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Journal of Clinical Oncology, Vol 23, No 27 (September 20), 2005: pp. 6596-6606 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.12.674 Late Effects of Hematopoietic Cell Transplantation Among 10-Year Adult Survivors Compared With Case-Matched ControlsFrom the Clinical Research Division, Fred Hutchinson Cancer Research Center; Department of Psychiatry and Department of Behavioral Sciences; Department of Medicine, School of Medicine; and School of Social Work, University of Washington, Seattle, WA Address reprint requests to Karen Syrjala, PhD, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., D5-220, Seattle, WA, 98109; e-mail: ksyrjala{at}fhcrc.org
PURPOSE: To determine late effects of hematopoietic cell transplantation (HCT) on health problems and health-related quality of life for 10-year survivors. PATIENTS AND METHODS: Four hundred five adults consented to the study before HCT. Medical records and standardized self-report measures were maintained prospectively. After 10 years, 137 survivors and nontransplant controls, case-matched on age, sex, and race, completed self-report of medical problems, symptoms, and health-related quality of life. RESULTS: Survivors and controls had similar rates of hospitalization and most diseases, but survivors reported an average of 3.5 medical problems versus 1.7 for controls (P < .001). Survivors reported more musculoskeletal stiffness, cramps, weakness and joint swelling (P < .001), cataract surgery (P < .001), hepatitis C (P = .004), sexual problems for men (P = .01) and women (P < .001), restrictions in social function (P = .002), memory and attention concerns (P = .003), urinary frequency or leaking (P = .006), use of psychotropic medication (P = .009), and denial of life and health insurance (P < .001). Survivors and controls did not differ in self-reported rates of osteoporosis, hypothyroidism, employment, marital satisfaction, divorce, or psychological health. CONCLUSION: Although indistinguishable in many respects, survivors had more medical needs than controls. Health problems were not focused on specific diseases or limited to survivors with readily identifiable risk factors. Musculoskeletal problems require both screening and research into etiologies and effective treatments. Osteoporosis and hypothyroidism may be underdiagnosed. Survivors require screening for sexual problems, urinary frequency, mood and need for antidepressants or benzodiazepines.
The number of long-term survivors of hematopoietic cell transplantation (HCT) is increasing rapidly; more than 45,000 patients receive HCT annually throughout the world.1 Patients with acute leukemia or chronic myeloid leukemia who survive without recurrent malignancy for 2 years after allogeneic HCT currently have an 89% probability of surviving for 5 or more years.2 Although research on late effects has increased, systematic information has not been available to guide oncologists or primary care physicians in routine monitoring and management of health care needs after 10 years for this population. Much of the research on HCT survivors after 5 years has focused on major medical events rather than daily health issues and symptoms. Late deaths, second cancers, and employment have been evaluated in large cohort studies.2-4 Several cross-sectional uncontrolled cohort studies have documented generally good quality of life among adults who survive 5 to 20 years after HCT.4-7 However, combining a wide range of surveillance times post-treatment makes it difficult to use these results to define time frames for screening late complications. Two recent studies have compared rates of late effects in 2- to 27-year survivors with control cohorts who have not had HCT. In comparing medical complications in survivors more than 2 years after HCT for chronic myelogenous leukemia with controls, one of these studies found that survivors had more ocular, oral, endocrine, gastrointestinal, musculoskeletal, neurosensory, and neuromotor impairments.8 The other study found poorer quality of life across most factors in survivors compared with controls.9 Risk factors for poorer outcomes have included chronic graft-versus-host disease (GVHD), unrelated stem cell donor, and total-body irradiation.2-4,8,10 Chronic GHVD resolves within 5 years for 95% of survivors,11,12 but remains a major risk factor for secondary malignancies and death, even among 10-year survivors.2-4 Nevertheless, some studies suggest that after resolution of chronic GVHD, quality of life can recover to the level enjoyed by survivors who never had chronic GVHD.13,14 A major constraint in determining late effects in HCT survivors has been their nationwide dispersion. This barrier has been overcome in part by research documenting that HCT recipients and other medical patients accurately report medical complications they are aware of, with 80% or greater agreement between self-report and medical records for most complications and medications,15-17 although osteoporosis and arthritis reports have lower rates of agreement.18 Here we report results for survivors who had a hematologic malignancy and were followed prospectively from before HCT. At 10 years, we compared these survivors with case-matched controls who did not have HCT to determine health-related problems that persist or have late onset. Based on previous research,2,4,12 we hypothesized that, compared with controls, the 10-year survivors would have (1) more medical problems overall and higher rates of musculoskeletal complications, hepatitis C, cataracts, hypothyroidism and osteoporosis; (2) more physical difficulties including fatigue; (3) more psychosocial difficulties including sexual dysfunction, poorer social function, and residual trauma from HCT; and (4) more refusals of life and health insurance. We did not expect to see differences at 10 years in rates of depression, work capacity or cardiovascular problems.4,5,7,12
Participants and Procedures The institutional review board approved all study procedures and forms. All patients signed written informed consent, were enrolled consecutively, and were followed from before transplant to 10 years. Of 758 adult US residents who were preparing for a first HCT at the transplant center between March 1987 and March 1990, 446 were invited to participate. Eligible participants were 18 years old or older, had sufficient English language proficiency to complete the assessments, and were available to complete the baseline assessment before beginning transplant-related treatment. Patients receiving stem cells from allogeneic donors (related or unrelated) or from autologous donation were eligible. Pretransplant assessment was conducted in the ambulatory clinic. Participants were followed until 10 years or death. Within 12 months after surviving 10 years, all consenting survivors were contacted by mail. Those who did not respond were contacted by phone to determine whether they wished to participate. If so, they returned the mailed forms or completed questions by phone. Surviving participants were also asked to nominate a case-matched control participant. If available, the control was a biologic sibling of the same sex and within five years of the survivor's age; this was the case for 60% of survivors. If no such person existed, survivors were asked to nominate a friend of the same sex whom they had known since before the transplant, within 5 years of the survivor's age, and of the same ethnicity, race and education (< four-year college degree v at least a college degree). For one survivor who had neither type of control, we recruited a community volunteer, unknown to the survivor or research staff, but matched on other criteria. As a normative population reference, we compared results with data from the Centers for Disease Control National Health and Nutrition Examination Survey (NHANES).19 To match our survivor sample, we selected respondents age 23 to 70 years (N = 4,020). The NHANES data are cited for those items that reasonably match our content. Because the NHANES methods did not match ours precisely, and because the samples were not matched on race/ethnicity, education, or income, these data do not substitute for the case-matched comparisons.
Measures Patient-reported outcomes have established reliability in various medical and nonmedical populations including HCT survivors.15-18 Standard self-report questions asked about age, sex, race and ethnicity, education, income, marital status, work, hospitalizations, major illnesses, number of outpatient visits within the last year, and current medications. Allogeneic recipients rated continuing difficulties caused by chronic GVHD from none to severe. A total of 85 diseases and symptoms were screened. Respondents indicated whether diseases had been diagnosed during the last 10 years, with a box to "check if you have it now." Medical problems such as joint pain and swelling or insomnia were reported as "never a problem" during the last 10 years, "no longer a problem," or "still a problem." If still a problem, symptom severity was rated as none, mild, moderate, or severe. The active diseases and problems with prevalence greater than 3% in either the survivors or controls were summed for an aggregate "number of medical problems"; 27 diseases or problems met these cutoff criteria. Musculoskeletal difficulties were considered as a single problem area since they frequently overlapped.
Standardized scales or measures with strong psychometric properties were used to measure health-related quality of life. The Short Form 36 Health Survey (SF36)20 measured eight dimensions, each scored 0–100, with composite T scores calculated for mental and physical components. On the 21-item Beck Depression Inventory,21 higher scores indicated greater depression. Normative data defined cutoff ranges of no depression (< 10), mild depression,10-15 moderate depression16-21 and severe depression (> 21). A 10-item subscale of the Symptom Checklist 90-Revised22 measured anxiety, with higher scores indicating more anxiety. Normative data defined cutoff scores for moderate to severe anxiety as T scores
Statistical Analysis Since the NHANES data did not exactly match our content or cohort sociodemographics, we did not test differences between the NHANES cohort and our survivors. We present the NHANES data only as reference information useful for considering whether the control cohort findings represent general population disease and symptom prevalence.
Figure 1 shows the flow of patients through the study. Of 446 patients invited to participate, 405 were eligible, consented, completed pretransplant assessment, and were followed. Of these, 147 survived to 10 years and 137 participated in the study. In addition to the 137 participating controls, 8 potentially eligible controls were screened but not enrolled. Two survivors did not want an eligible sibling contacted, and a friend or another eligible sibling was substituted. Three siblings declined to participate, and a nonsibling was substituted. Three nonsiblings declined participation, and another nonsibling was substituted. One survivor required screening of two controls before a third participated. Among all participants, one survivor and two controls provided partial information by telephone interview. To assess whether the surviving participants were representative of all HCT 10-year survivors at our center, we compared the 137 survivors with the 87 survivors who underwent transplantation during the same time frame but did not participate in the follow-up. Of these 87, 77 were among the 353 who did not consent, and an additional 10 consented but withdrew or were lost to follow-up before 10 years. Participating 10-year survivors and nonparticipating 10-year survivors differed only in the proportion that received busulfan instead of total-body irradiation before HCT (Table 1) . Although only 4 of 120 allogeneic transplant recipients were taking immunosuppressive medication at 10 years, 19% (23 of 120) reported moderate to severe residual sequelae from chronic GVHD. None of the 10-year survivors had been followed actively at the transplant center for over 5 years. Medical records of the survivor cohort indicated that the only transplant center medical contacts in the previous 5 years were for four participants not seen but were enrolled in a protocol for management of hepatitis C.
Among the outcomes listed in Tables 2 through 6, we found no differences between sibling versus friend controls, with exceptions that no siblings reported denial of insurance, versus 15% of the friends (P < .001), and more friends than siblings were married at the time of assessment (92% v 70%, respectively; P = .002). For example, in paired t tests, siblings were not more depressed (P = .56), anxious (P = .86), or more likely to report physical dysfunction on the SF36 (P = .75), or to report a larger total number of medical problems (P = .46).
The survivor and case-matched control cohorts had similar demographic characteristics (Table 2). Comparable proportions were working full time or defined their jobs as homemakers. Equivalent numbers were married (P = .77). Survivors and controls had equivalent frequencies of hospitalizations and outpatient medical visits during the previous year (Table 3). Contrary to expectation, survivors did not report osteoporosis, hypothyroidism, or thyroid replacement therapy more frequently than controls, nor were survivors more likely to be taking calcium supplements or a bisphosphonate.
Other health issues were more prevalent in survivors. As predicted, more survivors had hepatitis C (16 of 136 v 3 of 135; P = .004), and cataract surgery in the previous 10 years (51 of 136 v 1 of 135; P < .001). Almost twice as many survivors (44 of 136 v 23 of 135; P = .002) had moderate to severe musculoskeletal problems, even after excluding those with avascular necrosis or hip replacement that can result from high-dose glucocorticoids for treating chronic GVHD (Table 3). Despite these complications, survivors were not more likely to be using opioids, nonsteroidal anti-inflammatory drugs, cyclo-oxygenase 2 inhibitors, anticonvulsants, or antidepressants for pain. Urinary frequency and cognitive concerns were also more prevalent among survivors. To consider whether higher rates of "moderate-severe" symptoms may represent a response bias in survivors toward higher severity ratings of symptoms, or an issue of symptom severity rather than presence/absence, we also examined symptom prevalence by including "mild" in the presence/absence prevalence testing. Few results changed. Joint problems became marginally significant (P = .02), whereas rates of leg cramps and stiffness no longer differed significantly when we included mild symptoms in the presence category; the "one or more musculoskeletal problems" category differences did not change. In addition, sinusitis differed between groups when mild was included (P = .003) but not when the cutoff was moderate-severe. The nine active diseases and 18 symptoms or medical problems listed in Table 3 include those that had prevalence of > 3% among either the survivors or controls from among the 85 problems screened. These 27 medical problems were summed as an indication of health burden. In aggregate, survivors had a median of three medical problems versus one in controls (mean = 3.5 v 1.7, P < .001). Of the four survivors who had hip replacements, all reported a history of avascular necrosis, whereas an additional 8 of 136 survivors reported avascular necrosis but no joint replacement.
More than one in five survivors (28 of 136) indicated use of antidepressant or anti-anxiety medications (Table 4), more than twice the rate for controls (13 of 135; P = .009). Despite more prevalent use of psychotropic medications by survivors, depression did not differ from controls, whereas the rate of moderate to severe anxiety was marginally higher in survivors (P = .04; Table 5). We used standardized cutoff scores of
We found no differences in rates of divorce or separation, or quality of the marital relationship (Table 5). Almost a third of the female survivors reported bald or thinning hair (22 of 71; P < .001). More survivors had been refused life insurance or health insurance (53 of 136; P < .001). The two cohorts reported no lifestyle differences in eating, smoking, or exercise. As expected (Table 6), both male and female survivors more frequently reported specific sexual problems such as vaginal dryness, dyspareunia, or erectile dysfunction (P = .01 for males; P = .001 for females). Female survivors also reported more overall sexual dysfunction than controls (P = .004). SF36 scores indicated that physical and mental limitations persisted in long-term survivors (Fig 2), even though depression, anxiety, and work status did not differ from controls. As hypothesized, survivors fared less well in social function (P = .002). Social, work, and family roles of survivors were more impaired by emotional (P = .007) and physical (P = .004) limitations. Survivors were also marginally lower on the vitality scale (P = .017), indicating more fatigue. On average, survivors did not differ from controls in reports of bodily pain. However, survivors with musculoskeletal problems reported more bodily pain (P < .001) and fatigue (P < .001) than those without musculoskeletal problems.
The NHANES cohort of N = 4,020, matched for age and sex with our control cohort, had higher rates of Hispanic (27%) and nonwhite participants (24%), and more participants with high school or lower levels of education (51%). Despite these differences, the NHANES and our control cohorts had equivalent rates of hospitalization and outpatient visits (median of 2.0 outpatient visits and 12% rate of hospitalization in the last year) and similar rates of being married (69% for NHANES v our 77%). Among active diseases, the NHANES cohort matched our survivor cohort in rates of high blood pressure (21% for both) and our control cohort in rates of thyroid disease (4% for NHANES and our control cohort), hepatitis C (3% for NHANES and 2% for controls), second malignancies (2% for NHANES and 3% for the controls for skin cancer; 5% for other malignancies for NHANES and 4% for controls). The NHANES cohort had higher rates of diabetes (8% v 2% for controls). For other medical issues assessed in both the NHANES cohort and our control cohort, we found similar rates of memory and attention concern (6% in NHANES v 7% in controls) and antihypertensive or cholesterol medication (23% in NHANES v 18% in controls). Among psychosocial and lifestyle issues, 88% of male NHANES respondents were sexually active versus 86% of our controls, whereas 85% of female NHANES respondents were sexually active versus 74% of our controls; 32% of the NHANES cohort versus 30% of our controls exercised at least three times a week for 30 minutes; 21% of the NHANES group used tobacco regularly versus 16% of our controls. The NHANES assessment asked about only joint pain, aching or stiffness; 24% reported these problems for most of the last month, relative to 21% of the HCT controls and 38% of the survivors who reported moderate to severe joint problems or stiffness.
Ten years after HCT, the 137 survivors were indistinguishable from case-matched controls in many areas of health and psychosocial functioning, although survivors reported a greater number of medical problems and greater limitations in sexuality, insurance, and social, emotional and physical roles. Some of these problems are known to be associated with HCT, whereas others have not been recognized previously as late concerns. Musculoskeletal problems were frequent, whereas rates of self-reported osteoporosis and hypothyroidism were lower than expected, raising concern that these diseases may be underdiagnosed in long-term survivors. In contrast, rates of antidepressant or anti-anxiety use were higher than in controls and high relative to the general psychological health reported by survivors. Musculoskeletal symptoms were reported by 35% of the 10-year survivors who had not had avascular necrosis or a hip replacement. Possible causes of musculoskeletal problems include sedentary lifestyles combined with muscle loss related to treatment; myopathy or fibromyalgia related to glucocorticoid treatment, inflammatory cytokines, interleukins or prostaglandins; weakness or spontaneous fractures related to osteoporosis; scleroderma, strictures, fasciitis related to chronic GVHD; neuropathy related to chemotherapy; or connective tissue disorders.12,25 Fatigue is known to persist after HCT, 26-28 and was related to musculoskeletal complaints. Potential causes of fatigue include sleep disruption, altered production of interleukins and interferons, metabolic abnormalities, hormone deficiencies, enduring effects of total-body irradiation, inactivity, depression, and medications.29,30 Investigation is needed into the qualities and etiologies of these musculoskeletal complaints. Exercise can reduce fatigue and improve function after treatment for malignant diseases31 and needs to be tested for its impact on musculoskeletal symptoms. Hypothyroidism and osteoporosis can have major effects on mortality and morbidity.25,32-34 In contrast to the 9% of survivors in our study who reported thyroid medication use, another self-report study found a rate of 15% in long-term survivors.8 Although comprehensive endocrine testing earlier after HCT documented thyroid dysfunction in 47% of HCT survivors, the frequency of hypothyroidism was only 5%; other dysfunctions included low T3, chronic thyroiditis, and hyperthyroidism.33 In previous studies, as many as 68% of allogeneic recipients had sustained bone loss, particularly in the femoral neck and Ward triangle sites after 1 to 10 years, even when treated with bisphosphonates and hormone therapy.32,35 Risk factors predicting bone mineral density loss have included lack of estrogen supplementation in women,36,37 glucocorticoid therapy,25,32,38 and the use of cyclosporine or tacrolimus.25,32,38 In our survivor cohort, only 9% of women and no men were taking calcium supplements. Three explanations might account for the low rates of reported osteoporosis and bone mineral supplementation in our study: (1) bone mineral loss related to HCT was recognized and appropriately treated; (2) wide-spread use of hormone replacement therapy in female survivors reduced bone mineral loss; or (3) physicians are not sufficiently aware of bone mineral loss as a long-term consequence of cancer treatment, particularly in women with premature menopause. Since recent studies have discouraged the use of hormone replacement therapy,39 monitoring of bone mineral density and treatment of osteoporosis have gained importance after HCT, especially for women. The risk for specific secondary malignant neoplasms after HCT is three- to 25-fold higher than observed in age and sex-matched controls, with the cumulative incidence reaching approximately 6% at 15 years.3,40,41 Rates of nonbasal, nonsquamous cell carcinomas did not differ markedly between our cohorts, but were already at 6% in the HCT survivors. Relative risk for secondary malignancies can be expected to increase after 10 years, warranting intensified screening. Survivors should be tested for hepatitis C, particularly if they had transfusions or HCT before 1992, when screening of donors for this virus became possible. This infection generally does not cause clinical problems during the first decade after HCT,42 but untreated hepatitis C can evolve to cirrhosis after 15 years.43,44 Quality of life as reported on the SF36 was similar to that found by Kiss et al7 and Andrykowski et al.9 We found significantly lower social function among our survivors versus controls, consistent with Andrykowski et al. It remains unclear whether survivors are participating in fewer activities, and, if so, whether this resulted from physical limitations, loss of social connections, behavioral choices, or other factors. Although demographic characteristics were similar between our cohorts and the Andrykowski et al cohorts, our survivors had fewer significant quality-of-life differences relative to controls than the Andrykowski et al case-control comparisons. On the SF36 quality of life measure, some mean differences between cases and controls were similar, but differences in statistical significance could be explained by the higher power or lower effect sizes. Other differing outcomes may be explained by three survivor cohort differences in the group assessed by Andrykowski et al compared with our survivors: (1) their study included a higher percentage of autologous transplant recipients, who may have had more extensive treatment before beginning HCT; (2) they enrolled survivors with 2 to 22 year interval times, potentially including recipients who had not yet recovered from treatment effects as well as survivors who may have accumulated late effects after 10 years; and (3) variations in treatment regimens or follow-up protocols for transplant survivors between the different transplant centers may explain some differences. Concerns about memory were prevalent among our survivors, but other research indicates that, in most cases, these problems predate HCT.45 Sexual dysfunction remains one of the most prevalent and persistent long-term problems after HCT.5,23,46-49 Continuity of health insurance remains a high priority, as reflected in the 24% of survivors who had been denied health insurance after HCT, although 96% currently had health insurance, similar to controls. Survivors were no more likely than controls to avoid smoking or to maintain healthy eating habits and activity levels, despite their higher risk for complications related to these lifestyle choices. Depression before and after HCT has been associated with increased morbidity and mortality.13,50,51 More than half (56%) of depressed survivors were not being treated with antidepressants, suggesting that depression frequently escapes medical attention. At the same time, 65% of survivors taking antidepressants did not report depression. We cannot determine whether depression was effectively treated in these patients or whether treatment was prolonged unnecessarily. As positive outcomes, we found that survivors and controls had similar mental health; in addition, friends and siblings did not differ in psychological function, suggesting that HCT did not have differential long-term or late psychological impact for either survivors or their siblings. This result is consistent with reports indicating high rates of benefit-finding and low rates of post-traumatic stress symptoms, as well as other psychological growth, among cancer survivors.9,52 Several limitations may affect the generalization of our findings. Despite the relatively large sample size, statistical power to detect infrequent problems such as pulmonary complications was limited. Also, the sample size limited our ability to explore possible confounding or effect modification with other factors. Other late effects, such as secondary malignancies, may require longer follow-up to become evident.2,3,40 Ethnic and racial minorities, autologous HCT recipients and patients with diseases other than leukemia are under-represented in our cohort. Although sample sizes were small for autologous transplants and nonleukemia diseases, results for these groups were similar to those for other patients. For example, an equivalent percentage of autologous and allogeneic survivors reported musculoskeletal problems other than avascular necrosis. Questions can also be raised concerning whether our control cohort is appropriately matched to our survivors. Bias could have been introduced if patients had multiple eligible candidate controls and consistently selected a more or less healthy case-match, or if siblings introduced negative psychosocial health bias as a result of having experienced the HCT in a sibling. Our analyses did not indicate greater psychosocial impairment in sibling versus friend controls. Still one could argue that although siblings are excellent controls for biologic outcomes, their experience of transplant could influence their psychosocial outcomes in a manner we have not detected. We believe the NHANES data provide supporting evidence that the controls are not divergent from population norms in medical outcomes and lifestyle. Alternative methods for recruiting controls that could be used in future research in order to address possible biases include population-based methods such as random-digit dialing, not including siblings in the recruitment, or having survivors nominate as many potential matched controls as they can think of and then randomly selecting case-matched controls from among this sample. We cannot rule out the possibility that closer routine monitoring of survivors might have increased their rates of diagnoses of complications, or that they were more attentive to symptoms or more likely to rate them as moderate to severe because of response biases. The similarity between survivors and controls in the rate of medical visits, however, does not support these possibilities. We confirmed that no participating survivors received second transplants, nor were any seen for medical follow-up at the transplant center during the previous 5 years. In conclusion, 10 years after HCT, adult survivors were aware of a diverse array of diseases and symptoms, although potentially serious complications may remain hidden. These findings highlight the need for oncologists and other oncology health professionals to communicate to primary care providers guidelines for routine screening of diseases that might otherwise be considered relevant primarily to older patient populations. Specifically, survivors would benefit from guidelines for monitoring bone mineral density, thyroid function, early detection of secondary neoplasms, cardiovascular health, hepatitis C, sexual problems, depression and need for antidepressant or anti-anxiety medications. Other problems with higher than expected prevalence after HCT require both screening and research into etiologies, risk factors and effective treatments. These problems include urinary frequency, memory concerns and musculoskeletal complaints.
The authors indicated no potential conflicts of interest.
We thank Linda Sandwith, Janet Cowan, Tom Schroeder, Nicholas Hillyer, Holly Brooks, Ellen Fowler and Rene Delgado for their assistance, and the remarkable, dedicated transplant recipients, siblings and friends who have participated in this long-term study.
Supported by Grants No. CA63030 and CA78990 from the National Cancer Institute. Presented in part at the American Psychosocial Oncology Society 2nd annual meeting, Phoenix, AZ, January 27–29, 2005. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Horowitz MM: Uses and growth of hematopoietic cell transplantation, in Blume KG, Forman SJ, Appelbaum FR (eds): Thomas' Hematopoietic Cell Transplantation. Malden, MA, Blackwell Science Ltd, 2004, pp 9-15
2. Socie G, Stone JV, Wingard JR, et al: Long-term survival and late deaths after allogeneic bone marrow transplantation: Late Effects Working Committee of the International Bone Marrow Transplant Registry. N Engl J Med 341:14-21, 1999
3. Curtis RE, Rowlings PA, Deeg HJ, et al: Solid cancers after bone marrow transplantation. N Engl J Med 336:897-904, 1997
4. Duell T, van Lint MT, Ljungman P, et al: Health and functional status of long-term survivors of bone marrow transplantation. Ann Intern Med 126:184-192, 1997 5. Bush NE, Haberman M, Donaldson G, et al: Quality of life of 125 adults surviving 6–18 years after bone marrow transplantation. Soc Sci Med 40:479-490, 1995 6. Chiodi S, Spinelli S, Ravera G, et al: Quality of life in 244 recipients of allogeneic bone marrow transplantation. Br J Haematol 110:614-619, 2000[CrossRef][Medline]
7. Kiss TL, Abdolell M, Jamal N, et al: Long-term medical outcomes and quality of life assessment of patients with chronic myeloid leukemia followed at least 10 years after allogeneic bone marrow transplantation. J Clin Oncol 20:2334-2343, 2002
8. Baker KS, Gurney JG, Ness KK, et al: Late effects in survivors of chronic myeloid leukemia treated with hematopoietic cell transplantation: Results from the Bone Marrow Transplant Survivor Study. Blood 104:1898-1906, 2004
9. Andrykowski MA, Bishop EA, Cella DF, et al: Long-term health-related quality of life, growth, and spiritual well-being after hemotopoietic stem-cell transplantation. J Clin Oncol 23:599-608, 2005
10. Socie G, Clift RA, Blaise D, et al: Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: Long-term follow-up of 4 randomized studies. Blood 98:3569-3574, 2001 11. Sullivan KM: Graft-versus-host-disease, in Thomas ED, Blume KG, Forman SJ (eds): Hematopoietic Cell Transplantation. Boston, MA, Blackwell Science, 1999, pp 515-536 12. Syrjala KL, Martin PJ, Deeg HJ, et al: Medical and psychosocial issues in transplant survivors, in Chang AE, Ganz PA, Hayes DF, et al (eds): Oncology: An Evidence-Based Approach. New York, NY, Springer-Verlag, 2004
13. Syrjala KL, Langer SL, Abrams JR, et al: Recovery and long-term function after hematopoietic cell transplantation for leukemia or lymphoma. JAMA 291:2335-2343, 2004
14. Lee SJ, Fairclough D, Parsons SK, et al: Recovery after stem-cell transplantation for hematologic diseases. J Clin Oncol 19:242-252, 2001 15. Louie AD, Robinson LL, Bogue M, et al: Validation of self-reported complications by bone marrow transplantation survivors. Bone Marrow Transplant 25:1191-1196, 2000[CrossRef][Medline] 16. Okura Y, Urban LH, Mahoney DW, et al: Agreement between self-report questionnaires and medical record data was substantial for diabetes, hypertension, myocardial infarction and stroke but not for heart failure. J Clin Epidemiol 57:1096-1103, 2004[CrossRef][Medline]
17. Boudreau DM, Daling JR, Malone KE, et al: A validation study of patient interview data and pharmacy records for antihypertensive, statin, and antidepressant medication use among older women. Am J Epidemiol 159:308-317, 2004 18. Simpson CF, Boyd CM, Carlson MC, et al: Agreement between self-report of disease diagnoses and medical record validation in disabled older women: Factors that modify agreement. J Am Geriatr Soc 52:123-127, 2004[CrossRef][Medline] 19. Centers for Disease Control National Health and Nutrition Examination Survey (NHANES). http://www.cdc.gov/nchs/nhanes.htm, 2004 20. Ware JE, Sherbourne CD: The MOS 36-item Short-Form Health Survey (SF-36): I. Conceptual framework and item selection. Med Care 30:473-483, 1992[Medline] 21. Beck AT, Rush AJ, Shaw BF, et al: Cognitive Therapy of Depression. New York, NY, Guilford, 1979 22. Derogatis LR: SCL-90-R: Administration Scoring and Procedures Manual I. Baltimore, MD, Clinical Psychometrics Research, 1977 23. Syrjala KL, Schroeder TC, Abrams JR, et al: Sexual function measurement and outcomes in cancer survivors and matched controls. J Sex Res 37:213-225, 2000 24. Spanier GB: Measuring dyadic adjustment: New scales for assessing the quality of marriage and similar dyads. J Marriage Fam 38:15-28, 1976[CrossRef] 25. Stern JM, Sullivan KM, Ott SM, et al: Bone density loss after allogeneic hematopoietic stem cell transplantation: A prospective study. Biol Blood Marrow Transplant 7:257-264, 2001[CrossRef][Medline] 26. Andrykowski MA, Carpenter JS, Greiner CB, et al: Energy level and sleep quality following bone marrow transplantation. Bone Marrow Transplant 20:669-679, 1997[CrossRef][Medline] 27. Molassiotis A, Morris PJ: The meaning of quality of life and the effects of unrelated donor bone marrow transplants for chronic myeloid leukemia in adult long-term survivors. Cancer Nurs 21:205-211, 1998[CrossRef][Medline] 28. Hjermstad MJ, Knobel H, Brinch L, et al: A prospective study of health-related quality of life, fatigue, anxiety and depression 3–5 years after stem cell transplantation. Bone Marrow Transplant 34:257-266, 2004[CrossRef][Medline] 29. Cella D, Peterman A, Passik S, et al: Progress toward guidelines for the management of fatigue. Oncology 12:369-377, 1998[Medline] 30. Knobel H, Loge JH, Nordoy T, et al: High level of fatigue in lymphoma patients treated with high dose therapy. J Pain Symptom Manage 19:446-456, 2000[CrossRef][Medline] 31. Courneya KS, Friedenreich CM, Sela RA, et al: The group psychotherapy and home-based physical exercise (group-hope) trial in cancer survivors: Physical fitness and quality of life outcomes. Psycho-Oncol 12:357-374, 2003[CrossRef][Medline]
32. Schulte CS, Beelen DW: Bone loss following hematopoietic stem cell transplantation: A long-term follow-up. Blood 103:3635-3643, 2004 33. Tauchmanova L, Selleri C, Rosa GD, et al: High prevalence of endocrine dysfunction in long-term survivors after allogeneic bone marrow transplantation for hematologic diseases. Cancer 95:1076-1084, 2002[CrossRef][Medline] 34. Socié G, Cahn JY, Carmelo J, et al: Avascular necrosis of bone after allogeneic bone marrow transplantation: Analysis of risk factors for 4388 patients by the Societe Française de Greffe de Moelle (SFGM). Br J Haematol 97:865-870, 1997[CrossRef][Medline]
35. Tauchmanova L, Serio B, Del Puente A, et al: Long-lasting bone damage detected by dual-energy X-ray absorptiometry, phalangeal osteosonogrammetry, and in vitro growth of marrow stromal cells after allogeneic stem cell transplantation. J Clin Endocrinol Metab 87:5058-5065, 2002 36. Kauppila M, Irjala K, Koskinen P, et al: Bone mineral density after allogeneic bone marrow transplantation. Bone Marrow Transplant 24:885-889, 1999[CrossRef][Medline] 37. Kelly PJ, Atkinson K, Ward RL, et al: Reduced bone mineral density in men and women with allogeneic bone marrow transplantation. Transplantation 50:881-883, 1990[Medline] 38. Ebeling PR, Thomas DM, Erbas B, et al: Mechanisms of bone loss following allogeneic and autologous hemopoietic stem cell transplantation. J Bone Miner Res 14:342-350, 1999[CrossRef][Medline]
39. Rossouw JE, Anderson GL, Prentice RL, et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 288:321-333, 2002
40. Curtis RE, Travis LB, Rowlings PA, et al: Risk of lymphoproliferative disorders after bone marrow transplantation: A multi-institutional study. Blood 94:2208-2216, 1999 41. Flowers MED, Deeg HJ: Delayed complications after hematopoietic cell transplantation, in: Blume KG, Forman SL, Appelbaum FR (eds) Thomas' Hematopoietic Cell Transplantation. Oxford, UK, Blackwell Publishing, 2004 42. Strasser SI, Myerson D, Spurgeon CL, et al: Hepatitis C virus infection and bone marrow transplantation: A cohort study with 10-year follow-up. Hepatology 29:1893-1899, 1999[CrossRef][Medline]
43. Strasser SI, Sullivan KM, Myerson D, et al: Cirrhosis of the liver in long-term marrow transplant survivors. Blood 93:3259-3266, 1999
44. Peffault de Latour R, Levy V, Asselah T, et al: Long-term outcome of hepatitis C infection after bone marrow transplantation. Blood 103:1618-1624, 2004
45. Syrjala KL, Dikmen S, Langer SL, et al: Neuropsychological changes from before transplant to 1 year in patients receiving myeloablative allogeneic hematopoietic cell transplant. Blood 104:3386-3392, 2004 46. Molassiotis A, van den Aker OB, Milligan DW, et al: Quality of life in long-term survivors of marrow transplantation: Comparison with a matched group receiving maintenance chemotherapy. Bone Marrow Transplant 17:249-258, 1996[Medline] 47. Schimmer AD, Ali V, Stewart AK, et al: Male sexual function after autologous blood or marrow transplantation. Biol Blood Marrow Transplant 7:279-283, 2001[CrossRef][Medline]
48. Syrjala KL, Roth-Roemer SL, Abrams JR, et al: Prevalence and predictors of sexual dysfunction in long-term survivors of marrow transplantation. J Clin Oncol 16:3148-3157, 1998 49. Wingard JR, Curbow B, Baker F, et al: Sexual satisfaction in survivors of bone marrow transplantation. Bone Marrow Transplant 9:185-190, 1992[Medline]
50. Andrykowski MA, Brady MJ, Henslee-Downey PJ: Psychosocial factors predictive of survival after allogeneic bone marrow transplantation for leukemia. Psychosom Med 56:432-439, 1994
51. Loberiza FR Jr, Rizzo JD, Bredeson CN, et al: Association of depressive syndrome and early deaths among patients after stem-cell transplantation for malignant diseases. J Clin Oncol 20:2118-2126, 2002 52. Cordova MJ, Andrykowski MA: Responses to cancer diagnosis and treatment: Posttraumatic stress and posttraumatic growth. Semin Clin Neuropsych 8:286-296, 2003 Submitted January 18, 2005; accepted June 2, 2005. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
60.
2 and t tests were utilized to compare medical and demographic characteristics of the participating versus not participating 10-year survivors during the enrollment time frame and to compare sibling versus friend controls. Paired t-tests, McNemar, and Wilcoxon signed ranks tests were used to examine differences between survivors and case-matched controls. To offset multiple comparisons, two-tailed 
was set at .01. 
