Originally published as JCO Early Release 10.1200/JCO.2005.05.751 on August 8 2005

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Role of Depression As a Predictor of Mortality Among Cancer Patients After Stem-Cell Transplantation

From the Department of Psychiatry, Clinical Institute of Psychiatry and Psychology; and Stem-Cell Transplantation Unit, Department of Hematology, Institute of Hematology and Oncology, IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona, Spain

Address reprint requests to Jesús M. Prieto, MD, Espronceda 43 B, 17480 Roses, Spain; e-mail: jmprieto{at}comg.es

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: To determine the association between depression and survival among cancer patients at 1, 3, and 5 years after stem-cell transplantation (SCT).

PATIENTS AND METHODS: This was a prospective cohort study of 199 hematologic cancer patients who survived longer than 90 days after SCT and who were recruited in a University-based hospital between July 1994 and August 1997. Patients received a psychiatric assessment at four consecutive time points during hospitalization for SCT, yielding a total of 781 interviews. Depression diagnoses were determined on the basis of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.

RESULTS: Eighteen (9.0%) and 17 patients (8.5%) met criteria for major and minor depression, respectively. Multivariate Cox regression models found major depression to be predictive of higher 1-year (hazard ratio [HR], 2.59; 95% CI, 1.21 to 5.53; P = .014) and 3-year mortality (HR, 2.04; 95% CI, 1.03 to 4.02; P = .041) but not 5-year mortality (HR, 1.48; 95% CI, 0.76 to 2.87; P = .249). Minor depression had no effect on any mortality outcome. Other multivariate significant predictors of higher mortality were higher regimen toxicity in the 1-, 3-, and 5-year models; older age and acute lymphoblastic leukemia in the 3- and 5-year models; chronic myelogenous leukemia in the 3-year model; and lower functional status and intermediate/higher risk status in the 5-year model. Use of peripheral-blood stem cells predicted lower mortality in the 5-year model.

CONCLUSION: After adjusting for multiple factors, major depression predicted higher 1- and 3-year mortality among cancer patients after SCT, underscoring the importance of adequate diagnosis and treatment of major depression.

	INTRODUCTION

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Depression, which is defined by a wide variety of measures, has been associated with higher rates of mortality in a number of different clinical and community samples.^1-13 This association has been best established in patients with cardiovascular disease.^1-4 The question as to whether depression influences survival among patients with cancer has also been the subject of many research studies. Although the literature on this issue is divided, most authors suggest a connection.^9-13 In a recent literature review of 24 published studies, 15 reported positive associations between depression and cancer progression or mortality.⁹

Methodologic shortcomings in the cancer survival literature include retrospective designs, sampling bias, small sample size, the use of only one-time measurement of depression, and inadequate appraisal of the complex interrelations between depression and other predictors of death.^4,9 Moreover, most of the studies published have defined depression by using different patient-rated depression scale scores at a level suggestive of a clinical diagnosis, without using structured clinical interviews and/or standardized diagnostic criteria.^4,9 In contrast with depression as defined by standardized diagnostic criteria that take into account the overall time course of depressive symptoms to diagnose a depressive episode, patient-rated depression scales are limited by their ability to only assess depressive symptomatology within the last week of evaluation, with a consequent risk of misclassifying persons as depressed as a result of stressful life circumstances or health problems present at that moment.

Hematopoietic stem-cell transplantation (SCT) represents a highly aggressive and demanding medical therapy that has a profound impact at a physical and psychological level.^14,15 It is associated with severely toxic side effects, invasive medical procedures, frequent medical complications, and the risk of mortality from the procedure itself. Regarding studies on survival after SCT, only one prospective investigation with more than 100 patients examined the relationship between depression and mortality.¹² With a sample of 193 patients, Loberiza et al¹² found that depression was predictive of earlier mortality (between 6 and 12 months after SCT) but not later mortality (between 13 and 42 months after SCT). However, this study was limited because it used a nonvalidated measure of depression (a checklist of depression symptoms created by the authors) and measured depression only at 6 months after SCT. In a recent study of a sample of 72 patients, Akaho et al¹⁶ found that a psychological variable (a mixture of depression, anxiety, anger, fatigue, and confusion) evaluated 2 weeks before SCT was predictive of earlier mortality (between 3 and 8 months after SCT) but not later mortality (between 1 and 3 years after SCT). Oncologic studies investigating the impact of depression on survival may present contradictory results because of, in part, the length of the follow-up period.⁹ As survival time is extended, other intervening factors are more likely to account for mortality, thereby obscuring any possible relationship between depression and mortality.⁹ Most deaths after SCT occur within the first 3 years of the intervention, and the most acute reduction of the survival rates is observed within a period of 12 to 24 months after transplantation.¹⁷ Therefore, we considered it to be clinically relevant to study risk factors for short-, intermediate-, and long-term mortality after SCT. Specifically, the purpose of the current article was to study the effect of depression on 1-, 3-, and 5-year mortality after SCT. We evaluated depression with standardized diagnostic criteria (Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition¹⁸ [DSM-IV]) at four consecutive time points during hospitalization for SCT. Because depression is common in patients with cancer,^9,19,20 an association between depression and mortality would be of significant clinical importance. Effective treatment for depression is available; therefore, early recognition of the condition and adequate treatment could improve medical outcomes, such as survival after SCT.

	PATIENTS AND METHODS

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Patients
The methods used have been described in detail elsewhere.¹⁵ Briefly, patients were consecutively recruited from the SCT Unit, Hospital Clinic, Barcelona, between July 21, 1994, and August 8, 1997. Inclusion criteria were hematologic malignancy, an age of at least 16 years, no prior SCT, and verbal informed consent. In the current study and because of our intention to analyze the effect of the more prevalent DSM-IV depression groups (ie, major and minor depression), we excluded from analyses the only patient who was diagnosed with dysthymia not comorbid with major depression.

Procedures
As part of the pretransplantation assessment protocol, hematologists first informed their patients about the study evaluation of quality of life and psychosocial aspects related to SCT. On their admission to the transplantation unit, the research psychiatrist gave detailed information about the protocol design, objectives, and applicability of the study. Depression interviews were carried out at hospital admission and, subsequently, on a weekly basis from day of SCT (day 0) until discharge or death (days +7, +14, +21, and so on). To limit the number of dropouts (mainly as a result of hospital discharge), we used only medical and depression data from the hospital admission interview until the day +14 interview. At hospital admission, a Karnofsky performance status score²¹ was obtained from the hematologist. This scale is an index of physical disability developed for the evaluation of oncology patients, in which lower scores reflect greater impairment. After discharge, using a standardized form, the first author (J.M.P) abstracted medical diagnoses, laboratory results, vital signs, psychotropic treatment, and pertinent clinical data required to rate the Bearman Regimen Toxicity Scale²² and also reviewed medical and nursing records to compile all written information that might relate to the patient's psychological status during hospitalization. The data abstractor was formally blinded to the survival time of each patient. The Bearman Regimen Toxicity Scale is used to specifically rate the complications caused by chemotherapy or chemoradiotherapy during hospitalization for SCT, with higher scores reflecting higher toxicity. We derived mortality data by searching medical records and making follow-up calls. All reported deaths were verified by the patient's hematologist.

Psychopharmacologic treatments were prescribed either by the corresponding hematologist or by the research psychiatrist. Psychiatric intervention (pharmacologic treatment and/or brief psychotherapeutic sessions) could be prompted by referral by the hematologist or by decision of the research psychiatrist in accordance with the hematologist. No attempt was made to influence the amount or type of psychiatric therapy administered to patients. The clinical research protocol was reviewed and approved by the Department of Psychiatry's Committee on Clinical Research.

Depression Assessment
In a checklist format, the criterion items required for the DSM-IV depressive disorders were rated during the interview by the clinician as absent, subthreshold, or present during the past week. The alterations in some depressive symptoms, such as anorexia and fatigue, as a direct result of the neoplastic process or cytotoxic treatment present a methodologic problem for the diagnosis of depression in cancer patients.^9,19,20,23 Strict or unmodified DSM-IV criteria require a symptom to be counted toward the diagnosis of depression only if it is thought not to be caused by cancer or its treatment, with a consequent risk for underdiagnosis in the SCT setting. In our study population, the percentages of patients with the DSM-IV criterion item for loss of appetite rated as present at the time of hospital admission and at the following three weekly evaluations were 30.9%, 76.9%, 88.3%, and 85.1%, respectively, whereas for the DSM-IV fatigue criterion, these figures were 30.9%, 76.9%, 88.3%, and 85.1%, respectively (unpublished data). As in our previous report,¹⁵ we used a modified DSM-IV approach to diagnose major depression. For research purposes, the Memorial Sloan-Kettering Cancer Center (MSKCC) –modified DSM-IV approach is the best of the four possible diagnostic models available because it maximizes specificity.²³ It ensures the most homogeneous depressed group possible, with the fewest confounding variables, thereby increasing the clinical and statistical significance of the research data.²³ The MSKCC method eliminates anorexia and fatigue from the list of nine major depression criteria and requires only four (instead of five) of the remaining seven symptoms for diagnosis. To diagnose minor depression, we required two or three out of the seven symptoms in the MSKCC method. For diagnosis of a major or minor depression, the minimum required symptom criteria had to persist for most of the day, nearly every day, for at least 2 consecutive weeks (temporal criterion). If, in a particular weekly interview, a patient met symptom criteria for major depression and, in the following interview, met symptom criteria for minor depression, a diagnosis of minor depression was established. If, at the following interview, this patient did not meet criteria for any depression, the diagnosis was no depression. An episode of major depression may fluctuate in symptom severity over time. At the time of the first hospital interview, we explored the presence of a major or minor depressive episode during the previous weeks before hospital admission. A major depressive episode in partial remission was diagnosed when symptoms of a major depressive episode had been present during the previous weeks but minimum symptom criteria were not met at the time of the interview or there was a period without any significant symptoms of a major depressive episode lasting less than 2 months after the end of the major depressive episode.¹⁸ In accordance with DSM-IV criteria, patients with minor depressive episodes in partial remission were considered as having no depression. For the purposes of the present study, each patient was placed in one of the following three groups: no depression, minor depression (only current criteria), and major depression (whether currently meeting criteria or in partial remission).

Three interviewers participated in the study; the main investigator was a psychiatrist (J.M.P.), and the two other interviewers were a fourth-year psychiatric resident (J.A.) who participated in the study for the first 11 months and a psychiatrist (J.B.) who participated in the rest of the study. Each patient was interviewed by only one of the interviewers. Consensus diagnostic meetings were held every 2 months. At the meetings, the corresponding psychiatric interviewer reported the patient's psychological status from multiple data sources, including all weekly DSM-IV depression checklists, additional information from direct interviews (appearance, facial expression, attitude, and degree of collaboration), past personal and family psychiatric history obtained from the patient, opinions of the doctor and nurse responsible for the patient during hospitalization, opinions of the family regarding the past and current psychological status, and information from medical and nursing records regarding the medical and psychological status. The clinical presentation of each patient was meticulously reviewed in relation to the presence or absence of depressive symptoms on the DSM-IV depression checklists. After reviewing and discussing all available clinical data, diagnoses of depression were decided by consensus of two psychiatric interviewers (J.M.P. and J.A. or J.B.) with strict observance of the DSM-IV criteria. No inter-rater reliability assessment was carried out.

Statistical Analysis
To avoid mixing the acute risk of death associated with the transplantation procedure with the relation that may exist between depression and mortality, our primary analysis was performed in patients surviving longer than 90 days after SCT. The analysis was also performed in patients surviving longer than 30 days after SCT. Univariate and multivariate Cox proportional hazards models were used to determine the effect of independent predictors on survival times. Separate Cox models for 1-, 3-, and 5-year mortality were used to analyze the short-, immediate-, and long-term effects of depression on mortality after SCT. Survival time was measured in days from the date of SCT (day 0) to the date of cancer- or transplantation-related death or was censored at the corresponding 1-, 3-, or 5-year point after SCT. For the 1-year mortality model, all patients who were alive at 1 year were censored, including patients who died in years 2 to 5 after SCT. The 3- and 5-year mortality models were not conditional on living 1 and 3 years, respectively. For the 3- and 5-year mortality models, we analyzed the same sample of patients used for the 1-year mortality model, except that patients who were alive at 3 years were considered as censored in the 3-year mortality model and patients alive at 5 years were considered as censored in the 5-year mortality model. Baseline variables used as potential predictors were chosen a priori based on past work in the field and because of their clinical relevance.^4,9,12,19,20 We also included a variable encoding the year of study entry as an adjustment for practice variations. Risk factors evaluated at the time of hospital admission included age (continuous variable), sex, marital status (married or cohabitating v other), education (< 8 v > 8 years), admission Karnofsky score (90 to 100 v < 90), hematologic cancer diagnosis (acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, and other), disease risk status (low, intermediate, and high),²⁴ conditioning regimen (chemotherapy v chemoradiotherapy), type of SCT (autologous or syngeneic v allogeneic), source of stem cells (peripheral blood only or combined with bone marrow v bone marrow), smoking history (yes v no), dangerous alcohol intake (yes v no),²⁵ and period of study entry (July 1994 to June 1995, July 1995 to June 1996, and July 1996 to August 1997). Risk factors evaluated from hospital admission until day +14 after SCT included DSM-IV depression diagnosis (no, minor, and major depression), regimen toxicity score (continuous variable), graft-versus-host disease (grades 0 to 1 v 2 to 4), and documented infection (yes v no). We dichotomized, at a clinically relevant point, the Karnofsky score because its distribution was highly skewed.

All risk factors (except for the depression variable) with P < .20 in univariate analysis were included in a single multivariate model. The factors found to be significant in this single multivariate model plus a term for the depression variable were all included in a final multivariate model. Because age, sex, disease risk status, Karnofsky performance status, and regimen toxicity can be associated with depression,^4,9,19,20 all possible interaction terms between depression and these variables were tested in the final multivariate models. The proportional hazards assumption for all variables was examined using interactions between covariates and time and also by inspection of log minus log curves. Construction of time-dependent covariates was used whenever nonproportional variables were identified. Because of potentially unmeasured clinical variables associated with type of SCT and because there is an intrinsic difference in the risk of death,¹² all univariate and multivariate models were stratified according to type of SCT. No information was missing for any of the predictor variables. For this exploratory study, no adjustment of the alpha level for multiple tests was made. Statistical analyses were performed using the Statistical Package for the Social Sciences version 11.5 (SPSS Inc, Cary, NC).

	RESULTS

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Of 253 patients who received a SCT during the 3-year recruitment period, 234 met the eligibility criteria. Because of scheduling difficulties, 15 patients could not be interviewed at the first assessment and were excluded from the study. All patients who were approached agreed to be interviewed. Thus, the study cohort included 93.6% of the eligible population (219 of 234 patients). There were no differences in age, sex, hematologic diagnosis, or disease risk status between the 219 patients who participated in the study and the 15 patients who were excluded (P > .20). Among these 219 patients, 199 (90.9%) survived longer than 90 days after SCT. A total of 781 (98.1%) of 796 possible psychiatric assessments with DSM-IV were conducted at four consecutive time points from hospital admission to day +14 (199, 198, 197, and 187 assessments at the four time points). Missing observations were a result of compromised medical status (one at day 0, two at day +7, and four at day +14) or a result of scheduling difficulties (five at day +14). Attrition was a result of hospital discharge (three patients were discharged by the day +14 interview). Complete 5-year follow-up data were obtained for all patients except one, who was censored at the time of last hospital contact. Only one patient died from a cause (suicide) other than a cancer- or transplantation-related death and was censored at the time of death.

Table 1 lists the baseline characteristics of patients surviving longer than 90 days after SCT. Of these 199 patients, 18 (9.0%), 17 (8.5%), and 164 (82.5%) met modified DSM-IV criteria for major, minor, and no depression during hospitalization, respectively. Of the 18 patients with major depression, seven patients currently met diagnostic criteria, and 11 were in partial remission. Of the 17 patients with minor depression, six met symptom criteria for major depression on at least one occasion during hospitalization but not the temporal criterion of 2 consecutive weeks with major depression symptomatology. Of these patients with major and minor depressive episodes, 88.9% (16 of 18 patients) and 52.9% (nine of 17 patients) were diagnosed at the time of hospital admission. The median duration time from episode onset until day +14 after SCT was 45.5 weeks (range, 3 to 163 weeks) and 6.0 weeks (range 2 to 33 weeks) for major and minor depression, respectively. Of the 164 patients with no diagnosis of depression, eight patients met symptom criteria for major depression and eight met symptom criteria for minor depression in at least one weekly interview, but they did not meet the corresponding temporal criterion of 2 consecutive weeks with major or minor depressive symptoms.

View larger version (18K): [in this window] [in a new window]   Fig 1. Unadjusted Kaplan-Meier survival curves showing the probability of 5-year survival after stem-cell transplantation (SCT) by Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, depression status. (*) One patient censored because of loss to further follow-up. () One patient censored because of a suicide death.

Comparing modified and unmodified DSM-IV approaches to diagnose depression, we found that two patients who met modified DSM-IV criteria for major depression were diagnosed with minor depression when unmodified DSM-IV criteria were applied and that two patients who met modified DSM-IV criteria for minor depression were diagnosed as nondepressive using unmodified DSM-IV criteria. Additional statistical analyses were performed in which depression was diagnosed by unmodified DSM-IV criteria. However, we have not reported these data because they are similar to the original analyses (Table 3).

We noted similar results when the survival analysis was confined to the 213 patients who survived longer than 30 days after SCT (data not shown). In model 1, the strength of the association between major depression and mortality was attenuated (P = .043 for 1-year mortality and P = .09 for 3-year mortality). In model 2, we did not find any significant interaction predicting 1- and 3-year mortality; the results were identical to those in model 1.

	DISCUSSION

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To our knowledge, this is the largest oncologic study that uses standardized psychiatric diagnostic criteria to assess the impact of depression on mortality. After adjusting for multiple confounding factors, major depression during hospitalization for SCT was associated with a greater risk of dying than no depression at 1 and 3 years but not at 5 years.

The failure to detect a significant relationship between major depression and 5-year mortality might be related to the small number of major depressed patients, so that larger samples are needed to provide adequate statistical power. In a recent literature review of the impact of depression on cancer survival, it was reported that the average follow-up time in the positive studies was 5 years, whereas in the negative studies, the average follow-up time was 10 years.⁹ One might conclude that studies with longer follow-up are more definitive, but this is not necessarily the case. Longer follow-up may be possible in less lethal forms of cancer. In our study, most patients died within the first 3 years after SCT.

Our results are consistent with those of other studies showing that depression significantly increases the risk of death in different noncancer samples.^1-3,5-8 Comparison with other oncologic studies of depression predicting mortality is difficult because of differences in research methodology.^4,9 Several recent methodologically rigorous studies have reported that depression as a single variable was predictive of shorter cancer survival.^10-13 However, none of these studies used standardized psychiatric criteria to diagnose depression.

We found a trend for patients with minor depression to survive longer than patients with no depression. However, when using a more flexible or a more restrictive method to define the minor depression category, we did not obtain significance or a trend towards significance in the association between minor depression and mortality. Most medical studies of the effect of baseline minor or subthreshold depression on mortality find no risk associated^1,10 or an increased risk of mortality.^2,3,7 After reviewing the literature, we found only one study that reported a significant association between subthreshold depression in women and decreased mortality.²⁶ However, in that study, a more severe level of depression was not associated with mortality. Furthermore, at a theoretical level, the difference between minor and major depression is not so great as to suggest that the mortality risk associated with these two diagnoses should diverge so widely. In our study, six of the 17 patients diagnosed with minor depression had symptom criteria for major depression of 1 week in duration. Therefore, we consider that the trend towards significance of the association between minor depression and decreased mortality risk is likely to be a spurious finding.

Some studies using patient-rated scale scores to define different levels of depression suggest that the severity of depression shows a gradient of risk for subsequent mortality.^2,3,7 In these studies, patients with minor or subthreshold depression displayed an intermediate pattern of survival that was between patients with no depression and patients with a more severe level of depression. It is likely that methodologic differences between studies contribute to the divergences in the findings regarding the association between minor or subthreshold depression and mortality. Given the limitation of patient-rated scales for evaluating only depressive symptoms present during the week preceding the interview, it is impossible to know whether patients diagnosed as having subthreshold depression in a particular study would correspond to patients with DSM-IV major depression in partial remission. Furthermore, there is evidence that long-term depression states are more likely to lead to adverse health outcomes than short-term ones.^1,2,5,9,13 In our study, we found that major depression episodes represented longer term depression states than minor depression episodes (median duration time, 45.5 v 6.0 weeks, respectively). It may be that the association between minor or subthreshold depression and increased mortality risk is, in part, mediated by a chronic course of these depressive symptoms.

Compared with our primary analysis of patients surviving longer than 90 days after SCT, the strength of the association between major depression and mortality was attenuated when the analysis was confined to patients surviving more than 30 days. In the SCT setting, where the highly intensive conditioning treatment is associated with an acute mortality risk, the role of depression may be more difficult to detect in the first few months after SCT because of the strong cancer- or treatment-related biologic processes during this stage.

The mechanisms that could mediate or explain the association between depression and mortality are not well understood.⁹ First, depression may have direct pathophysiologic effects via neuroendocrine and immunologic functions that influence morbidity and mortality.^9,20,27-30 Second, depression may impact survival through behavioral mechanisms such as poorer adherence to medical treatment or health recommendations,^4,9,31,32 increased smoking and alcohol consumption,⁴ and suicide.^4,17 Finally, disease progression or treatment side effects may cause or mimic depression.^9,19,20,23 However, our depression measures did not include somatic symptoms that could be attributed to the neoplastic process or cytotoxic treatment, and survival analyses controlled for multiple confounding factors. Therefore, our results suggest that depression is not simply an artifact of declining health.

This study has several limitations. First, we did not measure inter-rater reliability, although we sought to maximize the reliability of our depression diagnoses by using standardized diagnostic criteria, serial observations, multiple sources of information, and discussion in regular meetings between investigators. Second, we did not measure several factors that could be predictors (eg, social support) or mediators (eg, treatment adherence) between depression and mortality. Third, the possible effects of psychiatric treatment on survival cannot be evaluated under the available study design. In such an observational sample, comparisons of outcomes based on treatment received are subject to substantial bias. Fourth, although our results provide additional support for the prognostic importance of depression, they do not establish that depression causes fatal cancer- or treatment-related events. For instance, we do not know whether patients who were depressed in the hospital were still depressed at the time of their deaths up to 5 years later. To establish a causal relationship, we need to perform longitudinal research combining repeated measurement of depression and its presumed pathophysiologic mechanisms, followed by adequately powered, randomized trials targeting the mechanisms implicated. Finally, the association between depression and disease outcome is based on a relatively small sample of major depressed patients. However, this association is strengthened by high recruitment and follow-up rates and a comprehensive set of clinical confounding variables considered for risk adjustment. Moreover, the use of a rigorous psychiatric diagnostic method coupled with serial evaluations increased the accuracy of depression diagnosis.

Coupled with the widespread tendency to excuse depression as an understandable and inevitable reaction to cancer and the consequent risk for depression underdiagnosis and undertreatment,^33,34 our findings highlight the critical importance of early recognition and treatment of major depression. Because of the substantial prevalence and chronicity of major depression at hospital admission, it would be better to conduct a first assessment after the patient agrees to undergo SCT. In cancer populations, the effect of psychopharmacologic and psychological interventions on treating depression has been reviewed and shown to be beneficial.^{9,19,20,35,36} Although a considerable body of research exists, the question of whether psychosocial intervention has a beneficial effect on cancer survival remains unresolved.^9,37-39 However, most of these intervention studies were designed to reduce distress in general and enhance coping rather than treat depressive disorders per se. Although it remains to be determined whether early recognition and effective treatment of major depression result in longer survival, they do have the potential to improve health care outcomes, reduce patient suffering, and enhance quality of life.^{9,19,20,35-37}

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank the patients who participated in this study and the medical and nursing staff for providing medical information. We also thank the statisticians from the Statistical and Consulting Service, Universitat Autònoma de Barcelona, for their assistance with the data analysis.

	NOTES

 
Supported by research grant Nos. FIJC 98/QV-JMP and FIJC 03/QV-JMP from the Josep Carreras International Leukemia Foundation.

The Josep Carreras International Leukemia Foundation had no role in the design, conduct, interpretation, and analysis of the study and review or approval of the manuscript.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted November 14, 2004; accepted April 5, 2005.

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