PEDIATRICS Vol. 120 No. 5 November 2007, pp. e1229-e1236 (doi:10.1542/peds.2007-0178)
ARTICLE |
Hearing Loss, Quality of Life, and Academic Problems in Long-term Neuroblastoma Survivors: A Report From the Children's Oncology Group
a Child Health Evaluation and Research Unit, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan
b Division of Hematology/Oncology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania
c Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee
d Division of Population Sciences, City of Hope National Medical Center, Duarte, California
e Pediatric Hematology-Oncology, Department of Pediatrics, University of California, San Francisco, California
f Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Illinois, Chicago, Illinois
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVES. Among a cohort of long-term neuroblastoma survivors, our aims were to (1) assess the association between treatment intensity and parent-reported hearing loss in the child, (2) evaluate the strength of the association between hearing loss and parent-reported academic and psychosocial difficulties in the child, and (3) examine the association between parent-reported academic and psychosocial difficulties in the child and the child's self-reported quality of life.
PATIENTS AND METHODS. Through a mailed survey that included the Pediatric Quality of Life Inventory 4.0 and an outcomes questionnaire for parents, we evaluated 137 children (aged 8–17 years) who were previously enrolled in 1 of 2 Children's Cancer Group neuroblastoma clinical studies.
RESULTS. Childhood survivors of neuroblastoma who had prevalent hearing loss, as reported by their parents, had at least twice the risk of an identified problem with reading skills, math skills, and/or attention and a similarly higher risk of a general learning disability and/or special educational needs than did neuroblastoma survivors without hearing loss. Consistent with this finding, hearing loss was associated with a 10-point-lower mean score in the school-functioning scale of the Pediatric Quality of Life Inventory 4.0. We also observed a clear pattern of poorer self-reported quality-of-life scores among children with parent-reported academic and psychosocial problems compared with those without such problems, particularly with school functioning, even after controlling for reported hearing loss.
CONCLUSIONS. We found evidence that long-term neuroblastoma survivors, especially those with hearing loss, are at elevated risk for academic learning problems and psychosocial difficulties. We also found strong concordance between parent-reported learning problems in the child and indications of distress in the child's self-reported quality of life.
Key Words: cancer • chemotherapy • cisplatin • education • psychosocial problems • treatment late effects • ototoxicity
Abbreviations: MYCN—myc myelocytomatosis viral–related oncogene, neuroblastoma derived • QoL—quality of life • COG—Children's Oncology Group • IRB—institutional review board • PedsQL—Pediatric Quality of Life Inventory 4.0 • CI—confidence interval • OR—odds ratio • RR—relative risk
Neuroblastoma is an embryonal malignancy of the sympathetic nervous system that predominantly occurs in infants and very young children; the median age of diagnosis is 19 months.1–4 The adrenal gland is the most common tumor location of origin, but neuroblastoma tumors may arise almost anywhere in the body, including the brain or spinal cord.4 Prognosis varies widely depending on risk stratification at diagnosis, with stage; age; myc myelocytomatosis viral–related oncogene, neuroblastoma derived (MYCN) status; DNA index; and histopathology as important predictors of survival probability.1
There is evidence that survivors of neuroblastoma may experience a number of long-term adverse effects from the tumor and its treatment.5–7 Hearing loss is one important potential treatment-related late effect, caused usually from exposure to platinum-containing chemotherapies, particularly cisplatin and myeloablative doses of carboplatin.8–16 High cumulative doses of platinum chemotherapy are included in multimodal treatment protocols for intermediate- and high-risk neuroblastoma. Platinum-related ototoxicity results from destruction of cochlear sensory hair cells. Because these specialized sensory cells are arranged tonotopically (in order of pitch), the initial hearing loss associated with platinum-based chemotherapy is generally in the high-frequency ranges (>2000 Hz) and results from sensory hair cell destruction that begins at the base of the cochlea and continues toward the cochlear apex, where the speech frequencies (500–2000 Hz) are impacted as cumulative doses of platinum chemotherapy increase.17 Even minimal-to-mild hearing loss in the high-frequency ranges can significantly impact language development, verbal abilities, and reasoning skills in young children.18 This is of particular concern in children with neuroblastoma who receive platinum-based chemotherapy, because they are often still in the process of acquiring language at the time of their treatment. Many of these children will experience therapy-related hearing loss initially affecting the high-frequency ranges. The impact of this high-frequency hearing loss on language development in young children is important and often underappreciated.13
The high-frequency speech phonemes are critical to speech intelligibility19 and the identification of verb tense and pleural forms.20 The English language relies heavily on fricative consonants (sounds such as "s," "f," and "th," which are produced by forcing air through a narrowing of the vocal tract) to convey the meaning of words. Because fricative sounds are primarily high frequency in nature, even mild-to-minimal losses in the high-frequency range have been associated with problems with language acquisition and speech discrimination, which are associated with increased academic and social-emotional difficulties in young children.18,21 Given the important age-dependent developmental tasks of speech and language acquisition and the recognition that these tasks mirror the usual age at neuroblastoma treatment, we were concerned about the potential effects on psychosocial and academic functioning among childhood survivors of neuroblastoma. The purpose of this report is to disseminate findings from a cross-sectional follow-up analysis of quality of life (QoL) among 137 survivors of neuroblastoma who were enrolled on 1 of 2 national clinical studies through the Children's Cancer Group (now part of the Children's Oncology Group [COG]). The aims of the analysis were threefold: (1) to describe the association between treatment intensity and parent-reported hearing loss in the child; (2) to evaluate the strength of the association between hearing loss and parent-reported academic and psychosocial difficulties in the child; and (3) to examine the association between parent-reported academic and psychosocial difficulties in the child and the child's self-reported QoL.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patients and Recruitment
Potential subjects included children enrolled previously in Children's Cancer Group studies CCG3881 or CCG3891. CCG3881 was a nonrandomized study of children diagnosed before 19 years of age with low- or intermediate-risk neuroblastoma between 1989 and 1995.22,23 CCG3891 was a randomized clinical trial comparing intensive chemotherapy (standard of care) versus the addition of autologous bone marrow transplantation for children diagnosed with high-risk neuroblastoma between 1991 and 1996.24 Children treated on CCG3881 were classified as low risk if they had stage I, II, or IVS disease; they received surgery and supportive care, with chemotherapy (cyclophosphamide) given only for symptomatic stage IVS. Fewer than 15% of patients received combination chemotherapy as a salvage for recurrence.23 Patients were classified as intermediate risk if they had stage III disease at <1 year of age, were
1 year of age with stage III and favorable biology (MYCN nonamplified, ferritin < 143 ng/mL, favorable Shimada), or were <1 year of age with stage IV disease and no MYCN amplification. These patients received 
9 months of combination therapy with cisplatin (total dose: 510 mg/m2), cyclophosphamide, doxorubicin, and etoposide. High-risk patients were treated on CCG3891 with either intensive induction chemotherapy for 5 months with cisplatin (300 mg/m2), cyclophosphamide, etoposide, and doxorubicin, followed by either 3 additional chemotherapy cycles with cisplatin (480 mg/m2), ifosfamide, etoposide, and doxorubicin or with myeloablative chemotherapy with carboplatin (1000 mg/m2), etoposide, and melphalan, with total body irradiation and autologous bone marrow transplant.24
We attempted to secure institutional participation for this follow-up study, including human subjects (institutional review board [IRB]) approval, from each of the 99 treating hospitals with 1 previously enrolled child on CCG3881 and or CCG3891 who were believed to be still alive when the current study began. We were successful in obtaining local IRB approval to open the study in 63 treating institutions. In most cases, local IRB procedures required the treating institution to obtain consent from the family before allowing us to contact the parents to offer study participation. The COG statistical office sent each treating institution a list of their potentially eligible patients for this purpose (the Children's Cancer Group was merged into COG during the early course of this study). Of the 843 children identified through COG who were alive at last contact and potentially eligible, we received permission from the treating institutions to contact the parents of 253 children. Of these, 10 did not meet study eligibility (5 were older than 18 years, 4 were from non–English-speaking households, and in 1 we could not clearly determine treatment status). Of the 243 eligible, 44 (18.1%) were lost to follow-up and never contacted, 8 (3.3%) actively refused, 51 (21%) did not respond to requests to participate or did not return study materials, 3 (1.2%) had parental but not child participation, and 137 children with 1 or both of their parents participated in the study after providing informed consent (68.8% of the 199 contacted; 56.4% of the 243 presumed eligible with permission to attempt contact). In addition to being previously enrolled on either CCG3881 or CCG3891, eligibility criteria required children to be in cancer remission, 
18 years of age when completing the QoL questionnaire, and to have participation from 1 or both parents with completion of a parent questionnaire (provided only in English).
Data Collection
Participating children completed the Pediatric Quality of Life Inventory 4.0 (PedsQL) Generic Core scales (www.pedsql.org), which is a global QoL instrument with established reliability, validity, and normative values in both healthy and clinical (normal) populations.25 The PedsQL has been used for studies in childhood cancer survivors26,27 and in school populations.28 The generic scales of the 23-item PedsQL measure functioning in physical, emotional, social, and school domains, with 2 summary scores considered here: psychosocial and total.
Participating parents completed an instrument devised by our clinical study team that asked simple questions on late effects after neuroblastoma treatment, including ones related to select medical problems, academic problems, and behavioral or mental health problems. The "Neuroblastoma Medical Follow-up" section of the questionnaire had directions that read, "Have you been told by a doctor or other health care professional that your child, who had neuroblastoma, currently has (or had in the past) any of the following." Response categories were "no"; "yes, in the past, but not now"; and "yes, and it continues." A comment field was also provided for parental response. Responses to "yes, in the past, but not now" were too few to evaluate separately, so they were combined with the other "yes" category for this analysis. We did not ask questions on severity or type of hearing loss or similar information for any of the other medical or psychosocial outcomes. No validation was made of the information provided by the parents. There were 83 parent pairs and 54 lone parents (52 mothers and 2 fathers) who completed the parent questionnaire. For parent dyads, each parent was instructed to complete the questionnaire independently; we also asked that the child complete the PedsQL instrument independent of his or her parents, although no effort to confirm compliance with these instructions was undertaken. A high degree of concordance between mother-father dyads was evident for each of the questions we address in this report, ranging from 94% for problems with writing skills and for behavioral concerns, to 91% for several of the measures, including problems with reading skills. Concordance was 93% for the hearing loss question. To maintain consistency of response, for this analysis only the mothers' responses, except for the 2 single fathers, were considered. Basic data on diagnostic characteristics and treatment protocol were received from the treating institution that accompanied the information data sheet that they forwarded to us with permission to contact the family.
Statistical Procedures
To evaluate whether and to what extent differences were apparent between the 137 study participants and the 106 presumed eligible nonparticipants, descriptive statistics were calculated for demographic and treatment variables and compared with 2 sample t tests or 
2 statistics. Fisher's exact test was used for categorical outcomes when cell sizes were <5. As described above for risk categorization, treatment intensity was categorized as low (CCG3881), intermediate (CCG3881), or high (CCG3891). The frequencies and percentages of parent-reported school problems and behavioral symptoms were also calculated to describe educational and psychosocial problems.
Raw values from responses to the Likert scale questions of the PedsQL were linearly transformed and for each scale were summed and divided by the number of questions to produce scores from 0 to 100. Means and SDs were compared between the participating children's responses and a normative sample of children used in validation of the instrument25 using 2-sample t tests. QoL scores from study subjects were compared using stratified analysis by treatment intensity (3 levels), hearing loss (yes or no), current age (dichotomized as 8–12 and 13–17 to correspond with the age-specific PedsQL instruments), and gender. No adjustments for multiple comparisons were made.29,30
A path model31 was constructed to evaluate the correlations and covariances between variables of interest and to guide the modeling of the effects of treatment intensity and hearing loss on academic and psychosocial outcomes and demographic characteristics. Based on the results of the path analysis (data not shown), multivariable logistic regression models were constructed to evaluate the strength of the associations between hearing loss and parental report of educational and psychosocial problems controlling for gender and to evaluate the associations between the children's self-reported QoL and parent-reported academic and psychosocial problems controlling for gender and hearing loss.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Subject Characteristics
No statistical differences were observed between participants and presumed eligible nonparticipants with regard to age at diagnosis, study protocol, MYCN amplification, Evans stage at diagnosis, treatment intensity, or gender. Participants, on average, were somewhat younger than nonparticipants and had fewer years since diagnosis (Table 1). Among the 137 study subjects, mean age at diagnosis was 1.4 years, mean age at interview was 12.1 years (range: 8–17 years), and 49.6% were female. Twenty-five subjects received high treatment intensity, 54 subjects received intermediate treatment intensity, and 58 subjects received low treatment intensity (Table 1).
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Frequency of Outcomes
Hearing loss was reported in 43 (31.4%) of the 137 children. No difference in the percentage with hearing loss was observed between boys and girls (Table 2).
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Parents were asked whether their child had "identified learning problems" with reading skills, writing skills, and math skills and whether their child had a general learning disability or special educational needs in school. Responses identifying a problem ranged from 31.4% for math-skill problems to 22.6% for a general learning disability (Table 2). Eighty children (58.4%) were reported as having no identified learning problem, 12 (8.8%) with 1 learning problem only, and 45 (32.8%) had
2 learning problems. Parents were also asked about whether their child had problems with poor attention, behavioral concerns, depression, and anxiety. Problem responses ranged from 27.7% for poor attention to 18.2% for depression (Table 2). Eight-five children (62.0%) were reported with none of the psychosocial problems, 19 (13.9%) with 1 problem only, and 33 children (24.1%) with 2 psychosocial problems.
Treatment Intensity and Hearing Loss
Hearing loss was reported in 52% of those who received high-intensity treatment, 44% of those who received intermediate-intensity treatment, and 10% of those who received low-intensity treatment. Relative to the low treatment intensity group, the odds of a reported hearing loss was 8.3-fold higher (95% confidence interval [CI]: 2.9–23.7) for children in the intermediate-intensity group and 9.9-fold higher (95% CI: 3.1–32.4) for children in the high-intensity group after controlling for gender (Table 3).
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Hearing Loss and Parent-Reported Academic and Psychosocial Problems
Hearing loss was generally associated with increased parental report of academic problems in the child. In particular, identified problems with reading skills, math skills, poor attention, general learning disability, and special educational needs in school had odds ratios (ORs) of
2 in those with hearing loss compared with those without, after controlling for gender. Substantive differences by hearing loss were not observed for problems with writing skills, behavioral concerns, anxiety, or depression (Table 3).
Hearing Loss and Child-Reported QoL
Hearing loss was associated statistically with poorer scores in child-reported QoL in school functioning (mean: 71.6 vs 81.6, P =.02, for those with versus without hearing loss, respectively) and the summary scores for psychosocial functioning (76.4 vs 82.8; P =.03) and total QoL (79.5 vs 84.6; P =.05; data not shown).
Child-Reported QoL and Parent-Reported Academic and Psychosocial Problems
Mean scores were not statistically or substantively different in any QoL domain or in the QoL summary scores between study subjects and population norms. No substantive or statistical differences were observed in mean QoL among study subjects by treatment intensity or age at survey.
Boys generally reported poorer QoL scores than girls in school and social functioning and in the psychosocial and total QoL summary scores. After controlling for gender and hearing loss, strong and consistent associations between mean child-reported QoL score and parent-reported academic and psychosocial problems were observed. Except for physical functioning, within each category of academic and psychosocial functioning, the mean QoL score among children with a parent-reported problem was substantially and significantly lower than in children without an identified problem (Table 4).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We found that childhood survivors of neuroblastoma who had prevalent hearing loss, as reported by their parents, had at least twice the risk of an identified problem with reading skills, math skills, and/or attention and a similarly higher risk of a general learning disability and/or special educational needs than did survivors of neuroblastoma without hearing loss. Although it is possible that the associations between parent-reported hearing loss and academic and psychosocial problems in children are influenced to some extent by shared method variance, consistent with these results is a clear pattern of poorer self-reported QoL scores among children with parent-reported academic and psychosocial problems, particularly with school functioning, compared with those without such problems, even after controlling for reported hearing loss. These findings, the first of their kind to our knowledge, are important for parents, teachers, and health care providers to understand the potential impact on the child's psychosocial well-being many years after cancer therapy. Hearing loss, an important adverse late effect of treatment with platinum-based drugs, may be particularly problematic in neuroblastoma survivors because of the very young age at which they are treated, thus potentially adversely affecting speech and language development and subsequent academic performance.13,19 Cisplatin is included in some treatment protocols for many other childhood cancers, including medulloblastoma, osteosarcoma, and germ cell tumors, so these results may be informative beyond that of the neuroblastoma setting.
Our results add to the small but emerging literature on long-term outcomes related to neuroblastoma. Laverdiere et al5 evaluated medical morbidity in 63 survivors of advanced-stage neuroblastoma with a median follow-up time of 7 years after diagnosis. One or more late complications was detected in 95% of survivors, including hearing loss (62%), primary hypothyroidism (24%), ovarian failure (41% of females), musculoskeletal problems (19%), and pulmonary problems (19%). Barr et al32 conducted a QoL study using a health utility index that compared 26 survivors of neuroblastoma to 52 Wilms' tumor survivors with both groups averaging 5 years since the end of treatment. Although QoL scores did not differ significantly between the 2 disease groups, morbidity burden, as reported by parents, was substantially greater for the neuroblastoma group than the Wilms' tumor group, with hearing loss largely responsible for the difference. As part of the Childhood Cancer Survivor Study, Ness et al7 compared limitations in physical performance and daily activities from a survey of 11481 long-term survivors of childhood cancer (children and young adults; 88% were 10 years postdiagnosis), including 802 survivors of neuroblastoma, with 3839 siblings of childhood cancer survivors. They found limitations in physical performance reported in 17% of long-term survivors of neuroblastoma, a risk that was 70% higher than expected from the sibling comparison group. Elevated risks for restricted personal care skills (relative risk [RR]: 3.8; 95% CI: 2.2–6.8), restricted routine activities of daily living (RR: 3.6; 95% CI: 2.5–5.4), and problems with health that prevented school or work attendance (RR: 5.1; 95% CI: 3.4–7.6) were also observed. Ness et al7 noted that, given the diagnosis period of the cohort (1970–1986), few high-risk neuroblastoma patients would have survived the required 5 years after diagnosis to be eligible for their study, so this neuroblastoma series, like ours, largely represented survivors of low- and intermediate-risk disease.
Although strengths of this study include the relatively large sample size and the inclusion of child self-reported QoL, several limitations need to be considered when interpreting the findings. Foremost, we were unable to confirm or characterize the type or severity of hearing loss reported, and we did not have data on any hearing treatments received, such as assisted devices or cochlear implants. Nor did we have data on actual school performance or confirmation of the psychosocial measures reported on by parents. However, the high degree of concordance between parent dyads for these measures, ranging from 91% to 94% agreement, is encouraging in relation to the validity of the responses that parents provided. Also of importance, because of our limited success in accessing and contacting potentially eligible parents through the many institutions that enrolled patients on the 2 neuroblastoma protocols, our study sample may not fully represent surviving patients. Among those who we were permitted to attempt to contact for study inclusion, no important differences were apparent between children who participated and those who did not. Unfortunately, we could not conduct a similar evaluation between the participating children and those children who we were not granted permission to contact from their treating institution.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We found evidence that long-term survivors of neuroblastoma, particularly those with hearing loss, are at elevated risk for academic learning problems and psychosocial difficulties. We also found strong concordance between parent-reported learning problems in the child and indications of distress as measured by the child's self-reported QoL. Overall, however, the children's self-reported QoL scores did not differ substantively from those of population norms, which is an encouraging finding that may reflect the resilience of these long-term childhood cancer survivors and their families.
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ACKNOWLEDGMENTS |
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This work was funded by American Cancer Society grant RSG-01-194-01-PBP, Hope Street Kids grant HSK 052102, and National Cancer Institute grant CA13539. A complete listing of grant support for research conducted by the Children's Cancer Group and the Pediatric Oncology Group before initiation of the Children's Oncology Group grant in 2003 is available online at www.childrensoncologygroup.org/admin/grantinfo.htm.
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FOOTNOTES |
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Accepted Apr 11, 2007.
Address correspondence to James G. Gurney, PhD, Department of Pediatrics, University of Michigan, 300 N Ingalls St, Room 6E02, Ann Arbor, MI 48109. E-mail: jamegurn{at}umich.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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