Performance Limitations and Participation Restrictions Among Childhood Cancer Survivors Treated With Hematopoietic Stem Cell Transplantation: The Bone Marrow Transplant Survivor Study

Background  Hematopoietic stem cell transplantation (HCT) may result in important disease- and treatment-related late effects. This study estimated physical, emotional, and educational limitations (performance limitations) and restrictions in the ability to perform personal care or routine daily activities (physical participation restrictions) and restrictions in the ability to participate in social roles (social participation restrictions) in a cohort of cancer survivors treated with HCT during childhood.

Methods  Study participants included 235 persons who had a malignancy or hematologic disorder, were treated with HCT before the age of 21 years, and survived at least 2 years after transplantation. A comparison group was recruited and frequency matched for age, sex, and ethnicity. Medical data were abstracted, and patients or parents (if <18 years at survey completion) completed a mailed 24-page questionnaire.

Results  Adult survivors of childhood cancer were more likely than the comparison group to report limitations in physical (prevalence odds ratio [OR], 2.2; 95% confidence interval [CI], 1.3-3.7) and emotional domains (OR, 2.9; 95% CI, 1.4-5.8) and to report physical participation restrictions (OR, 3.9; 95% CI, 1.9-8.2). Adult survivors were also less likely than the comparison group to be married (OR, 0.4; 95% CI, 0.2-0.6). Child survivors were more likely than similarly aged children to have participated in special education (OR, 3.0; 95% CI, 1.5-6.0), to report physical participation restrictions (OR, 10.8; 95% CI, 2.2-53.9), and to have behaviors that indicated impaired social competence (OR, 2.0; 95% CI, 0.9-4.2).

Conclusion  This study demonstrated that persons treated with HCT as children were at increased risk for performance limitations that restricted participation in routine daily activities and interpersonal relationships.

Hematopoietic stem cell transplantation (HCT) is used to treat a variety of malignant and nonmalignant disorders in children and adults.¹ Approximately 6000 HCTs are performed in the United States each year, with the number of recipients who are at least 5-year survivors estimated at 100 000.² Hematopoietic stem cell transplantation is associated with several disease-related and treatment-specific medical late effects^3-13 that have the potential to limit functional performance in physical, emotional, and educational domains. Over time, these limitations may adversely affect the individual’s ability to participate fully in life’s roles, such as engaging in daily activities or interacting socially.

Few studies of transplantation survivors have evaluated the prevalence of performance limitations across physical, emotional, and educational domains or the impact on the ability to participate physically and socially in life roles. Furthermore, few reports evaluate the association between performance limitations and participation restrictions in individuals who undergo transplantation during childhood.

The aims of this analysis were (1) to estimate the prevalence of performance limitations (physical, emotional, and educational) and physical and social participation restrictions in a cohort of patients who underwent transplantation before the age of 21 years and who survived at least 2 years after transplantation; (2) to compare performance limitations and participation restrictions in HCT survivors with those in a representative comparison group; and (3) to evaluate the extent to which performance limitations were associated with participation restrictions among HCT survivors.

This analysis is part of the Bone Marrow Transplant Survivor Study (BMT-SS), a collaborative study between City of Hope Cancer Center and the University of Minnesota. Eligibility criteria for this analysis included (1) HCT for hematologic or nonhematologic malignancy; (2) date of transplantation between January 1, 1974, and December 31, 1998; and (3) survival of more than 2 years after HCT. This analysis was restricted to English-speaking survivors younger than 21 years at the time of their transplantation and alive at the time of the initial survey. The human subjects review committees at both institutions approved all study questionnaires and protocols. All participants provided informed consent.

A total of 528 eligible patients were identified. Of these, 136 (25.7%) were lost to follow-up, 131 (24.8%) declined participation, and 26 (4.9%) had yet to complete the study questionnaire. A total of 235 survivors or their proxies completed a study questionnaire, which represents 60.0% of those successfully contacted. The comparison group included siblings of another cohort of cancer survivors¹⁴ who completed a questionnaire between 1996 and 2003 that contained identical study questions. Comparison group participants were frequency matched to cases at a ratio of 3:1 and randomly selected from 3845 eligible group members from within 6 age groups (<10 years, 11-14 years, 15-17 years, 18-29 years, 30-39 years, ≥40 years), 2 sex groups, and 2 race/ethnicity (white or other) categories.

Data collection was conducted by abstracting information from medical records and by having participants (aged ≥18 years at survey) or their parents (if participants were aged <18 years) complete the 24-page BMT-SS questionnaire about the presence and timing of medical conditions, the presence of performance limitations during a 2-year period before study participation, and the presence of current participation restrictions. This questionnaire has excellent (93%)¹⁵ agreement with reported major medical conditions when compared with medical records information. Marital status, educational attainment, and a measure of emotional health, the Brief Symptom Inventory (BSI),¹⁶ are part of the adult version of the BMT-SS. Participation in special education, social competence, and emotional health based on parental observation are included in the child version of the BMT-SS.

Adults. The primary outcome measures for adult participants treated during childhood were physical participation restrictions and marital status. Participants were classified as having a physical participation restriction if they answered yes to either of 2 questions: “Because of any impairment or health problems, do you need the help of other persons with personal care needs, such as eating, bathing, dressing, or getting around your home?” or “Because of any impairment or health problems, do you need the help of other persons in handling routine needs, such as everyday household chores, doing necessary business, shopping, or getting around for other purposes?” Marital status was determined by participants’ answers to the question, “Which of these possibilities best describes your current marital status?” A dichotomous value was assigned, in which 1 indicated married or living as married and 0 indicated unmarried.

Children. The primary outcome measures for younger participants were physical participation restrictions and social competence. Physical participation restrictions were classified as described for the adults. Social competence was scored by summing values from answers to 6 questions about current friendships and play behavior, adapted from the Child Behavior Checklist.¹⁷ Scores ranged from 4 (a child who had no friends, participated in few social activities, did not get along with others, and did not play well alone) to 19 (a child who had many friends, participated in multiple social activities, got along well with others, and could self-entertain). After examining the distributions of social competence, this variable was dichotomized using a cutoff point at or below the comparison group 10th percentile to represent social participation restrictions.

The risk factors of interest were limitations in physical, emotional, and educational performance.

Adults. Physical performance was scored by summing the answers to 6 questions about performance of particular physical activities: “Over the past 2 years, how long (if at all) has your health limited you in each of the following activities? (1) vigorous activities like lifting heavy objects, running, or participating in strenuous sports, (2) moderate activities like moving a table, carrying groceries, or bowling, (3) walking uphill or climbing a few flights of stairs, (4) bending, lifting, or stooping, (5) walking one block, and (6) eating, dressing, bathing, or using the toilet.” Scores of 1 to 3 were assigned to each question, with 1 indicating limited for more than 3 months; 2, limited for 3 months or less; and 3, not limited at all. This variable was also dichotomized using a cut point at or below the comparison group 10th percentile to indicate the presence of physical performance limitations. Emotional functioning was evaluated by scoring the BSI-18, an instrument designed to evaluate emotional health. Raw scores were converted to T scores based on population normative values provided in the scoring manual.¹⁶ On the basis of previous work by Derogatis,¹⁶ a T score of 63 or higher was used as the cutoff point for impaired emotional health. Educational attainment was classified according to participants’ answers to the question, “What is the highest grade or level of schooling that you have completed?” Participants were classified into 3 categories: (1) did not complete high school, (2) high school graduate, and (3) college graduate.

Children. Physical performance among children was scored as described for adults. Children’s emotional functioning was evaluated using a score based on 23 behavior questions answered by the child’s parent. The construct validity of this portion of the questionnaire was evaluated in a larger population of childhood cancer survivors¹⁴ using exploratory factor analysis, in which 5 factors were identified with maximum likelihood estimation. The correlations of the questions within and between each factor were identified to determine internal consistency. The mean values between participants and siblings were compared to evaluate discriminate validity (within-factor and between-factor correlations ranged from 0.75 to 0.89; survivors had higher scores than siblings, indicating greater problems with behaviors related to emotional health; P<.001). This variable was dichotomized using a cutoff point at or above the comparison group 90th percentile to indicate the presence of emotional performance limitations. Participation in special education was used as a crude measure of educational attainment among younger participants, recorded as a dichotomous variable based on the answer of the child’s proxy to the question, “In elementary, junior high, or high school, was your child ever in a learning disabled or special education program because of low scores on tests, problems learning or concentrating, emotional-behavioral problems, or missed school?”

Graft-vs-host Disease and Major Medical Conditions. The presence of chronic graft-vs-host disease (cGVHD) was determined by examining medical records. Consistent with the work of Hudson et al,¹⁸ the following major medical late effects, reported by survivors since transplantation, were analyzed: complete deafness; kidney dialysis; congestive heart failure; a history of myocardial infarction; angioplasty; bypass surgery or stroke; liver cirrhosis; heart, lung, or kidney transplantation; amputation; joint replacement or a second cancer; and current use of seizure medications, medications for heart problems or high blood pressure, chemotherapy, immunosuppressants, or oxygen.¹⁸

Personal Characteristics. Personal characteristics included study participants’ sex, race/ethnicity, age in years at survey completion, and age at transplantation, and time since transplantation.

All analyses were completed separately for participants younger than 18 years (children) at the time of the survey and those who were 18 years or older (adults). The analyses of educational attainment and marital status for adults were stratified into 2 groups to account for the possibility that 18- to 24-year-old survivors might still be completing formal education.

The HCT survivors were compared with the comparison group for the presence of a major medical condition, for each performance measure (physical, emotional, and educational), for physical participation restrictions and marital status (adults), or for physical and social participation restrictions (children) using multiple logistic regression. Restricting the analyses to the HCT survivor population only, logistic regression models were used to evaluate the association between the participants’ personal characteristics, conditioning regimen, cGVHD, or a major medical condition among HCT survivors who reported physical, emotional, and educational performance limitations. Finally, to determine the relation between measures of performance and the outcome variables of physical participation restrictions, marital status (adults), and social participation restrictions (children), each measure of performance was evaluated in survivor-survivor comparisons using multiple logistic regression, adjusting for sex, ethnicity, time since transplantation in years, and age at survey completion.

Participants were more likely than nonparticipants to be female (104 [44.3%] and 91 [34.1%], respectively) and white (199 [84.7%] vs 205 [76.8%]) but did not otherwise differ significantly from nonparticipants (Table 1). The mean age at survey completion was similar for the adult participants and the adult comparison group (mean ± SD, 26 ± 6 years). Among the children, both participants and members of the comparison group had mean ± SD ages of 13 ± 3 years. Mean age at transplantation was 10.7 ± 6.3 years, and mean survival time was 11.7 ± 5.7 years. The diagnosis and treatment characteristics of the study participants are given in Table 2.

Adults. We documented cGVHD in 37 (23.4%) of participants. Fifteen (9.5%) of adults reported current use of cardiac medications, and 15 (9.5%) reported current use of immunosuppressants. The other most common medical conditions reported by adults were a history of second cancer (14 [8.9%]) or stroke (9 [5.7%]). The HCT recipients were 10.3 times (95% confidence interval [CI], 6.1-17.4) more likely to report a major medical condition than were adults in the comparison group (data not shown).

Children. Nine (11.5%) of young survivors had documented cGVHD. Current use of cardiac medications was reported for 12 of children (15.4%), and current use of immunosuppressants was reported for 4 (5.1%). The other most common medical condition was congestive heart failure (4 children [5.1%]). Child survivors were 24.8 times (95% CI, 7.1-86.6) more likely to have a reported major medical condition than children in the comparison group (data not shown).

Adults. Limitations in physical performance were reported by 28 (17.8%) of adult survivors compared with 42 adults (8.9%) in the comparison group (odds ratio [OR], 2.2; 95% CI, 1.3-3.7). Adult survivors were almost 3 times (OR, 2.9; 95% CI, 1.4-5.8) more likely to have a BSI score that indicated an emotional difficulty. No significant differences in educational attainment were observed. Adult survivors were 3.9 times (95% CI, 1.9-8.2) more likely to report physical participation restrictions than the comparison group (Table 3).

Children. Limitations in physical and emotional performance did not differ significantly between survivors and the comparison group, although HCT survivors were 3.0 times (95% CI, 1.5-6.0) more likely to have participated in special education. The HCT survivors were also more likely than the comparison group to report a physical participation restriction (9.0% vs 0.8%; OR, 10.8; 95% CI, 2.2-53.9) and were twice as likely to have reported behaviors that indicated social participation restrictions (Table 3).

Adults. Adult survivors with physical performance limitations were more likely to have documented cGVHD (OR, 3.1; 95% CI, 1.3-7.5) or a reported major medical condition (OR, 3.4; 95% CI, 1.4-7.9) than those without physical performance limitations, after adjusting for age at interview and sex. Emotional performance limitations were not associated with any particular treatment variables or medical late effects. Adult survivors of races other than white were less likely than white survivors to graduate from high school (Table 4).

Children. After adjusting for sex, age at transplantation, cGVHD, and the presence of a major medical condition, the relative odds of a physical performance limitation were higher among the HCT survivors who had received total body irradiation (TBI) (OR, 15.9; 95% CI, 1.3-199.4) when compared with survivors who did not receive TBI. A strong association was also seen among those who were more than 10 years past diagnosis (OR, 31.7; 95% CI, 1.2-812.1) relative to those who had survived 2 to 5 years. Emotional performance limitations and participation in special education were not associated with any particular personal characteristic, treatment regimen, or medical late effect in children (Table 4).

Adults. The impact of the loss of performance on participation is given in Table 5. After adjusting for age at survey, time since transplantation, sex, and race/ethnicity, all domains of the performance limitations were associated with restricted abilities to perform personal care or to participate in routine activities among adult survivors of childhood HCT. Adult survivors with physical performance limitations were 22.1 times (95% CI, 6.3-77.9) more likely to need help with personal care or routine activities than those without physical performance limitations. Those with emotional performance limitations were 17.1-fold more likely (95% CI, 4.6-64.0) to report physical participation restrictions than those without, and participants who did not graduate from high school were 4.7 times (95% CI, 1.1-21.0) more likely than those who graduated from high school to report physical participation restrictions. Adult HCT survivors were 5 times less likely than those without physical performance limitations to be currently married (OR, 0.2; 95% CI, 0.1-0.9).

Children. Limitations in physical and emotional performance and the need for special education were associated with both physical and social participation restrictions in young HCT survivors (Table 5). Children with emotional performance limitations were 9.2 times (95% CI, 1.2-68.0) more likely than those without to have a physical participation restriction. These children were also far less able to participate socially, having 83.3 times (95% CI, 9.9-698.7) the risk of scoring within the lowest 10% of population norms when compared with children without an emotional performance limitation.

This study demonstrates that 10% of long-term HCT survivors who underwent transplantation during childhood report a physical participation restriction that limits independence in personal care or routine activities, a significantly higher proportion than found in a comparison group of similar sex and age. Although few quantitative studies of physical and social participation restrictions in individuals who received HCT as children exist, our findings support previous work in the adult HCT population, where the prevalence of physical participation restrictions has been estimated at 9.5% to 26.3%.^19-21 In our relatively young adult population, the proportion of survivors married or living as married was also lower (26.8%) than reported by other researchers in populations of survivors who received HCT during adulthood (57.0%-71.0%).^22-25 Among child participants in our study, 16.7% had a reported difficulty with social skills. Another recent study²⁶ of childhood HCT survivors reported an even higher proportion (25.0%) who indicated difficulty with social skills.

In our study, physical participation restrictions and not being in a marital relationship were significantly associated with physical performance limitations, independent of effects of age, length of survival, sex, and race/ethnicity. Physical performance limitations were most common in young adult HCT survivors who had a major medical condition, cGVHD, or both. These findings are consistent with much of the literature related to late effects and quality of life in HCT recipients, which shows that physical symptoms and physical performance limitations continue to be a problem for a small proportion of long-term survivors.^3,19,27-34

Among the child HCT survivors, our study demonstrated that physical and social participation restrictions were associated with limitations in physical and emotional performance and with the need for special education. Children who received TBI as part of their conditioning regimen were more likely to have impaired physical performance. Limitations in physical performance were more common in children with a longer survival time, perhaps indicating the loss of function over time. There is little information available about the effects of TBI on physical performance; however, TBI was previously reported to be associated with limitations in cognitive functioning in childhood HCT recipients.^35,36 Recent studies indicate that cognitive decline may not become apparent until later in the child’s development.³⁷

Methodologic limitations need to be considered when interpreting these results. First, given the relatively low response rate (60% of those successfully contacted), the possibility exists that participation bias influenced our estimates. Participants did not differ from nonparticipants by most sociodemographic or treatment factors, but we could not assess differences in medical late effects, performance limitations, or participation status. Second, our comparison group consisted of siblings of cancer survivors who are by nature indirect participants in the cancer experience and could conceivably have uncommonly high frequencies of performance limitations in the emotional or educational domains.^38,39 Third, sample size restrictions did not allow us to provide reliable statistical estimates of outcomes by type of cancer, specific conditioning regimen, transplantation type, or stem cell source. Fourth, the survey for the younger participants was completed by their parents, who may have expectations and interpretations that differ from those of their children in terms of both emotional performance and participation in social situations. Finally, because the data regarding medical late effects, performance limitations, and participation restrictions were collected simultaneously, we cannot be certain about the temporal association among these outcomes.

This study represents the first attempt, to our knowledge, to report in a comprehensive and systematic fashion the participation restrictions experienced by long-term cancer survivors who underwent transplantation during childhood. We have shown in this study that although most survivors lead independent and productive lives, a subset of individuals have persistent medical late effects or organ system impairments that result in performance limitations associated with impaired social skills, decreased physical independence, and decreased rates of marriage. Surveillance and long-term follow-up should include monitoring of children and adults treated during childhood who are at risk for functional loss so that they can be referred for intervention to restore function, provide compensatory strategies for function that cannot be restored, or adapt the environment to allow optimal participation in home and social environments.^40,41

Correspondence: James G. Gurney, PhD, Division of General Pediatrics, University of Michigan, 300 N Ingalls, Room 6E08, Ann Arbor, MI 48109-0456 (jamegurn@umich.edu).

Accepted for Publication: February 17, 2005.

Funding/Support: This study was supported by grant CA78938-02 from the National Institutes of Health, Bethesda, Md. Dr Bhatia is a Clinical Scholar of the Leukemia and Lymphoma Society, White Plains, NY. Dr Gurney receives support from the Children’s Cancer Research Fund at the University of Minnesota.