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Depression, Cigarette Smoking, and Hematopoietic Stem Cell Transplantation Outcome Grace Chang, M.D., M.P.H.1,2 E. John Orav, Ph.D.3,4 Tay McNamara, Ph.D.1 Mei-Yee Tong, M.S.1 Joseph H. Antin, M.D.4 – 6 1
Department of Psychiatry, Brigham and Women’s Hospital, Boston, Massachusetts.
2
Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.
3
Department of General Medicine and Primary Care, Brigham and Women’s Hospital, Boston, Massachusetts.
4
Department of Medicine, Harvard Medical School, Boston, Massachusetts.
5
Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts.
6
Department of Medical Oncology, Dana-Farber Partners Cancer Institute, Boston, Massachusetts.
BACKGROUND. The relationships between psychological and behavioral variables and patient outcomes after hematopoietic stem cell transplantation (HSCT) are not known definitively but have great potential importance, since this lifesaving procedure is used increasingly to treat a variety of malignancies. The objective of this study was to evaluate psychosocial predictors of long-term survival and disease recurrence after patients underwent allogeneic HSCT for chronic myelogenous leukemia (CML).
METHODS. In this prospective cohort study, 114 adults were admitted for allogeneic HSCT to the Brigham and Women’s Hospital between July, 1997 and January, 2002. The median follow-up was 882 days, and serial measures were taken for mood and substance use 6 months and 12 months posttransplantation. RESULTS. With a 93% participation rate by all potentially eligible patients and with ⬍ 3% of patients loss to follow-up, univariate predictors of long-term survival and recurrence were identified. Cox proportional hazards regression models for survival and recurrence were developed. Depressive symptoms, as measured by the most recent Beck Depression Inventory (BDI), increased the risk of death by 7% for each point increase in the BDI score (P ⫽ 0.006). Fourteen of 17 patients who developed recurrent disease were cigarette smokers with an average of 22.3 packyears. For each pack-year of cigarette smoking, the risk of recurrence increased by 1.7% (P ⫽ 0.01). CONCLUSIONS. This study assessed the role of psychosocial variables prospectively among a clinically homogeneous but representative cohort of patients who underwent allogeneic HSCT. Although additional confirmatory studies are pending, it appears that depressive symptoms posttransplantation and cigarette smoking prior to transplantation affect outcomes adversely and may represent opportunities to improve the morbidity and mortality associated with HSCT for patients with CML. Cancer 2004;101:782–9. © 2004 American Cancer Society. KEYWORDS: depression, cigarette smoking, chronic myelogenous leukemia, hematopoietic stem cell transplantation.
Supported by grants from the Alcoholic Beverage Medical Research Foundation (G.C.) and the National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism (K2400289; G.C.). Address for reprints: Grace Chang, M.D., M.P.H., Department of Psychiatry, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115; Fax: (617) 738-1275; E-mail:
[email protected] Received February 9, 2004; revision received May 7, 2004; accepted May 14, 2004.
T
he relationship is elusive between psychosocial variables and patient outcomes after hematopoietic stem cell transplantation (HSCT). Popularly known as bone marrow transplantation (BMT), HSCT is the second most frequent major organ transplantation performed in the United States and is a lifesaving procedure for selected patients with aplastic anemia, acute and chronic leukemias, and lymphomas.1– 4 The best efforts of investigators to examine the role of psychosocial factors, such as mood or health habits, have been challenged by small sample sizes, loss to follow-up, methodological problems (such as a lack of both pretransplantation and posttransplantation data), retrospective assessment of psychosocial variables, or failure to consider relevant disease and treatment variables.5,6 How-
© 2004 American Cancer Society DOI 10.1002/cncr.20431 Published online 30 June 2004 in Wiley InterScience (www.interscience.wiley.com).
Depression, Smoking, and HSCT Outcome/Chang et al.
ever, available evidence suggests a possible link that is worth examining. Several investigators have identified an association between transplantation outcomes and psychosocial variables. A retrospective review of 100 adult patients who underwent allogeneic BMT for acute leukemia identified 3 variables that affected outcome independently: illness status, presence of depressed mood, and extent of perceived social support.7 However, that study used no formal measures of mood or social support and analyzed only 2 variables simultaneously as predictors of survival, which was dichotomized into survival ⬍ 1 year or ⱖ 1 year. Another study of 193 patients who described depressive symptoms 6 months after undergoing autologous or allogeneic transplantation for varied malignancies had decreased survival 6 –12 months afterward transplantation (P ⫽ 0.04). A standardized measure of depression, however, was not obtained.8 Other investigations, however, do not support the association between psychosocial variables and transplantation outcomes. For example, a prospective study of 123 consecutive patients with diverse hematologic and solid tumors who underwent either autologous or allogeneic transplantation reported that no psychological variables were related to survival using either univariate or multivariate analysis.9 Another prospective study using standardized measures of mood and quality of life in 42 adult patients who underwent allogeneic BMT for either acute or chronic leukemia identified quality of the bone marrow graft as the only disease, treatment, or demographic variable significantly associated with BMT survival (P ⫽ 0.05).10 Less is known about the potential impact of alcohol and other substance use on HSCT outcomes. A retrospective case– control study of 34 patients who were matched for disease and stage, type of transplantation, pretransplantation conditioning regimen, and age, but only 50% of whom had substance abuse diagnoses, found reduced survival for patients who had substance abuse (P ⫽ 0.002). The difference in survival persisted even after stratifying for type of transplantation and cigarette smoking.11 The heterogeneity of these findings on the relation between psychosocial variables and transplantation outcomes may reflect not only the variety of diseases and treatments studied but also the length of followup. It is possible that clinical and psychosocial factors assume differential importance at various points during the recovery process.12 The objective of this study was to evaluate psychosocial predictors of long-term survival and recurrence after allogeneic HSCT for chronic myelogenous leukemia (CML). We hypothe-
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size that, when the acuity of other clinical factors abates, some psychosocial and behavioral variables, such as depression and cigarette smoking, will be associated with long-term outcomes after allogeneic HSCT.
MATERIALS AND METHODS Patients with CML who were admitted for allogeneic transplantation between July, 1997 and January, 2002 were invited to participate in this prospective cohort study during their first week of admission. In the first 12 months of the study, recruitment was limited to patients who received related donor transplantations. However, in subsequent months, recruitment was broadened to include patients who received unrelated donor transplantations, who have demonstrated equivalent outcomes.13–15 Participants agreed to an initial diagnostic interview, with follow-up interviews 6 months and 12 months after transplantation, and a review of their medical records. Patients were given an honorarium of $50.00 for the initial interview and an honoraria of $25.00 for each completed follow-up interview. This study was reviewed and approved by the Institutional Review Board of the Brigham and Women’s Hospital (Boston, MA). The initial diagnostic interview included 1) the alcohol and drug abuse modules from the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) to generate lifetime and current alcohol and substance use diagnoses16; 2) the Alcohol Timeline Followback (TLFB) to provide data on the quantity and frequency of alcohol consumption in the previous 180 days17; 3) a structured series of questions about the use of tobacco products, age of first and last use, quantity, and frequency; 4) the Alcohol Use Disorders Inventory (AUDIT), a 10-item questionnaire to assess alcohol consumption, symptoms, and consequences of alcohol use in the previous year18; 5) the Drug Abuse Screening Test (DAST), a 28-item instrument to assess the extent of problems related to drug use19; 6) the Beck Depression Inventory-revised edition (BDI), a 21-item measure for depression20; 7) the Functional Living Index-Cancer (FLIC), a 22-item measure of overall functional quality of the patient’s day-to-day life21; and the 8) the QL-Index (QLI), a 5-item qualityof life-index.22 Six-month and 12-month follow-up interviews included the FLIC, QLI, BDI, TLFB (to provide data on alcohol consumption in the previous 180 days), AUDIT, and information on cigarette smoking. Demographic data, including age, gender, marital status, and occupation, coded according to the Treiman Standard International Occupational Prestige Scale as
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a measure of socioeconomic status in a group for whom income may be affected adversely by illness, also were obtained at the initial interview.23 The first author administered all initial and follow-up interviews. Medical records were reviewed after transplantation using a standardized abstraction form. Pretransplantation information included medical history prior to the procedure and clinical data at the time of CML diagnosis, e.g., disease stage, white cell count, interval between diagnosis and HSCT, which have been shown in other studies to predict treatment outcomes. Transplantation variables included information on donor source (related or unrelated); cytomegalovirus (CMV) status of the donor-recipient pairs; admission and discharge liver function tests (i.e., alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase [LDH], alkaline phosphatase, total bilirubin, and direct bilirubin levels); complications during transplantation (e.g., acute graft-versus-host disease [GVHD], venoocclusive disease [VOD], sepsis, infection other than sepsis, renal disease, genitourinary disease other than renal, liver complications other than acute GVHD and VOD, central nervous system complications [such as mental status changes], pulmonary complications [such as acute respiratory distress syndrome], cardiovascular complications, and transplantation outcomes). Acute GVHD was graded according to the criteria established at the 1994 Consensus Conference; the maximum grade experienced by the patient was used.24 Posttransplantation data about chronic GVHD, including date of onset and severity, date of recurrence, and date and cause of death, were ascertained by review of on-line and paper medical records review as of March, 2003. Death and recurrence were considered as separate endpoints, because CML disease recurrences are responsive to treatment. The date of death was confirmed using the Social Security Death Index interactive search. The cause of death was ascertained from autopsy and death certificate data in the medical record.25
Data Analysis All analyses were carried out using the SAS statistical package (version 8.01; SAS Institute, Cary, NC). Simple descriptive statistics were calculated and are reported as percentages, means, standard deviations (SD), and ranges, as appropriate. Survival was calculated from the date of admission to the date of last clinical contact or death, whichever came first. Potential predictors of survival were tested individually using either the log-rank test for discrete variables or the Cox proportional hazards
model for continuous variables. Age was tested as a continuous variable and in groups divided by quartile (first quartile, 38 years; second quartile, 46 years; third quartile, 52 years), similar to groupings in other investigations.26,27 The 24 variables that were associated with long-term survival at the P ⬍ 0.10 level were then entered in a Cox proportional hazards model using forward selection with ␣ ⫽ 0.05 as the criterion for statistical significance. Results from the Cox proportional hazards model for survival were used to calculate projected survival curves, comparing a patient who had a last available BDI score of 7.76 with a more depressed patient who had a score of 10.86, with all other predictor variables held constant. These two prototypical last available BDI scores were chosen because they corresponded to the mean scores for patients who lived versus those who died. Potential predictors of disease recurrence posttransplantation were tested using either the log-rank test for discrete variables or the Cox proportional hazards model for continuous variables. The 8 variables that were associated with disease recurrence at the P ⬍ 0.10 level were then entered in a Cox proportional hazards model using forward selection with ␣ ⫽ 0.05 as the criterion for statistical significance. Results from the Cox proportional hazards model for recurrence were used to calculate projected recurrence curves for a patient who smoked 9.8 pack-years (the observed mean for patients who did not develop recurrent disease) compared with patient who smoked 22.3 packyears (the observed mean for patients who developed recurrent disease), with all other predictor variables held constant.
RESULTS One hundred fourteen of 122 patients (93.4%) with CML who were admitted for allogeneic HSCT between July, 1997 and January, 2002 agreed to participate in this study. Three patients declined (2.5%), and five patients (4.1%) did not speak English well enough to complete the study instruments or interviews. All 84 survivors completed the 6-month follow-up interview. Seventy-three of 75 survivors (97.3%) participated in 12-month follow-up interviews; only 2 survivors (2.7%) declined to complete any part of this portion of the study. Patients were followed for a median of 882 days after HSCT. The median patient age was 46 years (mean ⫾ SD, 44 ⫾ 9 years; range 22– 64 years). There were more male patients (60%), and most participants were married (70%). Most patients were Caucasian (93%), and the remaining patients were Asian (1.7%), African American or black (2.6%), Hispanic (1.7%), and Native American (1%). The mean ⫾ SD occupational score
Depression, Smoking, and HSCT Outcome/Chang et al.
was 47 ⫾ 13; examples include a retail manager and a garage operator (score range, from 16 [e.g., house cleaner] to 78 [e.g., physician]). Table 1 summarizes psychosocial and behavioral measures for the 114 patients. Overall, 38% of patients satisfied DSM-IV criteria for lifetime alcohol abuse or dependence, and none satisfied criteria for current alcohol diagnoses. All patients drank more in the 6 months prior to transplantation, averaging a total of about 65 drinks (10 drinks per month). In the immediate 6-month period after transplantation, alcohol consumption was reduced to no more than 6 drinks in that time (about 1 drink per month). Patients drank more in the 7–12 months after transplantation (3– 4 drinks per month) but did not resume pretransplantation levels of alcohol consumption. The mean DAST scores for the participants reflected the infrequency of other substance abuse or dependence diagnoses. The overall rate of cigarette smoking was 62%. All former cigarette smokers stated that they had not resumed cigarette smoking, and no patient initiated smoking in the 12 months after HSCT. The mean initial BDI score was 10 (range, 0 –37). This mean is within the nondepressed range of normal levels; for psychiatric patients, the mild-to-moderate depressed range of scores is 10 –18.28 About one-third of participants (32%) had scores in ⬎ 10. The majority of patients had stable-phase CML at the time of transplantation (n ⫽ 97; 85%). Nine patients (8%) had accelerated disease, 7 patients (6%) were in blast crisis, and the disease phase in 1 patient was not documented. One hundred seven patients (94%) received pharmacologic prophylaxis for GVHD with tacrolimus or cyclosporine plus methotrexate, whereas 7 patients (6%) underwent a T-cell depleted procedure. About one-half of patients (n ⫽ 58; 51%) received bone marrow from an anonymous, unrelated donor, and the remaining patients received bone marrow from a related sibling (46%) or from another relative (3%). Other aspects of match quality can be summarized as follows. Eighty-four percent of patients were 6/6 human leukemic antigen matches, and the remaining patients had 5/6 matches. Fifty recipient /donor pairs (44%) were negative/negative for CMV status, with the balance made up by all other combinations. The gender of recipient/donor pairs was male/male in 46 pairs (40%) and female/female in 27 other pairs (24%). Other combinations included male/female (20%), female/male (15%), or unknown (1%). Seventy-three patients (64%) had acute GVHD with a median onset of 28 days after bone marrow infusion. Most patients had Grade 1 (51%) or Grade 2 (26%) acute disease. Grade 3 (12%) and Grade 4 (11%)
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were less common. Forty-five patients had chronic GVHD, with a median onset of 207 days after bone marrow infusion, for whom the majority (64%) had extensive involvement. Seventeen patients (15%) developed recurrent disease a median of 389 days after HSCT. Fifty-two patients (45%) died and had a median survival of 142 days. Causes of death were pulmonary (n ⫽ 12; 23.1%), sepsis (n ⫽ 10; 19.2%), GVHD (n ⫽ 8; 15.4%), multiple organ system failure (n ⫽ 8; 15.4%), renal failure (n ⫽ 2; 3.8%), and others, including 3 unknown causes (n ⫽ 12; 23.1%).
Long-Term Survival Table 2 summarizes the univariate predictors of longterm survival and the multivariate model for longterm survival. A total of 24 variables that were assessed at the time of transplantation or thereafter were associated individually with survival (all P ⬍ 0.10). From these 24 variables, 8 were selected in the Cox proportional hazards model, with contributions from the time-varying covariates, transplantation variables, and pretransplantation variables. The patient’s risk of dying increased by 7% for each point increase in his or her last available BDI score in the multivariate model. Transplantation variables that increased the risk of death in the multivariate model included sepsis, which increased the risk 4-fold; central nervous system complications (e.g., delirium) and renal complications (e.g., azotemia), which each increased the risk over 3-fold; total bilirubin at discharge, which increased the risk of death by 6% per unit increase in total bilirubin; and discharge LDH level, which increased the risk of death by 0.2% per unit increase in LDH. White cell count at diagnosis, which increased the risk of death by 0.5% per 1000 cells, and disease phase at the time of HSCT admission other than stable, which was associated with a nearly 3-fold increased risk of death, also were included in the multivariate model. Figure 1 shows the projected survival after HSCT with all predictors equal except for the last available BDI score, which was set at prototypical values of 7.76 and 10.86. Thus, a higher BDI score, taking all other predictors into account, was associated with an increased risk of death.
Recurrence Table 3 summarizes the univariate predictors of disease recurrence and the multivariate model for disease recurrence. Variables with a hazard ratio (HR) ⬍ 1.0 were considered protective against disease recurrence (e.g., CMV donor/recipient status other than negative/negative). A patient who ever smoked in-
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TABLE 1 Psychosocial and Behavioral Variables (n ⴝ 114)
TABLE 2 Long-Term Survival: Univariate Predictors and Multivariate Model
Variable
Variable
Age (yrs) Mean ⫾ SD Range Gender (%) Male Female Marital status (%) Married Divorced Widowed Single Race (%) Caucasian African American Asian Hispanic Native American Occupation score Mean ⫾ SD Range FLIC score (initial) Mean ⫾ SD Range QL Index score (initial) Mean ⫾ SD Range Beck Depression Index score (initial) Mean ⫾ SD Range AUDIT score (initial) Mean ⫾ SD Range DAST score Mean ⫾ SD Range Lifetime diagnoses (%) Alcohol Cannabis Cocaine Opioids Current diagnoses (%) Alcohol Cannabis Cocaine Opioids Alcohol consumption 180 days before HSCT % of days Mean ⫾ SD drinks/drinking day Alcohol consumption 180 days after HSCT % of days Mean ⫾ SD drinks/drinking day Alcohol consumption 181–365 days after HSCT % of days Mean ⫾ SD drinks/drinking day Cigarette smoking Lifetime (%) Mean ⫾ SD pack-years
44 ⫾ 9 22–64 60 40 70 7 1 22 93.0 2.6 1.7 1.7 1.0 47 ⫾ 13.5 16–78 99 ⫾ 11 71–126 9.0 ⫾ 1.4 2–10 10 ⫾ 7 0–37 10 ⫾ 7 0–24 3⫾2 5–15 38 8 5 1 2 3 0 0 40 1.6 ⫾ 1.7 2.3 0.4 ⫾ 0.6 15 0.8 ⫾ 0.9 62 12 ⫾ 20
SD: standard deviation; FLIC: Functional Living Index–Cancer; QL Index: Quality of Life Index; AUDIT: Alcohol Use Disorders Inventory; DAST: Drug Abuse Screening Test.
Baseline variable CML, accelerated phase or blast crisis Diagnosis WBC (per 1000 WBC) Age ⱕ 39 yrs and ⬎ 39 yrs CMV status of donor/recipient Days between diagnosis and HSCT Transplantation variables Discharge ALT Discharge AST Discharge LDH Discharge AlkP Discharge T-bili Discharge D-bili Days to WBC ⬎ 500 after HSCT CNS complications Cardiovascular complications Pulmonary complications Liver complications Renal complications Genitourinary complications Venoocclusive disease Infection Sepsis Time-varying covariates Quality of Life Index Beck Depression Inventory Acute graft-versus-host disease Chronic graft-versus-host disease Multivariate model of long-term survival Sepsis CNS complications Renal complications CML, accelerated phase or blast crisis Last Beck Depression Inventory score Discharge T-bili Diagnosis WBC (per 1000 WBC) Discharge LDH
HR (95% CI)
P value
2.044 (1.044–4.002) 1.002 (1.000–1.004) 2.315 (1.128–4.750) 2.138 (1.184–3.860) 1.000 (1.000–1.001)
0.04 0.06 0.02 0.01 0.0008
1.005 (1.000, 1.009) 1.013 (1.005, 1.022) 1.002 (1.000, 1.003) 1.002 (1.000, 1.004) 1.093 (1.065, 1.121) 1.050 (1.031, 1.068) 1.047 (0.999–1.097) 3.494 (1.996–6.118) 1.669 (0.959–2.907) 2.921 (1.666–5.120) 2.182 (1.253–3.802) 4.267 (2.440–7.460) 0.301 (0.108–0.836) 3.183 (1.802–5.621) 1.838 (1.062–3.182) 3.246 (1.160–9.080)
0.03 0.004 ⬍ 0.0001 0.0003 ⬍ 0.0001 ⬍ 0.0001 0.06 ⬍ 0.0001 0.070 0.0002 0.006 ⬍ 0.0001 0.02 ⬍ 0.0001 0.03 0.02
0.823 (0.715–0.949) 1.036 (0.997–1.076) 1.173 (0.691–1.994) 1.542 (0.923–23579)
0.007 0.07 0.35 0.098
4.040 (1.079–15.118) 3.788 (1.573–9.119) 3.731 (1.503–9.262) 2.668 (1.085–6.562) 1.068 (1.019–1.120) 1.056 (1.007–1.108) 1.005 (1.002–1.008) 1.002 (1.001–1.003)
0.04 0.003 0.005 0.03 0.006 0.02 0.003 ⬍ 0.0001
HR: hazard ratio; 95% CI: 95% confidence interval; WBC: white blood cells; CMV cytomegalovirus; HSCT: hematopoietic stem cell transplantation; ALT: alanine aminotransferase; AST: aspartate aminotransferase; LDH: lactate dehydrogenase; AlkP: alkaline phosphatase; T-bili: total bilirubin; D-bili: direct bilirubin; CNS: central nervous system; CML: chronic myeloid leukemia; LDH: lactate dehydrogenase.
creased the risk of disease recurrence by over threefold. Three variables were selected in the Cox proportional hazards regression model of disease recurrence. For each pack-year of cigarette smoking, the risk of disease recurrence increased by 1.7%. Past hematologic problems (e.g. anemia; HR, 4.7) increased the risk of disease recurrence. CMV donor/recipient status other than negative/negative was protective against disease recurrence (HR, 0.16). Figure 2 shows the projected time to disease recurrence after HSCT with all predictors being equal except for mean cigarette pack-years. In this projection, a patient who had 9.8 pack years was compared
Depression, Smoking, and HSCT Outcome/Chang et al.
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FIGURE 1.
Projected survival associated with prototypic Beck Depression Inventory Scores.
FIGURE 2. Projected time to recurrence associated with a mean of 9.8 pack-years versus 22.3 pack-years.
TABLE 3 Disease Recurrence: Univariate Predictors and Multivariate Model Variable Baseline variables CML, accelerated phase or blast crisis Diagnosis WBC (per 1000 WBC) CMV donor/recipient status History of respiratory disease History of past hematologic problems Cigarette pack year Ever smoked or not Transplantation variables Cardiovascular complications Time-varying covariates Acute graft-versus-host disease Chronic graft-versus-host disease Disease recurrence: multivariate model History of hematologic conditions Cigarette pack-years CMV donor/recipient status
HR (95% CI)
P value
2.322 (0.662–8.148) 1.003 (1.000–1.007) 0.214 (0.061–0.745) 2.269 (0.838–6.145) 2.415 (0.691–8.435) 1.017 (1.003–1.032) 3.414 (0.979–11.905)
0.06 0.06 0.02 0.10 0.03 0.02 0.05
0.464 (0.163–1.317)
0.06
0.895 (0.330–2.424) 0.409 (0.115–1.454)
0.83 0.17
3.754 (1.004–14.034) 1.017 (1.004–1.03) 0.163 (0.044–0.603)
0.02 0.01 0.007
HR: hazard ratio; 95% CI: 95% confidence interval; CML: chronic myeloid leukemia; WBC: white blood cells; CMV cytomegalovirus.
with a patient who had 22.3 cigarette pack-years. Patients who developed recurrent disease averaged about twice as many cigarette pack-years as patients who did not develop recurrent disease (mean ⫾ SD; 22.3 ⫾ 34.0 pack-years vs. 9.8 ⫾ 15.4 pack-years; twosample test; P ⫽ 0.04). Therefore, when all other predictors were taken into account, the risk of disease recurrence increased for patients who smoked more.
DISCUSSION The main findings of the current study of 114 patients with CML who were followed for nearly 2.5 years after allogeneic HSCT suggest that depressive symptoms,
when measured with the BDI score most proximate to the time of demise, are associated with a 7% increased risk of death for each point increase in the total BDI score (P ⫽ 0.006). Medical variables associated with increased risk of dying included white cell count at diagnosis; disease phase at the time of HSCT; and transplantation-related events, such as sepsis, central nervous system complications, and renal complications. Cigarette smoking, by history, was associated with a 1.7% increased risk of CML disease recurrence for each pack-year of smoking after allogeneic HSCT (P ⫽ 0.01). Previous hematologic problems increased the risk of recurrence, but CMV donor/recipient status other than negative-negative was protective. The impact of the psychosocial variables— depressive symptoms on survival and cigarette smoking on recurrence—was assessed prospectively in the context of other medical variables, which was a strength of this study. Potential limitations to these findings may include reliance on patients with one type of malignancy undergoing treatment at one center of excellence. However, the inclusion of patients with disparate types of malignancies undergoing either autologous or allogeneic transplantation would have been problematic, given their widely differing morbidity, mortality, and treatment indication and success rates, unless sample sizes large enough to accommodate adjustment in statistical models were possible. The high level of participation and minimal loss to follow-up in this sample are protective against bias. Another possible limitation is that participants may have minimized their reported use of alcohol or other substances. However, their use was ascertained after HSCT admission, so that it is unlikely that they felt the need to “look good”
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to ensure a favorable decision to go forward with the procedure. Other investigators have found that research volunteers generally do not minimize reports of their drinking.29 The number of patients who developed recurrent disease after HSCT was small, and future studies focusing on disease recurrence despite treatment in patients with CML will be necessary to elucidate the possible role of cigarette smoking. Finally, information about treatment for depression posttransplantation and a measure of health status contemporaneous with the last BDI, such as the Medical Outcomes Study 36-Item Short Form Health Survey, would have been desirable and should be included in forthcoming investigations.30 The high prevalence of cigarette smoking, with an average of 22.3 pack-years among patients who developed recurrent disease (82%) and in the sample overall (62%), is noted, along with the higher than average rate of lifetime alcohol diagnoses (38%) for the entire sample. The estimated national lifetime prevalence of alcohol abuse and dependence disorders is 23.5% (or 9.4% and 14.1%, respectively).31 The overall prevalence rate of cigarette use by American adults is 25%.32 Some have proposed a link between smoking and the hematoproliferative malignancies, and alcohol’s role as a carcinogen has been documented.33–36 Although it is speculative, cigarette smoking and alcohol use by the participants may account for the observation that their mean age is nearly 1 decade less than the usual age of CML onset. Perhaps most noteworthy, the results of this study support and build on the findings of earlier investigations that identified depression as a potential adverse factor in HSCT outcome.7,8 Specifically, the risk of death increased 7% for each point increment in the last available BDI score in the cohort. The depressive symptoms may have reflected the participants’ physical status, particularly if they endorsed primarily somatic symptoms of depression. Although it is not possible at this time to explain the association between depressive symptoms and increased risk of mortality, some studies have suggested that patients with depression have reduced immune function.37 However, the clinical relevance of changes in the immune system of the depressed patient has been controversial, because there also is accumulating evidence that immune activation during various medical conditions is associated with a depressive syndrome in humans.38 – 40 Nonetheless, until these findings are replicated, it seems that evaluation for depression in the year after HSCT is a prudent recommendation. After all, depression is a common disorder, is distributed widely, and usually is associated with substantial symptom severity and role impairment.41 With more
patients surviving the immediate post-HSCT period,42 physician awareness about depression and its appropriate treatment are indicated, not only to improve quality of life but perhaps to prolong it.43– 45
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