Quality of life beyond 6 months after diagnosis in older adults with acute myeloid leukemia

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1 Critical Reviews in Oncology/Hematology 69 (2009) Quality of life beyond 6 months after diagnosis in older adults with acute myeloid leukemia Shabbir M.H. Alibhai a,b,d,e,, Marc Leach a, Vikas Gupta c,d, George A. Tomlinson a,f, Joseph M. Brandwein c,d, Fernando Suarez Saiz c, Mark D. Minden c,d a Division of General Internal Medicine & Clinical Epidemiology, University Health Network, Toronto, Canada b Geriatric Program, Toronto Rehabilitation Institute, Toronto, Canada c Department of Medical Oncology & Hematology, Princess Margaret Hospital, Toronto, Canada d Departments of Medicine, Toronto, Canada e Health Policy, Management and Evaluation, Toronto, Canada f Public Health Sciences, University of Toronto, Toronto, Canada Accepted 17 July 2008 Contents 1. Introduction Materials and methods Patients Outcome measures Statistical analysis Results Baseline characteristics Initial and subsequent treatment Changes in QOL over time Impact of complete remission on QOL Discussion Reviewers Conflict of interest statement Acknowledgements References Biography Abstract Although intensive chemotherapy may improve survival in older people with acute myeloid leukemia (AML) without adverse cytogenetics, its impact on quality of life (QOL) is mixed and most patients complain of fatigue up to 6 months after diagnosis. Little information is available on longer-term QOL outcomes. We prospectively followed 20 patients age 60 or older with AML who provided QOL data more than 6 months after diagnosis. Over the first 6 months, there were clinically important improvements in global health, role function, social function, and emotional function. Physical function and cognitive function were stable over time. Over the next 6 months, social function and fatigue improved, and other domains remained stable. Achievement of complete remission appeared to be associated with improvements in global health, physical function, and role function without negatively affecting other health domains. This information may aid discussions with patients about treatment Elsevier Ireland Ltd. All rights reserved. Keywords: Aged; Acute myeloid leukemia; Quality of life; Functional status; Treatment Corresponding author at: University Health Network, Room EN , 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4. Tel.: ; fax: address: shabbir.alibhai@uhn.on.ca (S.M.H. Alibhai) /$ see front matter 2008 Elsevier Ireland Ltd. All rights reserved. doi: /j.critrevonc

2 S.M.H. Alibhai et al. / Critical Reviews in Oncology/Hematology 69 (2009) Introduction Quality of life (QOL) has been shown to be significantly affected at the time of diagnosis of acute myeloid leukemia (AML) in patients age 60 or older [1,2]. In addition, fatigue is the most common, distressing, and persistent symptom in these patients [3]; it impacts adversely on QOL, leads to restrictions in activities, and is particularly severe during chemotherapy. We have previously shown stable or slightly improving QOL over the 6 months after diagnosis in patients age 60 or older with AML, but little impact on fatigue during the same time frame. Additionally, there was little improvement over 6 months in either QOL or fatigue with achievement of complete remission [2,3]. During the first 6 months after diagnosis of AML, patients undergo multiple cycles of chemotherapy, which may have deleterious short-term effects on QOL and fatigue [4 7]. Additionally, the majority of older patients without adverse-risk cytogenetics who undergo intensive chemotherapy can expect to live at least 1 year after diagnosis [8 10]. Whether QOL and fatigue improve beyond the initial 6 months of diagnosis, after most surviving patients have undergone successful intensive chemotherapy and achieved complete remission (CR), is important for both patients and their physicians. Thus, understanding the longer-term QOL issues in this population is important. Only one prior study has reported QOL outcomes beyond 6 months in older patients with AML [1]. In that study, of 21 patients age 60 or older at baseline who underwent intensive chemotherapy, 9 patients and 5 patients provided QOL data at 6 months and 12 months, respectively. In general, overall QOL appeared to improve based on responses of 5 patients who survived to 12 months, although details were not provided and domain-specific QOL information and results with respect to fatigue were not available. Thus, there is virtually no information on QOL and fatigue outcomes beyond 6 months in older adults with AML. We had previously recruited and followed a group of 65 patients age 60 or older with AML, evaluating QOL and fatigue [1,3]. Patients were followed out to 6 months, at which time 75% of patients undergoing intensive chemotherapy were alive. In the current study, we extended follow-up among 6-month survivors for an additional 6 months. 2. Materials and methods 2.1. Patients Study design and patient recruitment have been described in detail previously [2]. In brief, we approached consecutive, newly diagnosed, English-speaking patients age 60 or older with AML prior to starting chemotherapy. Patients with another active malignancy or life expectancy of less than 1 month were excluded. Patients were recruited from the Princess Margaret Hospital (PMH), an academic tertiary care cancer center and the major referral center for most patients with acute leukemia in the Greater Toronto Area (catchment area of 4.5 million). Follow-up visits were conducted at 1 month, 4 months, 6 months, 9 months, and 12 months. All patients provided written, informed consent. The study was approved by the PMH Research Ethics Board. The majority of patients underwent intensive chemotherapy (IC). IC consisted of one or two courses of induction chemotherapy (3 days of daunorubicin 60 mg/(m 2 day) 1 and 7 days of cytosine arabinoside (Ara-C) 100 mg/(m 2 day) 1 ). Patients who did not achieve CR with the first course of induction received mitoxantrone (10 mg/(m 2 day) 1 ) and etoposide (100 mg/(m 2 day) 1 ) each for 5 days and highdose Ara-C (1 g/m 2 q12h for four doses) (NOVE-HiDAC protocol) as second induction. Patients who achieved CR after first induction went on to immediate consolidation chemotherapy. First consolidation consisted of the same regimen as induction. Most patients received a second consolidation with mitoxantrone (10 mg/(m 2 day) 1 ) and etoposide (100 mg/(m 2 day) 1 ) each for 5 days Outcome measures QOL was measured with the European Organization for the Research and Treatment of Cancer core 30-item questionnaire (QLQ-C30), and fatigue was measured with the Functional Assessment of Cancer Therapy (FACT) Fatigue (FACT-F) subscale. The QLQ-C30 features a global health measure, five functional scales (physical, role, cognitive, emotional, and social), and several symptom scales or items [11]. A 10-point difference in QOL on either the global health measure or functional scale of the QLQ-C30 is clinically important [12]. Similarly, a 3-point difference in FACT-F is clinically important [13] Statistical analysis In the current analysis, we included all patients who attended at least one follow-up visit beyond 6 months. Remission status was recorded at 6 months. Comparisons of baseline characteristics among participants who did or did not provide QOL data beyond 6 months were performed using Student s t-test and the chi-square test for continuous and categorical variables, respectively. We explored the impact of achieving CR on QOL outcomes by comparing mean QOL scores for each domain at each time among patients who had or had not achieved CR at the 6-month time point. Due to the small number of patients with follow-up beyond 6 months (n = 20), our longitudinal analyses were primarily descriptive. No attempt was made to impute missing data. Where formal statistical comparisons were performed, a p-value of 0.05 was considered significant. Analyses were performed using SAS version 8.2 (SAS Institute, Cary, NC).

3 170 S.M.H. Alibhai et al. / Critical Reviews in Oncology/Hematology 69 (2009) Results 3.1. Baseline characteristics A total of 65 patients (mean age 72.1 years, 71% male) were enrolled between June 2003 and January Of these, 20 patients provided QOL data beyond 6 months. Of the remaining 45 patients, 18 had died, 14 were too ill to continue participating, and 5 patients were missed at 6 months. The remaining eight patients provided data up to and including the 6-month visit but did not provide data beyond 6 months; they were therefore excluded from further analyses. Baseline data for patients who did and did not provide QOL data beyond 6 months are summarized in Table 1. In general, patients who provided QOL data beyond 6 months were slightly younger, composed of relatively more women, and had a better cytogenetic profile compared to patients who did not provide data beyond 6 months. In terms of QOL, patients who provided QOL data beyond 6 months had better baseline physical function and less fatigue, but were otherwise comparable to patients who did not provide data beyond 6 months. Among the 20 patients, global health was moderately impaired at baseline, as were role function and social function. Emotional function was less affected, whereas both physical function and cognitive function were relatively preserved. At baseline, 100% of patients reported some degree of fatigue Initial and subsequent treatment Nineteen of the 20 patients (95%) underwent intensive chemotherapy, and one patient received temozolomide (an oral investigational agent) monotherapy; 14 (70%) were in CR at the 6-month assessment. Between months 1 and 4, 12 patients received 1 or 2 rounds of consolidation chemotherapy, 4 underwent reinduction with NOVE-HiDAC, 3 received temozolomide (2 of whom had failed induction and the third had achieved CR with temozolomide monotherapy), and 1 received maintenance chemotherapy with 6-mercaptopurine and methotrexate. Between months 4 and 6, 6 patients received one more round of consolidation, 2 received temozolomide, 2 received maintenance chemotherapy, and 10 received no further chemotherapy. Among patients in CR at 6 months, 6 received no further treatment between months 6 and 9, 2 underwent further consolidation chemotherapy, 3 received temozolomide, 1 underwent peripheral stem-cell transplantation, and 2 received maintenance chemotherapy. Among patients not in remission at 6 months, 4 received no further chemotherapy and 2 received decitabine, another investigational nonintensive chemotherapy agent over the next 3 months. Between 9 and 12 months, of patients in CR at 6 months, 4 received no further chemotherapy, 1 underwent consolidation, 2 had relapses and underwent reinduction with NOVE-HiDAC, 2 received temozolomide, and 1 received maintenance chemotherapy. Of patients not in CR at 6 Table 1 Baseline characteristics of patients who did (n = 20) and did not (n = 45) provide quality of life data beyond 6 months after diagnosis Characteristic Patients with data beyond 6 months Patients without data beyond 6 months p-value* Sample size Mean age, years (range) 69.6 (62 77) 73.2 (61 86) p = Gender, % male 55% 78% p = 0.062# Cytogenetics a p = 0.416# Favorable 5% 4% Intermediate 80% 60% Unfavorable 15% 36% ECOG performance status, mean (range) 0.9 (0 3) 1.2 (0 4) p = Karnofsky, mean (range) 78.0 (40 100) 73.6 (20 100) p = Treatment p = 0.010# Intensive chemotherapy 95% 64% Other 5% 36% FACT-F b, mean (range) 35.4 (16 48) 30.6 (1 52) p = Quality of life domains of QLQ-C30 c Global health, mean (range) 52.5 (0 83) 47.8 (0 100) p = Physical function, mean (range) 80.3 (40 100) 66.8 (0 100) p = Role function, mean (range) 50.8 (0 100) 46.7 (0 100) p = Emotional function, mean (range) 70.0 (8 100) 76.5 (8 100) p = Cognitive function, mean (range) 85.0 (33 100) 84.1 (0 100) p = Social function, mean (range) 52.5 (0 100) 49.6 (0 100) p = *t-test unless otherwise specified; # Chi-square. FACT-F: Functional Assessment of Cancer Therapy Fatigue subscale; QLQ-C30: European Organization for the Research and Treatment of Cancer 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 FACT-F scores range from 0 to 52, with higher scores representing less fatigue. c Quality of life domains are scaled from 0 to 100, with higher scores representing better function.

4 S.M.H. Alibhai et al. / Critical Reviews in Oncology/Hematology 69 (2009) Fig. 1. Mean scores for global health and five domains of quality of life over time among patients followed out beyond 6 months after diagnosis. In the above figure, mean scores for patients providing quality of life data at that time point are depicted. Changes of at least 10 points are considered clinically significant. Higher scores are associated with better quality of life. months, 1 received no therapy and 2 received decitabine during this time Changes in QOL over time Over 12 months, mean global health improved from 52.5 at baseline to 68.6 at 12 months. Role function improved dramatically from 50.8 to 73.1, as did social function (from 52.5 to 80.8). Emotional function improved from 70.0 to Physical function and cognitive function appeared to remain stable over time. These data are summarized in Fig. 1. Fatigue scores improved from 35.4 to 40.2 over 12 months, and are shown in Fig. 2. Over time, the percentage of patients reporting some degree of fatigue was 95%, 100%, 89%, 84%, and 85% at 1 month, 4 months, 6 months, 9 months, and 12 months, respectively. Among these 20 patients, most of the improvements in QOL domains occurred in the first 6 months. Social function and fatigue were the two aspects of QOL that continued to improve between 6 months and 1 year after diagnosis (Figs. 1 and 2). Global health and the other QOL domains remained relatively stable in months 7 12 after diagnosis. Fig. 2. Mean FACT fatigue scores over time. In the above figure, mean fatigue scores are shown for all responding patients at that time point. Higher scores are associated with less fatigue Impact of complete remission on QOL Achievement of CR by 6 months appeared to be associated with better QOL outcomes in some but not all domains. Specifically, in the domains of global health, physical function, and role function, patients in CR appeared to have better QOL (i.e. a difference of at least 10 points) than patients who had not achieved CR (Fig. 3). However, due to small sample sizes, confidence intervals around individual estimates were wide. In other domains, the two groups were generally similar at most time points (Fig. 3). 4. Discussion Our study is the largest QOL study of older adults with AML. It extends the findings of our previous study, in which we demonstrated adverse effects on QOL between baseline and 6 months after diagnosis of AML [2]. Our current analysis demonstrates that most domains of QOL appear to exhibit clinically important improvements over 12 months after diagnosis, along with some improvements in fatigue over the same time frame. Among patients who survive and provide QOL data beyond 6 months, our results suggest that much of the improvement occurs within the first 6 months after diagnosis, during which time most patients would have completed intensive chemotherapy. Beyond the first 6 months, social function and fatigue continued to improve, and other QOL domains remained relatively stable. There was no evidence of deterioration in any health domain that we assessed. Only one prior study has reported QOL outcomes beyond 6 months in older patients with AML [1]. In that study, of 21 patients at baseline who underwent intensive chemotherapy, 9 patients and 5 patients provided QOL data at 6 months and 12 months, respectively. In general, overall QOL, measured by the FACT general questionnaire, suggested improvement among the 5 patients who survived to 12 months, although details were not provided and domain-specific QOL information was not available.

5 172 S.M.H. Alibhai et al. / Critical Reviews in Oncology/Hematology 69 (2009) Fig. 3. Changes in mean quality of life scores by domain among patients who achieved or did not achieve complete remission by 6 months. In the above figure, mean scores in each domain of quality of life are shown for all responding patients at that time point, separated into those who did or did not achieve complete remission by 6 months. Higher scores are associated with better quality of life and less fatigue. Error bars represent ±1.96 standard errors of the mean.

6 S.M.H. Alibhai et al. / Critical Reviews in Oncology/Hematology 69 (2009) Given the limited published information to date, we believe that our results provide valuable additional information about QOL in older people with AML who survive at least 6 months after intensive treatment. This should come as welcome news to older patients with AML who select intensive chemotherapy and the clinicians who counsel and treat these patients. While intensive treatment is associated with significant toxicities, a sizable proportion of patients with non-high-risk cytogenetics achieve complete remission and remain disease-free at 12 months. For these patients, our data suggest that QOL appears to improve significantly over time, particularly in areas of role function and social function, as well as, to a lesser extent, both global health and emotional function. Fatigue also appears to steadily improve out to 12 months of follow-up, although the mean change in fatigue score was relatively small (about 5 points over 12 months, with 3 points being the minimal clinically important difference [13]), and most patients continue to report some degree of fatigue. This suggests that fatigue remains an important symptom 12 months after diagnosis and treatment. Cancer-related fatigue is likely due to multiple factors [14,15], and although the acute side effects of chemotherapy have mostly resolved by 6 12 months, other modifiable risk factors need to be identified and intervention studies designed if we are to achieve greater gains in QOL in this group of patients. Our study is also the first to describe the impact of achieving CR on QOL outcomes among older adults with AML. Although our analyses were purely descriptive by virtue of a small sample size and an exploratory analysis, they provide interesting insights into possible QOL benefits of CR. Beyond its obvious positive impact on overall survival, achieving CR may be associated with improvements in global health, physical function, and role function, without major deleterious effects over 12 months on other QOL domains. Effects on fatigue are less clear. These findings are preliminary and must be viewed cautiously. Further research is clearly warranted. Several limitations must be kept in mind when interpreting our data. First and foremost, our sample size is quite small, and precluded formal statistical explorations. There was significant attrition over time, much of which is to be expected due to the nature of AML. It is quite possible that patients who dropped out of the study had poorer outcomes than remaining participants. However, our study design and sample size did not allow us to formally evaluate this issue. Moreover, the impact of attrition may have particularly impacted on estimates of QOL at the 12-month time point. Although virtually all of our patients underwent intensive chemotherapy and survived beyond 6 months and are therefore a select group, this group is becoming increasingly common, particularly in larger centers. Additionally, few patients who opt for best supportive care will survive beyond 6 months [16]. Thus our findings regarding QOL and fatigue are clinically relevant for that population of patients who survives beyond 6 months after diagnosis, most of whom have undergone intensive chemotherapy and achieved complete remission. Our small sample size also precluded our ability to perform statistical analyses (including handling remission status and subsequent treatments as time-varying covariates) on the impact of complete remission on health outcomes. This area warrants further study. Additionally, since all of our patients were enrolled from a single institution and were fluent in English, our findings may not be generalizable to other settings and patient groups. In summary, among older patients with AML who undergo intensive chemotherapy and survive beyond 6 months, there is suggestion of improvement in most domains of QOL and global health over time, with some reduction in fatigue. These results must be viewed with caution in light of our small sample size and patient attrition, and warrant replication with a larger cohort of patients. Reviewers Lillian Sung, M.D., F.R.C.P.C., The Hospital for Sick Children, Division of Hematology/Oncology, 555 University Avenue, Toronto, ON M5G1X8, Canada. Janette Vardy, M.D., Ph.D., Sydney Cancer Centre, Concord Repatriation and General Hospital, Department of Medical Oncology, Hospital Road, Concord, Sydney 2139, Australia. Conflict of interest statement None of the authors have any financial conflicts of interest to declare. 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 for their support and all of the study patients for their participation. References [1] Sekeres MA, Stone RM, Zahrieh D, et al. Decision-making and quality of life in older adults with acute myeloid leukemia or advanced myelodysplastic syndrome. Leukemia 2004;18(4): [2] Alibhai SMH, Leach M, Kermalli H, et al. The impact of acute myeloid leukemia and its treatment on quality of life and functional status in older adults. Critical Reviews in Oncology/Hematology 2007;64: [3] Alibhai SM, Leach M, Kowgier ME, Tomlinson GA, Brandwein JM, Minden MD. Fatigue in older adults with acute myeloid leukemia:

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