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Scholastic Achievements of Childhood Leukemia Patients: A Nationwide, Register-Based Study

Arja H. Harila-Saari, Päivi M. Lähteenmäki, Eero Pukkala, Pentti Kyyrönen, Marjatta Lanning, Risto Sankila

From the Department of Pediatrics and Adolescence, Oulu University Hospital, Oulu; Department of Pediatrics and Adolescence, Turku University Hospital, Turku; Finnish Cancer Registry, Helsinki; and the School of Public Health, University of Tampere, Tampere, Finland

Address reprint requests to Arja Harila-Saari, MD, PhD, Department of Pediatrics and Adolescence, Oulu University Hospital, PO BOX 23, 90029 OYS, Oulu, Finland; e-mail: arja.harila-saari{at}oulu.fi

	ABSTRACT

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Purpose Studies concerning the scholastic achievement of survivors of childhood leukemia have yielded controversial results. We studied the school marks of childhood leukemia survivors in a register-based study.

Patients and Methods Three hundred seventy-one patients with a diagnosis of leukemia before the age of 16 years who were born between 1974 and 1986 and alive on their 16th birthday were identified from the Finnish Cancer Registry. Five matched controls were sought for each patient from the Population Register Center of Finland. Information on the ninth-grade school report was obtained from Statistics Finland. The overall mark average and the marks (scale 4 to 10) for mother tongue, foreign language, mathematics, and physical education were compared between the patients and controls.

Results The ninth-grade school report was obtained by 97.6% of the patients and 98.5% of the controls. The patients whose treatment included cranial irradiation had a lower overall mark average (mean difference, –0.24; 95% CI, –0.33 to –0.15) and lower marks for all assessed school subjects compared with their controls. Of the patients treated with chemotherapy alone, only the females with leukemia diagnosed before 7 years of age had lower school marks than their controls. The biggest difference was observed in the marks for foreign language among the irradiated females diagnosed at a young age (mean difference, –1.0; 95% CI, –1.25 to –0.74).

Conclusion Leukemia treatment that includes cranial irradiation impairs scholastic achievement. It is noteworthy that treatment of leukemia with chemotherapy alone impairs school performance only in females diagnosed before school age.

	INTRODUCTION

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The great majority of patients with childhood leukemia become long-term survivors.^1,2 Along with the rapidly growing number of long-term survivors, knowledge of the possible influences of the disease and its treatment on cognitive functions and educational achievement has become an increasingly important issue. The development of CNS treatment in addition to combination chemotherapy has been one main factor contributing to the improved survival of children with leukemia.³ In the 1970s and early 1980s, CNS treatment consisted of cranial irradiation and intrathecal chemotherapy. Reports of intellectual dysfunction after cranial irradiation led to the replacement of irradiation by intrathecal and high-dose CNS-directed chemotherapy in most current protocols.^3,4

Numerous studies have addressed the issue of cognitive functions after treatment of leukemia in children, most often through intelligence quotient (IQ) measurement.^5-8 It is generally agreed that cranial irradiation is detrimental to cognitive functions at least in children treated at a young age.^6-8 The research results on children treated without cranial irradiation have been controversial.^8,9

It has been suggested that it is more important to study the child's functioning than his or her performance in neuropsychological or IQ tests, because the relationship between these two phenomena is not straightforward. There are a few previous studies concerning the school performance of leukemia patients. In some studies, irradiated leukemia patients have been found to have more learning difficulties, more need for special education, and lower scholastic achievement compared with their siblings, voluntary controls, or leukemia patients not exposed to cranial irradiation.^10-14 Others have reported no difference in scholastic achievement between irradiated leukemia patients and healthy controls^15,16 or between irradiated and nonirradiated leukemia patients.¹⁷ One study found an increased risk for the use of special education services and a decreased school completion rate among leukemia patients treated with chemotherapy alone,¹³ whereas two studies failed to reveal any effect on scholastic achievement.^14,18

In the present nationwide, register-based study, we evaluated school performance after childhood leukemia in an unselected group of patients and population-based matched controls. Our aim was to assess performance in several school subjects in different treatment groups after childhood leukemia. The results should allow recognition of the subgroups in need of follow-up and supportive interventions. Knowledge of the cognitive sequelae of treatment is also valuable for the development of new protocols.

	PATIENTS AND METHODS

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Patients
The Finnish Cancer Registry has collected data on Finnish cancer patients since 1953. It is more than 99% complete and very accurate.¹⁹ All patients with a leukemia diagnosis before 16 years of age who were born between 1974 and 1986 and alive on their 16th birthday were included in the present study. These birth cohorts were chosen on the basis of the availability of school report data. Information on the treatment (chemotherapy and radiation therapy) was also obtained from the Finnish Cancer Registry.

The Finnish Cancer Registry does not include information about the irradiation dose or the details of the chemotherapy protocol. The Nordic leukemia protocols were updated several times during the study period. The commonly used dose of cranial irradiation was 24 Gy until 1986 or 1990, depending on the protocol, and 18 Gy thereafter. Intrathecal medication consisted of methotrexate alone. Triple intrathecal therapy was administered only to patients with CNS leukemia. The main steroid used in the protocols was prednisone. The high-dose methotrexate treatment was 1 g/m² until 1992 and 5 or 8 g/m² thereafter, depending on the risk group.

For each case, five matched controls were selected from the Population Register Center of Finland. The controls were matched for month and year of birth, municipality at the time of diagnosis, and sex, and participants had to be alive on their 16th birthday.

The parents of the patients and the controls were identified from the Finnish Population Register. The parents' level of education was obtained from the examination registry of Statistics Finland. Success at school is associated with the parents' level of education,²⁰ which was taken into consideration in the statistical analysis. The identification of patients and controls as well as the record linkage procedures were performed on the basis of the personal identification code given to each resident of Finland.

A total of 371 leukemia patients fulfilled the inclusion criteria. Their median age at diagnosis was 5.6 years. A total of 1,844 matched controls were identified for them. Eleven controls were lacking because some patients came from small municipalities where fewer than five children fulfilled the inclusion criteria for controls. Parents could be identified for 99.6% of the children. Information of the parent's level of education was available for 62% of the patients and 66% of the controls.

School Report Data
The ninth-grade school reports were obtained from Statistics Finland. Finnish children normally start school in the year of their seventh birthday and complete it in the year of their 16th birthday. The educational system is coordinated by the National Board of Education. The Finnish school report has a scale of marks from 4 (failed) to 10 (best). The mean overall average for all school subjects in 1998 was 7.9 ± 1.0.²¹ National requirements exist for mark 8 (good) for each school subject.

The overall averages of the school marks for mother tongue (Finnish for 94% and Swedish for 6% of the pupils), the first foreign language (English for 93%; Swedish, German, French, or Russian for 7%), mathematics and physical education were chosen into the analyses. The overall average of all school subjects was included to represent the pupils' cognitive abilities.²² The mark for mother tongue correlated with the school marks for other subjects classifiable as humanities and natural sciences (biology, geography, and history), the mark for the first foreign language with the marks for other foreign languages and the mark for mathematics with the marks for physics and chemistry.²² The mark for physical education was chosen to represent the possible physical consequences of treatment.

The ninth-grade school report was missing for 2.4% of the leukemia patients (nine of 371) and for 1.5% (28 of 1,844) of the controls. The requisite information on school marks was available for 353 patients, who were included into the analysis. Of them, 139 had received cranial irradiation (39%), whereas 214 had been treated solely with chemotherapy (61%). Age at diagnosis was younger than 7 years for 214 patients (61%).

Statistical Analysis
The data were analyzed using a multiple linear regression model, which included age, sex, possible use of CNS irradiation, and the difference in school marks between the patients and their matched controls (dependent variable).

The irradiation dose was greater during the earlier years of treatment. The effect of the year of diagnosis on school marks between the irradiated patients and their controls was analyzed. The year of diagnosis was divided into 5-year categories (before 1985, 1985 to 1989, 1990 to 1994, and 1995 or after), because division by shorter periods was not possible due to the small number of patients. The effect of this variable was analyzed using the same multiple linear regression model.

The analysis was carried out in strata defined by the patients' exposure to cranial irradiation (yes or no) and age at diagnosis (before or after 7 years of age) and separately for both sexes. All of the models included a constant term representing the estimate for the difference in the marks between the patients and controls and parents' education as an independent variable. The significance of the differences was tested with the Wald test (SAS, eighth revision, 1999-2001; SAS Institute, Cary, NC). These stratified results of the data are presented in the tables. A negative value for the mean difference indicates that the patients had lower school marks than did the controls.

Because the educational level of one of the parents was unknown for 38% of the patients and 34% of the controls, this parameter was replaced in the missing cases by the arithmetic mean of the parental education level of all children in the study population. The models were also assessed with the data without this replacement. The parameter estimates of these models were in keeping with the models where the replacement was done.

The study was accepted by the Ethical Committee of the Hospital District of Southwestern Finland. Appropriate permissions were issued by the Ministry of Social Affairs and Health, Statistics Finland, and the Population Register Centre of Finland.

	RESULTS

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Overall Average
The overall averages of the leukemia patients was slightly lower than that of the controls (mean difference, –0.10; 95% CI, –0.15 to –0.05). The difference was statistically significant in the irradiated patients (mean difference, –0.24; 95% CI, –0.33 to –0.15), but not in the nonirradiated patients (mean difference, –0.02; 95% CI, –0.09 to 0.06).

The overall averages for the two treatment and two age groups are shown in Table 1. The female patients with leukemia diagnosed before 7 years of age had a lower overall average than the controls regardless of the type of treatment. The male patients diagnosed before 7 years of age had a significantly lower overall average compared with the controls only if cranial irradiation had been used in addition to chemotherapy. The leukemia patients diagnosed after the age of 7 years showed no decline in their overall average compared with their controls; the females treated with chemotherapy alone had an even significantly better overall average than their controls. The difference in the overall mark average between irradiated and nonirradiated leukemia patients was significant among the patients diagnosed before school age, but not among the older patients. The difference compared with the controls was significantly greater in females than in males in the group of young, nonirradiated patients (P = .04).

Theoretical School Subjects
Tables 2 through 4 show the results for the three theoretical school subjects. The young leukemia patients who had received cranial irradiation had significantly lower marks than did their controls for mother tongue, mathematics, and first foreign language. The reduction was greater in females (mean difference, –0.62 to –1.00 mark units) than in males (mean difference, –0.37 to –0.47 mark units) in all these school subjects. The young nonirradiated female leukemia patients had significantly lower marks for all theoretical school subjects compared with the controls, whereas no difference between the patients and controls was seen among the young nonirradiated males.

Physical Education
The irradiated leukemia patients had lower marks for physical education compared with the controls regardless of the age at diagnosis (Table 5). In the nonirradiated group, a slight lowering was observed in the younger patients, which remained significant in females in the analysis by sex. The older nonirradiated males had even better marks for physical education than their controls.

	DISCUSSION

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We found that nearly all leukemia survivors complete basic education in Finland. A decline of school marks was observed in leukemia patients treated with chemotherapy and cranial irradiation as well as in females treated at a young age with chemotherapy alone. The decline was most pronounced in the young females diagnosed before school age and in the marks for foreign language.

The availability of whole-population register data and the possibility to use marks from school records were the strengths of our study, which allowed us to assess even minor differences in school performance. The controls were matched for the place of residence at the time of diagnosis because the marking principles may vary slightly by region. Matching by school was not possible because of the small number of pupils in many Finnish schools. The potential influence of parents' education was taken into account in the analysis. The most significant limitation of this study is the lack of treatment data, which hampered the analysis of the effects of different treatment modalities or doses.

Previous studies have evaluated the achieved level of education^{11,12,15,16,23} or the utilization of special education services,^12,13,15 and only one study has included any information of school marks.¹⁵ The information of education in these studies has been self-reported, participation rate has varied from 61% to 91%, and siblings have been used as controls, all of which are methodologically suboptimal solutions. Two studies used healthy volunteers as controls.^11,14 Only one study used registry-based identification of patients, healthy controls, and information on the level of attained education.¹⁶ In that study, all leukemia patients were analyzed as one group without any information on treatment, and no difference in the attained level of education was observed between the patients and controls.

A high proportion (97.6%) of our childhood leukemia survivors had completed the Finnish comprehensive school, which did not differ significantly from the controls. In the study by Haupt et al,¹⁵ 92.4% of leukemia survivors had completed high school, which did not differ from their sibling controls. However, in the study by Mitby et al,¹³ only 85.8% of leukemia survivors had completed high school, compared with 91.3% of their siblings. The excellent school completion rate of our patients may be explained by the differences in school systems and the educational support available for children with cancer in Finland. Special hospital schools provide education, including bedside instruction, for hospitalized children. The patient's own municipality is responsible for arranging home instruction when the child is at home but not able to attend school because of cancer. School re-entry after a cancer diagnosis is facilitated by a rehabilitation nurse. Remedial teaching is generally available, and it aims to support learning before any educational deficits have developed. Education is highly valued in Finnish society, and the Finnish school system has been shown to be highly effective and uniform.²⁴

The detrimental effects of cranial irradiation on young children have been well documented^6,17,25-27 and have caused cranial radiation to be withdrawn from the therapy of children under 5 years of age.^6,28 In the Nordic countries after 1992, less than 10% of children with leukemia have received cranial irradiation.⁴ The young irradiated patients in our series had the most conspicuous decline in the school marks, indicating the presence of greatest intellectual deficits. Our findings are in concordance with the previous studies that have identified young age at diagnosis^12,13,15,26 and exposure to cranial irradiation^10-15,23,26 as risk factors for a poorer educational outcome in children with cancer.

The decline in school marks was most pronounced in the irradiated patients diagnosed before 1985. One possible explanation is the smaller dose of cranial irradiation given to the leukemia patients diagnosed later. Other factors, such as improved support for school work, may also have contributed to leukemia patients' improved school performance.

Female leukemia patients were found to have a greater decline in school marks in several school subjects. Mitby et al also found female leukemia survivors to show a greater difference compared with controls in the utilization of special education services.¹³ Haupt et al¹⁵ found a greater difference in school marks among females, but only in children diagnosed with leukemia before school age and exposed to 24 Gy of cranial irradiation. No sex differences were found in two studies,^12,14 both of which involved methodologic problems, such as low participation rates.

The role of chemotherapy alone in producing cognitive deficits is controversial. Studies using random assignment have failed to document any difference in cognitive effects between irradiated and nonirradiated leukemia patients.^29-31 However, some studies have found no cognitive effects of chemotherapy compared with healthy controls,^26,27,32 whereas others have revealed adverse cognitive effects, which seem to be more subtle than those produced by irradiation.^9,33 In our results, the school performance of chemotherapy-treated leukemia survivors was significantly impaired only in females diagnosed before school age. A randomized study by Waber et al³⁴ showed that high-dose methotrexate was detrimental to cognitive functions, but only in girls. The use of high-dose methotrexate is typical for the Nordic leukemia protocols,⁴ and that may be one factor contributing to our findings.

The greatest decline was observed in the foreign language, indicating impairment of verbal learning. The previous studies have more frequently revealed deficits in nonverbal functions.^9,35,36 However, the learning of foreign languages has not been used as an indicator of verbal skills in the previous studies. The learning of foreign languages for Finnish pupils cannot be based on things learned before, since the Finnish language is unrelated to any of the languages studied at school. Finnish is a phonetically transparent language, which means that it is written as it is pronounced. Learning linguistically more demanding nontransparent languages, such as English, may thus cause a special burden on Finnish children. Learning difficulties after leukemia treatment have been suggested to occur especially in the functions required for learning new things and in memory functions,⁷ both of which are needed in learning foreign languages.

The Finnish basic education system seems to be successful in providing the majority of childhood leukemia patients with a solid foundation for further schooling. However, all patients who receive cranial irradiation, as well as females diagnosed at a young age and treated with chemotherapy alone, are at risk for treatment-related declines in school marks. They should be followed up carefully and provided timely intervention to assist their education.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Arja H. Harila-Saari, Päivi M. Lähteenmäki, Eero Pukkala, Risto Sankila

Financial support: Arja H. Harila-Saari, Päivi M. Lähteenmäki

Administrative support: Arja H. Harila-Saari, Päivi M. Lähteenmäki, Marjatta Lanning, Risto Sankila

Provision of study materials or patients: Arja H. Harila-Saari, Päivi M. Lähteenmäki, Eero Pukkala, Risto Sankila

Collection and assembly of data: Arja H. Harila-Saari, Päivi M. Lähteenmäki, Eero Pukkala, Risto Sankila

Data analysis and interpretation: Arja H. Harila-Saari, Päivi M. Lähteenmäki, Eero Pukkala, Pentti Kyyrönen, Risto Sankila

Manuscript writing: Arja H. Harila-Saari, Päivi M. Lähteenmäki, Eero Pukkala, Pentti Kyyrönen, Marjatta Lanning, Risto Sankila

Final approval of manuscript: Arja H. Harila-Saari, Päivi M. Lähteenmäki, Eero Pukkala, Pentti Kyyrönen, Marjatta Lanning, Risto Sankila

	NOTES

Presented in part at the Annual Meeting of the Nordic Society of Paediatric Haematology and Oncology, Lillehammer, Norway, May 8-11, 2005, and the International Society of Paediatric Oncology Annual Congress, Oslo, Norway, September 16-19, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted November 6, 2006; accepted May 24, 2007.

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