test for normally distributed continuous vari-

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ables, the Mann–Whitney u-test for non-normally distributed continuous variables, and the chi-square test for categorical variables. To examine changes over time in QOL and functional status, we used repeated measures mixed effects models, which allowed for inclusion of patients with partial data (resulting from death or drop-out) [49]. We first examined if there were differences between IC and non-IC groups in each outcome both at baseline and over time (using a time by treatment interaction term) and adjusting for important baseline characteristics (ECOG performance status, age, and cytogenetics). Where the analysis suggested there was no interaction by group (i.e. the trajectories of the two groups remained similar over time), we reported changes over time for all patients, while noting, if significant, the difference between the groups. If there was a time by treatment interaction, changes over time were examined separately by treatment group. In this analysis, QOL scores were not assigned to a patient for time points where the patient was dead, but prior QOL scores reported by the same patient at a prior time point while he was alive were included in the mixed effects models. A similar strategy was used for functional status measures. For all statistical comparisons, a p-value of 0.05 was considered significant. No correction was made for multiple significance testing [50]. Analyses were performed using the mixed procedure in SAS version 8.2 (SAS Institute, Cary, NC). We performed two complementary analyses of QOL outcomes following the recommendations of Osoba et al. [51] and Donaldson and Moinpour [52]. First, to examine if changes in QOL outcomes were clinically meaningful, we calculated change scores at each time point relative to baseline by group [51]. Patients were considered improved if their QOL score improved by more than the minimum clinically important difference in that domain (10 points for all QLQC30 domains [35]), as worse if they declined by the same amount, or as unchanged. Fisher’s exact test was used to compare the two groups at each of the three time points. Second, to assess the potential impact of attrition (due to disease progression) and missing data, we examined the association between missingness and observed QOL by using Kendall’s tau rank correlation between covariates (e.g. anemia) for key QOL domains (e.g. global health, fatigue) and the likelihood of having a missing value at a given study time point [53], along with graphical analyses of QOL as a function of proximity to death [49]. These suggested that data were likely not missing at random for QOL (data not shown). We then proceeded with an extreme case sensitivity analysis [53,54]. We used multiple imputation on missing values for patients who were still alive but had not responded at a given time point. Random values were imputed from a normal distribution with mean and variance equalling the observed 20th percentile and the sample variance, respectively, at a given time point. These estimates varied across QOL domains and time points. QOL data were not imputed if a patient was deceased at a given time point. We then repeated our analyses using linear growth curve models incorporating the imputed data. Standard errors

were adjusted for the multiple imputation process and tests of significance were based on an F-test [55]. As data for functional status measures appeared to be missing at random, an extreme case sensitivity analysis was not performed for these outcomes [53]. Finally, as one of the major short-term goals of IC is the achievement of CR, which is associated with prolonged survival compared to patients who do not achieve CR, we examined whether achievement of CR was associated with improved QOL. This latter analysis was restricted to patients who had undergone IC. As this was an exploratory analysis, and given the restrictions associated with our small sample size, these analyses were descriptive in nature.

3. Results 3.1. Baseline characteristics One hundred and thirty seven potentially eligible patients were approached for participation between June 2003 and January 2006, of whom 65 consented to participate. Reasons for non-participation included lack of interest (n = 36), felt too unwell (n = 20), felt too tired (n = 10), too much pain (n = 3), and unknown (n = 3). Compared to participating subjects, non-participants were similar in age and gender distribution (data not shown). QOL and functional status information were not available for non-participants. Baseline data for participating subjects are summarized in Table 1. Thirty percent had unfavorable cytogenetics. No patient had moderate or greater cognitive impairment. Global health was moderately impaired at baseline in comparison to data from the general population [56]. Of the five domains of the QLQ-C30, the most affected were role function and social function; cognitive function was least affected (Table 1). Forty-eight patients (74%) received IC, whereas 17 patients (26%) were in the non-IC group. The non-IC group included patients who received temozolomide (n = 8), decitabine (n = 2), low-dose Ara-C (n = 1), and best supportive care alone (n = 6). In the IC group of patients, 20 (42.6%) achieved CR, compared to 1 patient (5.9%) in the non-IC group. Compared to the non-IC group, patients who received IC were younger (70.2 years versus 77.1 years, p < 0.001) and tended to have slightly better performance status and fewer patients with adverse cytogenetics (Table 1), although neither these variables nor gender, median ECOG score (1 versus 1), or Karnofsky performance status were statistically significantly different (all p-values >0.05, Table 1). At baseline, IC patients had better physical function scores (77 versus 53, p < 0.001) but were otherwise similar to non-IC patients in QOL domains and functional status measures. At 6 months, 69% of patients were alive (75% in the IC group, 53% in the non-IC group, p = 0.002 by the logrank test). There was significant patient attrition over time due to death, disease progression, and other factors, although attrition was similar in the IC and non-IC groups (Table 2).

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Table 1 Baseline characteristics of patients (n = 65) Characteristic

All patients

IC

Non-IC

Sample size Mean age (range) Gender (% male)

65 72.1 (61–86) 71

48 (74%) 70.4 (61–84) 73

17 (26%) 76.9 (66–86) 65

Cytogenetics (%)a Favorable Intermediate Unfavorable

5 66 30

7 67 26

0 61 39

Secondary AML (%) Charlson comorbidity score, mean (range)

40 0.51 (0–3)

38 0.44 (0–3)

47 0.71 (0–3)

ECOG performance status (%) 0–1 2 3+

70 25 5

74 23 2

59 29 12

Karnofsky, mean (range)

75 (20–100)

77 (40–100)

70 (20–100)

Quality of life domains of Global health, mean (range) Physical function, mean (range) Role function, mean (range) Emotional function, mean (range) Cognitive function, mean (range) Social function, mean (range)

49.2 (0–100) 71.0 (0–100) 48.0 (0–100) 74.5 (8–100) 84.4 (0–100) 50.5 (0–100)

51.9 (0–100) 77.5 (40–100) 48.6 (0–100) 76.0 (8–100) 87.2 (33–100) 49.7 (0–100)

41.7 (0–75) 52.6 (0–87) 46.1 (0–100) 70.1 (25–100) 76.5 (0–100) 52.9 (0–100)

Barthel Index, mean (range)c Lawton–Brody Scale, mean (range)d Mini-mental status exam score, mean (range) Geriatric Depression Scale, mean (range)e

96.4 (60–100) 13.6 (3–17) 28.0 (22–30) 3.5 (0–14)

96.9 (60–100) 13.9 (3–17) 28.7 (23–30) 3.0 (0–14)

95.0 (80–100) 12.6 (8–17) 26.2 (22–30) 4.8 (1–9)

QLQ-C30b

AML: acute myeloid leukemia; ECOG: Eastern Cooperative Oncology Group; IC: intensive chemotherapy; QLQ-C30: core 30-item quality of life questionnaire. a Totals may not add up to 100% because of rounding. One patient did not have cytogenetics done and was excluded from this analysis. b Quality of life domains are scaled from 0 to 100, with higher scores representing better function. c Barthel Index scores range from 0 to 100, with higher scores representing greater independence. d Lawton–Brody scale scores range from 0 to 17, with higher scores representing greater independence. e Geriatric Depression Scale scores range from 0 to 15; lower = better. A cut-off of 5 or higher is suggestive of depression.

3.2. Changes in QOL over time and by treatment group There was no evidence of a time-by-treatment group interaction for any QOL variable (Fig. 1), therefore we report a common estimate of change over time for each outcome measure. Over time, global health improved (p = 0.020), as did role function (p = 0.001), social function (p = 0.016), and emotional function (p = 0.047), whereas physical function and cognitive function did not change significantly over time (all p-values > 0.05). Additionally, physical function and emotional function, but not other QOL variables, showed evidence of a constant difference between treatment groups (p = 0.027, 0.049). For both of these variables the IC group maintained higher scores than the non-IC group over time. Depression scores remained stable over time and did not differ between groups (data not shown). 3.3. Changes in functional status over time and by treatment group There was no evidence of a time-by-treatment group interaction for either measure of functional status (Fig. 2),

therefore we report a common estimate of means over time for each outcome measure. Over time, Barthel Index scores remained stable, with mean scores of 96.4, 96.1, 96.7, and 96.7 at baseline, 1 month, 4 months, and 6 months, respectively, in all patients. In contrast, Lawton–Brody scale scores declined slightly between baseline and 6 months (p < 0.05), with mean scores of 13.6, 12.0, 12.7 and 11.9 at baseline, 1 month, 4 months, and 6 months, respectively, in all patients. Receipt of IC was not associated with worsening functional status scores compared with the non-IC group (p > 0.10). 3.4. Clinically important changes in QOL over time In general, change scores from baseline to 1 month, baseline to 4 months, and baseline to 6 months were similar between IC and non-IC patients. The majority of patients improved or remained stable in all QOL domains. Physical function scores improved more in the non-IC group from baseline to both 4 months and 6 months, although the number of patients in the non-IC group at later time points was few (Table 3).

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Table 2 Response rates and reasons for non-completion of study by time points Reason

Therapy

1 month

4 months

6 months

Death (cumulative)

IC Non-IC

4 3

9 7

11 7

Patient withdrew from study (cumulative)

IC Non-IC

0 2

7 3

11 3

Withdrew due to illness

IC Non-IC

0 1

4 1

7 1

Withdrew for personal reasons

IC Non-IC

0 1

3 2

3 2

Unknown

IC Non-IC

0 0

0 0

1 0

Patient refused to complete questionnaire

IC Non-IC

2 0

1 0

0 0

Patient too unwell to complete

IC Non-IC

5 0

3 1

4 0

Other reasons

IC Non-IC

0 0

2 0

1 0

Reason not documented

IC Non-IC

1 0

0 0

0 0

Response rate among enrolled population (%)

IC Non-IC

36/48 (75%) 12/17 (71%)

26/48 (54%) 6/17 (35%)

21/48 (44%) 7/17 (41%)

Response rate among surviving patients (%)

IC Non-IC

36/44 (82%) 12/14 (86%)

26/39 (67%) 6/10 (60%)

21/37 (57%) 7/10 (70%)

IC: intensive chemotherapy; QOL: quality of life. Note: The above data for deaths and withdrawals are cumulative (e.g. the 11 patients who died within 6 months in the IC group include the 4 who died within 1 month and the 9 who died within 4 months).

3.5. Impact of missing data among patients who withdrew In the extreme case sensitivity analysis, changes in QOL over time by treatment group were examined after imputing missing data for patients who withdrew. After adjusting standard errors for the multiple imputation processes, scores in all domains remained stable (all p-values > 0.05). The impact of imputation of missing data is shown for global health in Fig. 3. 3.6. Impact of achieving CR Among patients undergoing IC, achievement of CR appeared to be associated with a modest improvement in the physical function domain compared to IC patients who did not achieve CR, but did appear to impact on global health or other QOL domains (Fig. 4).

4. Discussion Recent studies have demonstrated that patients age 60 or older can achieve CR in 50–60% of cases and, at least in patients with standard risk cytogenetics, this translates

into improvements in overall survival compared to what is generally achieved with supportive care alone [12,57]. However, intensive chemotherapy is associated with significant treatment-related mortality and the survival benefits are modest. As such, it is important for older patients and their clinicians to understand fully the risks associated with intensive chemotherapy, including effects on quality of life and functional status, both of which are important to older adults with cancer. Our study is the largest to date and only the second study to examine QOL in older adults with AML. We found that QOL was affected at baseline primarily in the domains of global health, role function, and social function. Physical function was less affected, in comparison to the study of Sekeres et al. [22]. Although this difference may be due, in part, to patient selection, direct comparisons are difficult because the patient populations are somewhat different and the QOL measures in the two studies were different. Although our study did not feature a comparison group of healthy older adults to contextualize QOL scores among subjects with AML, age-stratified reference data are available from a Norwegian population study of 1965 adult men and women [58]. Compared to men and women aged 70 or older in that study, our patients at baseline had lower global health scores (49 versus 66–70),

Fig. 1. Quality of life over time among patients treated intensively and non-intensively. Specific domains of quality of life shown are global health (panel A), physical function (panel B), role function (panel C), emotional function (panel D), social function (panel E), and cognitive function (panel F).

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Table 3 Change scores over time and by treatment group Outcome

Response

N Global health

Improved Unchanged Worse

Baseline to 1 month

Baseline to 4 months

Baseline to 6 months

IC

Non-IC

IC

IC

36

12

26

36% 53% 11%

25% 50% 25%

32% 44% 24%

p-Value* Physical function

p = 0.525 Improved Unchanged Worse

14% 47% 39%

Improved Unchanged Worse

36% 25% 39%

p-Value* Role function

Emotional function

47% 47% 6%

p-Value* Cognitive function

p-Value*

8% 52% 40%

17% 42% 42%

48% 24% 28%

Improved Unchanged Worse

44% 44% 12%

8% 67% 25%

44% 22% 33%

50% 0% 50%

17% 67% 17%

20% 56% 24%

17% 33% 50%

6% 56% 39%

p = 0.645

44% 24% 32%

50% 0% 50% p = 0.523

71% 0% 29% p < 0.001

50% 28% 22%

57% 0% 43% p = 0.304

39% 44% 17%

29% 57% 14% p = 0.846

33% 22% 44%

p = 0.423 33% 33% 33%

7 43% 43% 14% p = 1.000

p = 0.453

p = 0.297 Improved Unchanged Worse

33% 50% 17%

p = 0.347 25% 67% 8%

31% 44% 25%

67% 17% 17%

Non-IC

21

p = 0.007

p = 0.353

p-Value* Social function

25% 50% 25%

p = 0.374 Improved Unchanged Worse

6 33% 17% 50% p = 0.384

p = 0.550

p-Value*

Non-IC

29% 43% 29% p = 0.645

44% 28% 28%

57% 14% 29% p = 0.856

*

p-Values refer to Fisher’s exact test comparing the distribution of change scores between intensively treated (IC) and non-intensively treated (non-IC) patients.

role function (48 versus 78–83), social function (51 versus 80–82), and emotional function (75 versus 84–88) but similar physical function (71 versus 68–78) and slightly better cognitive function (84 versus 78). Although Hjermstad et al. did not report standard deviations along with mean scores, differences of 5 points between groups were generally statistically significant, and a difference of 10 points or more between groups in a QOL domain was considered moderate to large [58]. Our study is the first to examine functional status in older adults with AML. Among men and women who were highly functional at baseline, basic activities of daily living appear to be relatively intact and instrumental activities of daily living decline slightly over a period of 6 months. Although we found a 1.59 point decline in mean scores in instrumental activities of daily living, it is important to put this loss in context. A 2-point decline on the Lawton–Brody measure is equivalent to going from being independent to requiring some assistance with two of eight functional tasks (e.g. shopping, medication use). Although there are no comparative data in either younger or older adults with AML, and limited data on ADL changes in older patients with cancer, Chen et al.

examined the impact of chemotherapy on 37 patients age 70 or older with a variety of malignancies (excluding AML) [23]. The investigators reported small declines in instrumental ADL between baseline and end of treatment. Although our results are qualitatively similar to those of Chen et al., there are important differences in patient populations, time periods of assessments, and instruments between the two studies that limit direct comparisons. Our results are somewhat surprising, given the intensive treatment and prolonged hospitalizations associated with AML. There are three possible explanations for our findings. First, most of our patients were highly functional at baseline, which may have provided some resistance to functional decline. Additionally, prior to death, patients may have deteriorated rapidly rather than slowly, which may distinguish hematological cancers from solid tumors. Second, our instruments may be relatively insensitive to declines in function, particularly among highly functional older adults at baseline. Third, we may not have measured functional status frequently enough during the 6-month follow-up period to detect declines prior to death. Unfortunately, given the design and limitations of our study, we cannot determine which of these possibilities is correct,

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Fig. 2. Mean scores in instrumental (panel A) and basic (panel B) activities of daily living over time. Patients are stratified into those who received intensive chemotherapy or other treatment.

Fig. 3. Influence of imputing missing data due to non-response or patient withdrawal on global health.

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although based on informal interviews with patients and clinicians, along with self-reported QOL scores in physical and role function domains, the first explanation is at least partially correct. The significant attrition over time in our study, although anticipated given the natural history of AML in this population, warrants careful interpretation of our results. Generally the sickest patients tend to die or withdraw prematurely from studies, leading to apparent improvements in QOL among survivors. Additionally, non-response or study withdrawal among surviving patients is also a concern, although it is less clear if non-responding patients have better or worse health than responders. We attempted to evaluate such possible attrition bias with two complementary techniques. Our primary analysis, which did not explicitly consider attrition, suggested that global health and three of five QOL domains improved over time, whereas physical function and cognitive function did not appreciably change over time. These findings were fairly consistent using both a complete case regression analysis and through comparisons of rates of clinically significant change, although in the latter analysis, physical function appeared to increase more among non-intensively treated patients. Given our small sample size in this group, this preliminary finding warrants replication. When attrition was considered with an extreme case sensitivity analysis, in which we assumed that patients with missing data tended to have fairly poor QOL, global health and every QOL domain remained stable over time regardless of treatment. These discrepant findings highlight the importance of minimizing drop-outs and maximizing participation among sick patients with the use of short, simple questionnaires. Additionally, ignoring missing data from drop-outs can lead to incorrect (usually overly optimistic) conclusions, particularly if dropout rates are different between groups. Can our results inform clinical practice? We believe it is reasonable for physicians to inform their patients who opt for intensive chemotherapy that the majority will likely have stable QOL over time. While this may be hailed as good news by some, an alternate view is that there remains a lag between improved disease outcomes (remission, survival) with intensive chemotherapy and QOL. It is quite possible that with further follow-up beyond 6 months, QOL may improve further, especially in patients who achieve and maintain complete remission. As such, further research is needed to understand the factors that impact on QOL in this population. It is also important to point out that QOL also remains stable in the majority of patients who opt for less aggressive treatment approaches; this information may be of value when counselling patients about treatment options. With respect to functional status, it is reasonable at present for physicians to inform their older patients that a diagnosis of AML has limited impact on functional status over a 6-month period of time if they have a high level of function at baseline. Additionally, patients who opt for intensive chemotherapy can expect no additional adverse impact on their functional status.

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Fig. 4. Quality of life over time among patients stratified by treatment and remission status. Patients treated with intensive chemotherapy were divided into those who achieved or did not achieve complete remission (CR) at 1 month; patients treated non-intensively were analyzed as a group. Specific domains of quality of life shown are global health (panel A), physical function (panel B), role function (panel C), emotional function (panel D), social function (panel E), and cognitive function (panel F).

Our study has several strengths. It is the largest study in this population to date. We used validated self-reported QOL and functional status instruments at key time points. We also included a diverse sample of older patients treated both intensively and non-intensively. Our sample included only patients with AML and we employed a variety of analyses to explicitly examine the impact of attrition. Several limitations must also be kept in mind when interpreting our data. First and foremost, despite being the largest study to date, our sample size is relatively small, particularly in our non-intensively treated group. As such, we may have missed small but clinically important differences in some domains of QOL over time. Additionally, few patients in our study received purely supportive care, limiting our ability to understand the QOL of this group separately from those who received non-intensive investigational agents. Another important limitation involves the non-randomized design of our study. Treatment selection

is predicated on many clinical factors, including disease biology, co-morbid medical conditions, and patient preferences. Some of these factors may have impacted on QOL. However, the primary goal of our study was to examine changes in health outcomes over time within each group. Between-group comparisons were a secondary objective and should be viewed as hypothesis-generating. Such comparisons can only be properly addressed in randomized trials. Importantly, we have demonstrated the feasibility of measuring QOL and functional status in such patient groups. It is also important to note that our sample included older men and women who were highly functional and independent at baseline. Whether older adults with functional limitations at baseline, who would likely be more frail and have less reserve, would have similar outcomes cannot be determined from our data. This is an important area for future research in geriatric oncology. Finally, since all of our patients were enrolled from a single institution and were fluent in

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English, our findings may not be generalizable to other settings. In summary, AML is associated with a significant impact on the QOL of older adults at the time of diagnosis. Over time, QOL generally remains stable. Receipt of intensive chemotherapy does not appear to lead to worse QOL than best supportive care, although this observation must be viewed cautiously in light of the aforementioned limitations. Among patients with high functional status at baseline, there is a slight decline in IADL and no decline in basic ADL over 6 months, regardless of treatment. Future studies need to focus on understanding the gap between clinical improvement and QOL as well as better understanding QOL and functional status in more frail populations with AML and among those who opt for purely supportive care.

Reviewers Shinsaku Imashuku, MD, PhD, Kyoto City Institute of Health and Environmental Sciences, 1-1 Higashitakada-cho, Mida, Nakagyo-ku, Kyoto 604, Japan. William Dale, MD, PhD, Assistant Professor of Medicine, University of Chicago, Section of Geriatrics, Department of Medicine, MC6098, 5841 South Maryland Ave, Chicago, Illinois 60637, United States. Janette Vardy, MD, PhD, Medical Oncologist, Sydney Cancer Centre, Concord Repatriation General Hospital, Hospital Road, Concord, New South Wales, 2139, Australia.

Acknowledgements This study was supported by a grant from the Canadian Institutes of Health Research. Dr. Alibhai is a Research Scientist of the National Cancer Institute of Canada. This study was also supported in part by the Toronto Rehabilitation Institute and by unrestricted funds from the Ontario Ministry of Health. We would like to thank the physicians and nurses in the Leukemia Program at the Princess Margaret Hospital for their support and all of the study patients for their participation.

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Biography Shabbir M.H. Alibhai is an assistant professor in the Departments of Medicine and Health Policy, Management, and Evaluation at the University of Toronto. He is a staff physician and researcher at the University Health Network and Toronto Rehabilitation Institute, and a Research Scientist of the National Cancer Institute of Canada. His research interests are in geriatric oncology, particularly in understanding the impact of treatment on quality of life and related areas in older people with acute leukemia or prostate cancer.