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Physical performance limitations among adult survivors of childhood brain tumors
Article first published online: 1 APR 2010
Copyright © 2010 American Cancer Society
Volume 116, Issue 12, pages 3034–3044, 15 June 2010
How to Cite
Ness, K. K., Morris, E. B., Nolan, V. G., Howell, C. R., Gilchrist, L. S., Stovall, M., Cox, C. L., Klosky, J. L., Gajjar, A. and Neglia, J. P. (2010), Physical performance limitations among adult survivors of childhood brain tumors. Cancer, 116: 3034–3044. doi: 10.1002/cncr.25051
- Issue published online: 11 JUN 2010
- Article first published online: 1 APR 2010
- Manuscript Revised: 15 SEP 2009
- Manuscript Accepted: 15 SEP 2009
- Manuscript Received: 31 AUG 2009
- physical performance;
- brain tumor;
- cancer survivor;
Young adult survivors of childhood brain tumors (BTs) may have late effects that compromise physical performance and everyday task participation. The objective of this study was to evaluate muscle strength, fitness, physical performance, and task participation among adult survivors of childhood BTs.
In-home evaluations and interviews were conducted for 156 participants (54% men). Results on measures of muscle strength, fitness, physical performance, and participation were compared between BT survivors and members of a population-based comparison group by using chi-square statistics and 2-sample t tests. Associations between late effects and physical performance and between physical performance and participation were evaluated in regression models.
The median age of BT survivors was 22 years (range, 18-58 years) at the time of the current evaluation, and they had survived for a median of 14.7 years (range, 6.5-45.9 years) postdiagnosis. Survivors had lower estimates of grip strength (women, 24.7 ± 9.2 kg vs 31.5 ± 5.8 kg; men, 39.0 ± 12.2 kg vs 53.0 ± 10.1 kg), knee extension strength (women, 246.6 ± 95.5 Newtons [N] vs 331.5 ± 5.8 N; men, 304.7 ± 116.4 N vs 466.6 ± 92.1 N), and peak oxygen uptake (women, 25.1 ± 8.8 mL/kg per minute vs 31.3 ± 5.1 mL/kg per minute; men, 24.6 ± 9.5 mL/kg per minute vs 33.2 ± 3.4 mL/kg per minute) than members of the population-based comparison group. Physical performance was lower among survivors and was associated with not living independently (odds ratio [OR], 5.0; 95% confidence interval [CI], 2.0-12.2) and not attending college (OR, 2.3; 95% CI 1.2-4.4).
Muscle strength and fitness values among BT survivors were similar to those among individuals aged ≥60 years and were associated with physical performance limitations. Physical performance limitations were associated with poor outcomes in home and school environments. The current data indicated an opportunity for interventions targeted at improving long-term physical function in this survivor population. Cancer 2010. © 2010 American Cancer Society.
Brain tumors (BTs) account for approximately 20% of cancers in children ages 0 to 19 years. The incidence in the United States is approximately 29 per 1,000,000 persons or 2277 new cases per year.1 Although multimodal treatment approaches often are successful, resulting in a cure for nearly 70% of children with BTs, patients frequently suffer significant long-term deficits. Physical, sensory, cognitive, neurologic, and endocrine complications are reported.2
Impairments of the central nervous system as a consequence of either the tumor or its treatment may alter cognitive, emotional, and/or physical performance. Less than optimal function in these domains may influence activities of daily living and greatly affect the BT survivor's ability to fully participate in expected roles at home, school, and work. Although there is a substantial body of literature that documents the prevalence and types of cognitive and emotional problems experienced by childhood BT survivors,3-9 physical performance limitations, although recognized,5, 10-15 are poorly quantified. The etiology of these limitations and their impact on life roles among childhood BT survivors is largely unknown.
In this article, we report the results from a study that was designed to document the prevalence of and risk factors for specific impairments likely to be associated with physical performance limitations. In addition, we assess the association between observed limitations in physical performance and the inability of BT survivors to participate fully in expected social roles.
MATERIALS AND METHODS
BT survivors aged ≥18 years who were treated between 1970 and 2000 when <21 years of age were recruited randomly from clinical populations at St. Jude Children's Research Hospital and the University of Minnesota Children's Hospital. Pregnant women or individuals who were receiving treatment for an active tumor were not eligible. A population-based comparison group also was enrolled and was frequency matched to participants by age group (ages 18-29 years, 30-39 years, 40-49 years, and 50-59 years), sex, and zip code. Lists of randomly selected names and residential addresses were generated for sex-matched and age-matched individuals within the zip codes of eligible BT survivors using Melissa Data services (available at: http://www.melissadata.com accessed on March 23, 2010). Potentially eligible comparison group members received letters to introduce the study and return post cards to indicate their interest or disinterest. Both BT survivors and comparison group members were reimbursed for participation and had home visits to eliminate the potential for healthy participation bias based on inability to travel to the hospital. Institutional approval for human subjects research and consent from all study participants or legal guardians were obtained before completing study measures.
Outcomes of Interest
The study outcomes, which were evaluated during the home visit, were body mass index (BMI), sensation, muscle strength, fitness, physical performance and participation. The examiners (C.R.H., L.S.G., and K.K.N.) measured weight in kilograms and standing height to the nearest centimeter with a portable electronic scale and a tape measure. BMI was calculated as weight in kilograms divided by height in meters squared and was classified as underweight (<18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), and obese (≥30 kg/m2). Visual deficits that were documented by a physician and not corrected by glasses and partial or complete hearing loss diagnosed by audiogram were verified by examination of patients' records. Touch sensation was tested with a 5.07 Semmes Weinstein monofilament.16, 17 Hand grip and knee extension strength were assessed using hand-held myometry. Muscle weakness was classified as present if values were ≥2.5 standard deviations below expected means for age and sex.18, 19 Exercise tolerance was estimated with the Duke Activity Status Index, a questionnaire that estimates peak oxygen uptake and that is correlated with values recorded by gas analysis during graded exercise testing (r = 0.81).20 Individuals were classified as impaired if their estimated peak oxygen uptake was ≥2.5 standard deviations below age- and sex-predicted values.21
Physical performance limitations were evaluated with the Physical Performance Test (PPT), the Berg Balance Test (Berg), and the Functional Status Index (FSI). The 7-item PPT includes a series of timed tasks: writing a sentence, eating, dressing, picking up a small object, putting an object on a shelf, standing and turning, and walking. The PPT is internally consistent and has excellent test-retest reliability.22 A score of 28 on the PPT indicates no physical performance deficit.22 The Berg appraises ability to maintain an upright position during typical movements. The Berg has high internal consistency and high inter-rater and intrarater reliability.23 A score of ≤45 on the Berg indicates the risk for a fall. An individual who had no impairment will score 56 on the Berg.23 The FSI is a questionnaire that measures physical performance in 3 dimensions: assistance, difficulty, and pain. It is internally consistent and has test-retest reliability.24 A score of 54 on the FSI (range, 54-252) indicates no disability.24
Participation status was evaluated by asking open-ended questions about employment, education, and current living situation. Employment was categorized as employed or student, sheltered employment, or unemployed. Individuals in the sheltered employment category required direct supervision/assistance of a caregiver/coach at work. Four survivors required caregiver assistance to answer these questions. Educational attainment was classified as less than high school, high school graduate, or more than high school; and living situation was classified as independent, living with family support beyond housing or shared meals, or custodial care. Young adults who still were completing their education but who were living with their parents were included in the independent category.
Demographic and Treatment Information
Demographic information was obtained from study participants and/or caregivers. Treatment information was obtained from medical records using trained abstractors. Tumor type and location, surgical interventions, and chemotherapy agents and doses were recorded. Cranial and spinal radiation doses were abstracted using written descriptions from medical records, treatment diagrams, and photographs taken in treatment positions. By using the methods described by Packer et al,25 4 different anatomic segments were identified (frontal cortex, temporal lobe, posterior fossa, and parietal or occipital cortex). The maximum dose was estimated for each segment.
Cognitive performance was evaluated with version 2 of the Kaufman Brief Intelligence Test,26 which results in an Intelligence Quotient (IQ) Composite with a population mean of 100 and a standard deviation of 15. Internal consistency and test-retest reliability are documented.
Descriptive statistics were calculated to describe the study participants. Percentages for impaired BMI, sensation, muscle strength, and fitness were compared between groups (BT survivors and members of the population-based comparison group) with the Fisher exact test.30 Means were calculated for physical, cognitive, and emotional performance scales and were compared between groups with 2-sample t tests. The results are presented with effect sizes (mean differences between groups divided by pooled standard deviations).31 Percentages for categories of employment, education, and living situation also were compared between groups with the Fisher exact test.30 In the analyses that were limited to survivors, associations between diagnosis and treatment variables and impairments or physical performance outcomes were evaluated in multivariate logistic regression models32; associations between impairments and scores on the PPT, Berg, and FSI were evaluated in multivariate linear regression models33; and associations between performance limitation and participation were evaluated in multivariate logistic regression models.32 SAS version 9.2 (SAS Inc., Cary, NC) was used for all analyses.
Participants included 78 of the first 132 eligible BT survivors who were selected randomly for contact. Nonparticipants included 19 individuals (14.4%) who could not be located and 35 individuals (26.5%) who actively or passively declined participation (Fig. 1). Members of the population-based comparison group included 78 of 99 individuals who responded to an invitation that was mailed to randomly selected names/addresses from a public use database based on BT participants' age, sex, and zip code (Fig. 1). BT participants did not differ from nonparticipants by sex, current age, age at diagnosis, survival time, or tumor type (P > .50). Fifty-four percent of survivors were men, and 85.9% reported their race/ethnicity as white. Sex and race distributions of comparison group members were identical to those of BT survivors. Survivors' current age ranged from 18.4 years to 58.3 years (median age, 22 years). Comparison group members were slightly older (median age, 25 years; range, 18-54 years). Additional characteristics of the survivors are listed in Table 1. Greater than 50% of survivors were aged <10 years when they were diagnosed, and 84.6% had survived for ≥10 years since diagnosis. The most common tumor type was astrocytic, and the most common tumor location was the cerebellum. Seventy-seven percent of survivors had undergone surgical resection as part of their treatment, 66.7% had received cranial radiation, and 30.8% had received chemotherapy.
|Age at diagnosis, y|
|Time since diagnosis, y|
|Primary tumor location|
|Brainstem and spine||2||2.6|
|Extent of surgery|
|Near total resection||13||16.7|
|Gross total resection||36||46.2|
|Specific chemotherapy agents|
|Cranial and spinal||23||29.5|
|Cranial dose, cGya||5400||3600-7020|
|Site specific radiation doses, cGy|
BMI and sensory, muscle strength, and fitness impairments are listed in Table 2. Obesity was prevalent in 35.9% of survivors and in 26.9% of comparison group members. Less than 4% of comparison group members experienced sensory loss, whereas 20.5% of survivors had loss of touch sensation, 26.9% had a visual deficit, and 23.1% had hearing loss. Leg muscle weakness was prevalent in 55.1% of survivors and in 11.5% of the comparison group. Knee extension strength values among BT survivors were comparable to norms reported for individuals ages 60 to 69 years in the general population (women, 246.6 ± 95.5 Newtons [N] vs 269.8 ± 81.6 N; men, 304.7 ± 116.4 N vs 381.7 ± 80.8 N).18 Hand grip strength was ≥2.5 standard deviations below expected in 20.5% of survivors but in no comparison group members. Poor exercise tolerance also was more common in BT survivors than in the comparison group. Average peak oxygen uptake estimates among BT survivors (women, 25.1 ± 8.8 mL/kg per minute; men, 24.6 ± 9.5 mL/kg per minute) were within ranges typically reported for individuals ages 60 to 69 years in the general population (women, 22-27 mL/kg per minute; men, 26-31 mL/kg per minute).21
|Body mass index|
|Underweight (<18.5 kg/m2)||1||1.3||4||5.1||.37|
|Normal weight (18.5-24.9 kg/m2)||26||33.3||23||29.5||.12|
|Overweight (25-29.9 kg/m2)||23||29.5||30||38.5||.31|
|Obese (≥30 kg/m2)||28||35.9||21||26.9||.30|
|Poor exercise tolerancea||26||33.3||5||6.4||<.001|
|Muscle Weakness||Survivors||Comparison Group||P|
|Hand grip, kg|
|Knee extension, N|
|Exercise tolerance (VO2) mL/kg/min|
Mean scores on physical, cognitive, and emotional performance measures are listed in Table 3. Physical performance deficits were evident among BT survivors when compared with the general population with effect sizes ≥0.75 for the FSI, Berg, and PPT. On average, cognitive performance was impaired among BT survivors and not among members of the comparison group. Emotional health did not differ between the 2 groups.
|Performance||Survivors||Comparison Group||Effect Size||P|
|Functional Status Indexa||77.3||42.3||54.8||3.1||0.75||<.001|
|Berg Balance Testb||48.6||12.4||56.0||1.0||0.85||<.001|
|Physical Performance Testb||21.5||7.9||26.8||1.4||1.06||<.001|
|Kaufmann Brief Intelligence Test 2 (composite)||83.1||23.1||102.7||14.3||1.01||<.001|
|Brief Symptom Inventory 18|
|Global status index||49.1||11.0||46.8||8.3||0.23||.16|
|Participation||Survivors||Comparison Group||Effect Size||P|
|High school graduate||27||34.6||8||10.3||—|
The percentages of participants in each category of employment, educational attainment, and living situation are listed in Table 3. BT survivors were more likely to be in sheltered employment or unemployed than comparison group members. Survivors also were less likely to have educational achievement after high school or to live independently than comparison group members.
Effects of Treatment on BMI, Sensation, Muscle Strength, Fitness, and Overall Performance
The results of the final multivariate logistic regression models that were designed to evaluate associations between treatment and BMI, sensory impairments, muscle strength impairments, and fitness impairments among BT survivors are provided in Table 4. Sex, current age, extent of surgery, and tumor type were included in original models but did not demonstrate independent associations with the outcomes, did not alter the strength of associations appreciably for other variables, and, thus, were not included in the final models. After adjusting for tumor location, segment-specific doses, and treatment with either vincristine or platinum, age at diagnosis was the only predictor of hand weakness and poor exercise tolerance.
|Variable||Obesity||Loss of Touch Sensation||Leg Weakness||Hand Weakness||Reduced Exercise Tolerance|
|OR||95% CI||OR||95% CI||OR||95% CI||OR||95% CI||OR||95% CI|
|Received platinum or vincristine|
|Age at diagnosis, y|
Figure 2 illustrates the multivariate associations between treatment variables and scores on the PPT, Berg, and FSI for BT survivors. After adjusting for tumor location and radiation to the temporal lobe and frontal cortex, radiation to the posterior fossa or occipital/parietal lobe, treatment with platinum or vincristine, and aged <5 years at diagnosis were associated with lower scores on the PPT and the Berg and with higher scores on the FSI (all P values <.05). These 4 treatment variables explained 25% of the variance on the FSI, 26% of the variance on the Berg, and 34% of the variance on the PPT.
Effects of BMI, Sensation, Muscle Strength, and Fitness on Overall Performance
Figure 3 illustrates the multivariate associations between sensory, muscle strength, and fitness impairments and scores on the 3 physical performance tests for BT survivors. After adjusting for obesity, grip strength, peak oxygen uptake, and normal/corrected to normal vision were associated with higher scores on the PPT and the Berg and with lower scores on the FSI (all P values <.05). These 3 variables explained 36% of the variance on the FSI, 47% of the variance on the Berg, and 55% of the variance on the PPT.
Effects of Physical Performance on Participation
Associations between performance and participation were evaluated in multivariate models with dependent living status, unemployment, and not attending college as separate outcomes. After adjusting for emotional health and cognitive performance, a 1 standard deviation decrease (5.87 points) on the PPT increased the odds of a dependent living situation by 5.0 (95% confidence interval [CI], 2.0-12.2) and increased the odds of not attending college by 2.3 (95% CI, 1.2-4.4). In the same models, a 1 standard deviation decrease (15 points) in IQ increased the odds of a dependent living situation by 2.0 (95% CI, 1.1-3.7), increased the odds of unemployment by 1.8 (95% CI, 1.1-2.8), and increased the odds of not attending college by 2.4 (95% CI, 1.4-4.0).
To our knowledge, this study is 1 of the first to document specific deficits in muscle force production and exercise tolerance among adult survivors of childhood BTs. The results indicate that young age at diagnosis is the strongest predictor of weakness and poor fitness. In this report, we also describe associations between poor exercise tolerance, muscle weakness, and overall physical performance and between segment-specific radiation, treatment with vincristine or platinum, young age at diagnosis, and overall physical performance. BT survivors with poor physical performance outcomes face several life challenges. Even after taking into account cognitive status and emotional health, we document that physical performance limitations are associated with restricted participation in both home and educational environments.
Our results are striking, because our measures of muscle strength, peak oxygen uptake, and overall physical performance scores are slightly lower than the published reference norms for individuals in the seventh decade of their lives.18, 21 The survivors who we tested had a median age of 22 years. This information indicates that childhood BT survivors may be particularly vulnerable to declines in physical performance that typically accompany aging, perhaps increasing their risks for other health problems associated with inactivity, like osteoporosis, cardiovascular disease, and obesity.34-38 Muscle weakness and reduced exercise capacity are known independent predictors of heart disease, osteoporosis, and mortality in the general population,39-44 and also may predict an increased risk for chronic disease and early death in childhood BT survivors.45, 46
Our findings of an association between young age at diagnosis and muscle weakness, poor fitness, or diminished overall motor performance are consistent with 1 investigation that included survivors of other types of childhood cancer and diverge from 2 other studies that evaluated predictors of motor performance among childhood BT survivors. Talvensaari et al47 reported that age at diagnosis explained 44% of the variation in isokinetic trunk strength among 46 survivors of leukemia or solid tumors a median of 9.4 years off treatment. Conversely, Helseth et al48 observed no association between age at diagnosis and score on the locomotion section of the Karnofsky performance index among 28 medulloblastoma survivors. In addition, another study12 indicated that boys who were aged ≥9 years at diagnosis, were treated for BT, and received local irradiation had the worst motor outcomes when examined by a neurologist.
Again, in contrast to published findings, we observed no association between segment-specific radiation and impaired fitness. Jakacki et al49 reported maximal cardiac index values below the fifth percentile in 19 of 26 BT survivors who had received craniospinal radiation, and Jenney et al50 reported an association between craniospinal radiation and reduced values of transfer for carbon monoxide among 70 survivors of childhood leukemia. However, we did observe an association between segment-specific radiation and both muscle strength and overall physical performance. These findings are consistent with data from a study that included 75 long-term survivors of acute lymphoblastic leukemia51 in which cranial radiation was associated with leg weakness and with data from the Childhood Cancer Survivor Study in which self-reported physical performance limitations were 1.4 times more likely among survivors who received radiation compared with those who did not receive radiation.52
The association between grip strength and overall motor performance is supported by other reports that describe performance outcomes in children with other cancer types. Marchese et al53 reported that knee extension strength explained 63% of the variation in performance on the Timed Up and Go test among 16 children with acute lymphoblastic leukemia (ALL). Hartman et al54 described an association between grip strength and performance on the Movement ABC test among 64 survivors of ALL, Wilms tumor, B-non-Hodgkin lymphoma, or malignant mesenchymal tumors; and Gerber et al55 reported an association between muscle weakness and functional loss among 30 pediatric sarcoma survivors.
The impact of poor overall motor performance on participation in life roles is consistent with other research among childhood BT survivors. Odame et al56 reported an association between self-reported physical performance and participation in physical activity among 25 adolescent survivors of childhood BT, and Sutton et al57 reported an association between self-reported physical performance and scores on a BT-specific scale of the Functional Assessment of Cancer Therapy Questionnaire (FACT-Br) among survivors of germinoma who had received craniospinal radiation. The FACT-Br includes items related to everyday tasks like driving and attending work. Physical performance also was a strong indicator of participation in the Childhood Cancer Survivor Study cohort, in which survivors with limitations in physical performance were less likely than those without physical performance limitations to be employed, graduate from high school, or be married.58
We acknowledge that our study has potential limitations. First, our participation rate among survivors was only 59%. It is possible that those who chose to participate in our study had either more or fewer limitations than those who did not participate, which would bias our results. However, participants did not differ from nonparticipants on demographic or treatment factors, and we made every attempt to allow eligible participants to enroll, performing evaluations in their homes, and accommodating evening and weekend visits. Nonresponse to the mailed invitation among potential comparison group members also was high. Our comparison group members were not more or less healthy than the general population, except that they had a higher than expected prevalence of leg weakness. This would result in an underestimate of the degree of this impairment among BT survivors. Finally, although we selected validated instruments and measurement techniques for exercise tolerance and muscle strength, used limited numbers of examiners, and conducted extensive training to assure reliability, we did perform testing in the home. The use of self-reported data and field testing are subject to measurement error and may have reduced the precision of our estimates.59, 60
In summary, on average, adult survivors of childhood BT have significant muscle weakness and poor exercise tolerance. Although this result was not unexpected, this research makes clear the strong association between muscle weakness, poor exercise tolerance, and overall physical performance, which, in turn, interfere with abilities to participate fully in life roles. Recognition of this association provides ready targets for interventions to address these important problems. Rehabilitation strategies to restore, teach compensatory strategies for losses in, or recommend environmental adaptations to optimize function should be designed and tested for both adult survivors and for children currently undergoing therapy. Aerobic and resistance training interventions may be particularly beneficial for this population and will need tailored adaptations to take into account comorbid cognitive and other neurologic deficits.
CONFLICT OF INTEREST DISCLOSURES
Funded by the American Cancer Society (RSGPB-06-210-01-CPPB). Additional funding at St. Jude Children's Research Hospital was provided by the American Lebanese Syrian Associated Charities and, at the University of Minnesota, by the Masonic Cancer Center.
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