Abstract

INTRODUCTION

Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer in India. In the current scenario, the overall cure rates for pediatric ALL have improved up to 65-70%[1] due to central nervous system (CNS) prophylaxis, however, cognitive functioning is compromised by this[2,3,4,5,6] which includes cranial radiotherapy (CRT), intrathecal methotrexate (IT-MTX), and high-dose methotrexate (HD-MTX) literature reviews suggest that children treated with HD-MTX and IT-MTX perform better than children treated with CRT and IT-MTX. The complexity of different treatments for ALL has concluded that these can have an impact on the neuropsychological functioning. Children treated with CRT performed poorly in comparison to those treated with either HD-MTX or IT-MTX group on most neuropsychological functions. From the western review, it can be concluded very few data are available in the neurocognitive sequelae effect with HD-MTX and CRT,[7] there is also paucity of data in India. Moreover, the combined effect of HD-MTX and CRT is unknown. Therefore, a systematic prospective study was conducted to assess the immediate effect of neuropsychological functioning among the children with ALL children treated with combined HD-MTX and CRT at the Regional Cancer Center in Chennai, South India.

MATERIALS AND METHODS

RESULTS

Thirty patients were enrolled for the study, of which 24 completed all the three assessments and they were included in the analysis. Sample characteristics are shown in Table 2. Of the 24 patients included for analysis, 13 (54.2%) were male and 11 (45.8%) were female, age ranged between 6 and 15 years with the mean age being 10.70 years. The duration of the first assessment from diagnosis ranged from 1 to 68 days (mean ± standard deviation (SD) = 20.00 ± 3.56). The duration between first and second assessment ranged from 90 to 217 days (mean ± SD = 146.54 ± 6.46) and it ranged from 117 to 223 days (mean ± SD = 166.54 ± 6.58) from the diagnosis. The duration of the second and third assessment ranged from 180 to 360 days (mean ± SD = 246.26 ± 9.27) and 364-558 days (mean ± SD = 524.45 ± 15.02), respectively, from diagnosis.

Table 2

DISCUSSION

The present study suggests that BFM 86 protocol including CRT and IT-MTX along with HD-MTX had an immediate effect on the neuropsychological functioning among children with ALL. Immediately after receiving IT-MTX and HD-MTX, there was no effect, however, in combination with CRT, there was a significant impact observed after 17.48 months from the time of diagnosis. A review study which was conducted by Copeland[11] concluded that neuropsychological impairments usually become evident within 1-3 years following the cranial irradiation and also showed that deficits are progressive.

In the present study, it was found that there was a significant impairment in many domains of neuropsychological functioning in children with ALL after receiving CNS prophylactic treatment, namely PIQ, visuo-perception, visuo-spatial, processing speed, planning, IVM, verbal attention, and verbal fluency.

On Malin's intelligence scale for Indian children (MISIC), when compared between the three assessments, it was found that PIQ of children significantly decreased at third assessment (98.5) compared with first (102.01) and second (105.6) assessment after receiving CNS prophylactic treatment. Though, there was a difference, the median intelligence score fell within the average range (90-109) as per Wechsler intelligence quotient (IQ) classification[8] in the three assessments for the children. The median IQ scores of children with ALL increased in the second assessment when compared to the first and third assessment. First assessment was done immediately after the diagnosis and during the induction period when the child was coping with the diagnosis, new environment, and the treatment procedures compared to the second assessment. Overall median score was within the average category in all the three assessments, three children scored below average (80-89) in the baseline assessment. Of them, two moved to average category during the second assessment and one child scored below average in all the three assessments. In addition, two children moved to below average category in the third assessment from the average category in the first two assessments.

Three Indian studies have reported the effect of CNS prophylactic treatment on neuropsychological functioning of children treated for ALL. Jain et al.,[12] conducted a retrospective study comparing children with ALL (n = 35) who received CNS prophylactic treatment with their healthy siblings (n = 20) who were between the age group of 5-15 years. Results showed that children with ALL performed significantly poorer when compared to their healthy siblings, the difference in their mean scores was 13.6 where the children with ALL received 20 Gy CRT. In the present study, the difference between the second assessment and third assessment was 7.09. Another prospective longitudinal study conducted by Abraham and Appaji,[13] 19 children with ALL treated with CNS prophylactic treatment were found to have significant decline in IQ and deficit in analytical reasoning. Contrary to the above two studies, a comparative study conducted by Bhattacharya et al.,[14] concluded that there was no significant difference in IQ between the children who received CNS prophylactic treatment and children with solid tumor who received only chemotherapy.

However, in line with Jain and Appaji studies, a western study was conducted by Anderson and Ochs[15,16] who revealed that children with ALL who received cranial irradiation and chemotherapy had poorer intellectual and educational skills in comparison to children who received only chemotherapy or healthy controls.

In the present study, after induction and consolidation phase, that is, before CRT, there was no significant difference in the neuropsychological functioning, which was also concluded from the studies which was conducted by Brown et al.,[17] and Anderson et al.,[15] where, they did not find any short-term effect in the neurocognitive functioning of the children with ALL treated with CNS directed chemotherapy only. Current study indicated a significant impairment on three of the MISIC sub tests; visuo-perception visuo-spatial, processing speed; planning and IVM, between the three assessments. The results of the present study is that certain neuropsychological domains are impaired which were consistent with the previous studies, where these three functions were reported to have impaired repeatedly after receiving CNS prophylactic treatment (visuo-perception,[9,15] visuo-spatial,[9,15] processing speed,[11,15,18] planning and IVM[11,16]). In addition to these functions, nonverbal ability such as perceptual organization and working memory were also found to have impairment in a study conducted by Anderson.[15] In the present study, though there was a decline in the scores of third assessment when compared to the first and second assessment, the impairment was not significant.

Verbal fluency and verbal attention were measured by ideation fluency and vigilance test respectively. On the ideation fluency test, there was a significant impairment in verbal fluency after receiving CNS prophylactic treatment. Result was consistent with the findings of Espy et al.,[18] who, have reported that there is a decline in verbal fluency. The decline in ideation fluency was observed after the radiation therapy was administered.

On Vigilance test, significant impairment was noted in verbal attention during the third assessment. There was a gradual increase in error scores in verbal attention from baseline to third assessment. This decline in verbal attention is progressive after the commencement of treatment. It is possible that both cranial radiation and chemotherapy had influenced verbal attention. Similarly, the study done by Langer et al.[19] and Giralt et al.,[20] concluded that cranial irradiation in combination with MTX therapy was associated with deficits in attention. Moreover, similar impairment in attention was reported in an Indian study conducted by Jain et al.,[12] though, there was a difference in the dosage of CRT administered, 20 Gy in Jain's study whereas, 18 Gy in the current study used.

There was no gender difference in neuropsychological functions. This is in contrast to the previous evidence[3,11,15] where it was reported that females were more affected than males after receiving CNS prophylactic therapy. Most of the previous evidences suggest that females are more prone for neurocognitive side effects than males due to gender difference which is due to the brain development.[3,11] This was not observed in the present study, which may be due to small sample size and less representation of female patients (n = 5).

Among the age groups between 6-10 years and 11-15 years, the children were found to have deficits in perceptual organization, verbal attention, and verbal fluency after receiving CNS prophylactic therapy. Most of the studies suggested that age of treatment is a proxy variable for underlying neurodevelopment maturity. While development of cortical gray matter peaks at approximately 4 years of age, cortical white matter volume continues to rise until 20 years of age. Therefore, those who are younger at the time of radiation treatment generally have less or fully developed white matter. Since both younger and older patients have shown to lose white matter volume at similar rates, the younger irradiated patients continue to display reduced total white matter volume following radiation treatment. These deficits in white matter volume among younger patients have also been associated with increased intellectual morbidity.[21]

In this study, although there was a decline in all the neuropsychological functions among all the children with ALL, long-term follow-up of these patients will reveal whether, this cognitive dysfunction is constant or deteriorating or improving. The current results must be interpreted in the context of some of the common limitations of clinical research. The effects of other contributing factors such as economical, social, environmental, and familial factors are not studied. The present study did not try to find the significant relationship or difference between chemotherapy and radiation. The sample was collected from a single institution and there was no control group. Current results are restricted to the age group of 6-15 years; hence, it cannot be generalized to other age groups. The present study strongly suggests that there is a decline in the cognitive function, early intervention (after 1-year) on cognitive rehabilitation is vital for all survivors. Academic achievement was not measured as the children were hospitalized during the intensive phase of the treatment and subsequently had intermittent admissions, and therefore, not attending their regular school. Hence, there is a need for future studies focusing on academic achievement as well as intervention. Hospital-based educational activities and intervention stimulating the cognition can help these children resume their routine and academic activities at the earliest.

The present study implicates that combined use of CRT and HD-MTX had an immediate effect on the neurocognitive functions among children with ALL. Cognitive rehabilitation is vital to improve their overall level of cognitive functioning and quality of life. Involving parents and teachers in the recovery process is crucial. The current study has focused on the short-term cognitive effects of CNS prophylaxis treatment and this can be expanded to look into the long term effect.

The present study supports the need for continued evaluation of neurocognitive functioning in Indian children with ALL, who are receiving CNS prophylactic therapy to identify potential neurocognitive sequelae of treatment. Prevention of neurocognitive sequelae through rehabilitative measures and continuation of school and pharmacotherapy for these children is recommended.

ACKNOWLEDGMENT

Footnotes

Abstract

INTRODUCTION

Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer in India. In the current scenario, the overall cure rates for pediatric ALL have improved up to 65-70%[1] due to central nervous system (CNS) prophylaxis, however, cognitive functioning is compromised by this[2,3,4,5,6] which includes cranial radiotherapy (CRT), intrathecal methotrexate (IT-MTX), and high-dose methotrexate (HD-MTX) literature reviews suggest that children treated with HD-MTX and IT-MTX perform better than children treated with CRT and IT-MTX. The complexity of different treatments for ALL has concluded that these can have an impact on the neuropsychological functioning. Children treated with CRT performed poorly in comparison to those treated with either HD-MTX or IT-MTX group on most neuropsychological functions. From the western review, it can be concluded very few data are available in the neurocognitive sequelae effect with HD-MTX and CRT,[7] there is also paucity of data in India. Moreover, the combined effect of HD-MTX and CRT is unknown. Therefore, a systematic prospective study was conducted to assess the immediate effect of neuropsychological functioning among the children with ALL children treated with combined HD-MTX and CRT at the Regional Cancer Center in Chennai, South India.

MATERIALS AND METHODS

RESULTS

Thirty patients were enrolled for the study, of which 24 completed all the three assessments and they were included in the analysis. Sample characteristics are shown in Table 2. Of the 24 patients included for analysis, 13 (54.2%) were male and 11 (45.8%) were female, age ranged between 6 and 15 years with the mean age being 10.70 years. The duration of the first assessment from diagnosis ranged from 1 to 68 days (mean ± standard deviation (SD) = 20.00 ± 3.56). The duration between first and second assessment ranged from 90 to 217 days (mean ± SD = 146.54 ± 6.46) and it ranged from 117 to 223 days (mean ± SD = 166.54 ± 6.58) from the diagnosis. The duration of the second and third assessment ranged from 180 to 360 days (mean ± SD = 246.26 ± 9.27) and 364-558 days (mean ± SD = 524.45 ± 15.02), respectively, from diagnosis.

Table 2

DISCUSSION

The present study suggests that BFM 86 protocol including CRT and IT-MTX along with HD-MTX had an immediate effect on the neuropsychological functioning among children with ALL. Immediately after receiving IT-MTX and HD-MTX, there was no effect, however, in combination with CRT, there was a significant impact observed after 17.48 months from the time of diagnosis. A review study which was conducted by Copeland[11] concluded that neuropsychological impairments usually become evident within 1-3 years following the cranial irradiation and also showed that deficits are progressive.

In the present study, it was found that there was a significant impairment in many domains of neuropsychological functioning in children with ALL after receiving CNS prophylactic treatment, namely PIQ, visuo-perception, visuo-spatial, processing speed, planning, IVM, verbal attention, and verbal fluency.

On Malin's intelligence scale for Indian children (MISIC), when compared between the three assessments, it was found that PIQ of children significantly decreased at third assessment (98.5) compared with first (102.01) and second (105.6) assessment after receiving CNS prophylactic treatment. Though, there was a difference, the median intelligence score fell within the average range (90-109) as per Wechsler intelligence quotient (IQ) classification[8] in the three assessments for the children. The median IQ scores of children with ALL increased in the second assessment when compared to the first and third assessment. First assessment was done immediately after the diagnosis and during the induction period when the child was coping with the diagnosis, new environment, and the treatment procedures compared to the second assessment. Overall median score was within the average category in all the three assessments, three children scored below average (80-89) in the baseline assessment. Of them, two moved to average category during the second assessment and one child scored below average in all the three assessments. In addition, two children moved to below average category in the third assessment from the average category in the first two assessments.

Three Indian studies have reported the effect of CNS prophylactic treatment on neuropsychological functioning of children treated for ALL. Jain et al.,[12] conducted a retrospective study comparing children with ALL (n = 35) who received CNS prophylactic treatment with their healthy siblings (n = 20) who were between the age group of 5-15 years. Results showed that children with ALL performed significantly poorer when compared to their healthy siblings, the difference in their mean scores was 13.6 where the children with ALL received 20 Gy CRT. In the present study, the difference between the second assessment and third assessment was 7.09. Another prospective longitudinal study conducted by Abraham and Appaji,[13] 19 children with ALL treated with CNS prophylactic treatment were found to have significant decline in IQ and deficit in analytical reasoning. Contrary to the above two studies, a comparative study conducted by Bhattacharya et al.,[14] concluded that there was no significant difference in IQ between the children who received CNS prophylactic treatment and children with solid tumor who received only chemotherapy.

However, in line with Jain and Appaji studies, a western study was conducted by Anderson and Ochs[15,16] who revealed that children with ALL who received cranial irradiation and chemotherapy had poorer intellectual and educational skills in comparison to children who received only chemotherapy or healthy controls.

In the present study, after induction and consolidation phase, that is, before CRT, there was no significant difference in the neuropsychological functioning, which was also concluded from the studies which was conducted by Brown et al.,[17] and Anderson et al.,[15] where, they did not find any short-term effect in the neurocognitive functioning of the children with ALL treated with CNS directed chemotherapy only. Current study indicated a significant impairment on three of the MISIC sub tests; visuo-perception visuo-spatial, processing speed; planning and IVM, between the three assessments. The results of the present study is that certain neuropsychological domains are impaired which were consistent with the previous studies, where these three functions were reported to have impaired repeatedly after receiving CNS prophylactic treatment (visuo-perception,[9,15] visuo-spatial,[9,15] processing speed,[11,15,18] planning and IVM[11,16]). In addition to these functions, nonverbal ability such as perceptual organization and working memory were also found to have impairment in a study conducted by Anderson.[15] In the present study, though there was a decline in the scores of third assessment when compared to the first and second assessment, the impairment was not significant.

Verbal fluency and verbal attention were measured by ideation fluency and vigilance test respectively. On the ideation fluency test, there was a significant impairment in verbal fluency after receiving CNS prophylactic treatment. Result was consistent with the findings of Espy et al.,[18] who, have reported that there is a decline in verbal fluency. The decline in ideation fluency was observed after the radiation therapy was administered.

On Vigilance test, significant impairment was noted in verbal attention during the third assessment. There was a gradual increase in error scores in verbal attention from baseline to third assessment. This decline in verbal attention is progressive after the commencement of treatment. It is possible that both cranial radiation and chemotherapy had influenced verbal attention. Similarly, the study done by Langer et al.[19] and Giralt et al.,[20] concluded that cranial irradiation in combination with MTX therapy was associated with deficits in attention. Moreover, similar impairment in attention was reported in an Indian study conducted by Jain et al.,[12] though, there was a difference in the dosage of CRT administered, 20 Gy in Jain's study whereas, 18 Gy in the current study used.

There was no gender difference in neuropsychological functions. This is in contrast to the previous evidence[3,11,15] where it was reported that females were more affected than males after receiving CNS prophylactic therapy. Most of the previous evidences suggest that females are more prone for neurocognitive side effects than males due to gender difference which is due to the brain development.[3,11] This was not observed in the present study, which may be due to small sample size and less representation of female patients (n = 5).

Among the age groups between 6-10 years and 11-15 years, the children were found to have deficits in perceptual organization, verbal attention, and verbal fluency after receiving CNS prophylactic therapy. Most of the studies suggested that age of treatment is a proxy variable for underlying neurodevelopment maturity. While development of cortical gray matter peaks at approximately 4 years of age, cortical white matter volume continues to rise until 20 years of age. Therefore, those who are younger at the time of radiation treatment generally have less or fully developed white matter. Since both younger and older patients have shown to lose white matter volume at similar rates, the younger irradiated patients continue to display reduced total white matter volume following radiation treatment. These deficits in white matter volume among younger patients have also been associated with increased intellectual morbidity.[21]

In this study, although there was a decline in all the neuropsychological functions among all the children with ALL, long-term follow-up of these patients will reveal whether, this cognitive dysfunction is constant or deteriorating or improving. The current results must be interpreted in the context of some of the common limitations of clinical research. The effects of other contributing factors such as economical, social, environmental, and familial factors are not studied. The present study did not try to find the significant relationship or difference between chemotherapy and radiation. The sample was collected from a single institution and there was no control group. Current results are restricted to the age group of 6-15 years; hence, it cannot be generalized to other age groups. The present study strongly suggests that there is a decline in the cognitive function, early intervention (after 1-year) on cognitive rehabilitation is vital for all survivors. Academic achievement was not measured as the children were hospitalized during the intensive phase of the treatment and subsequently had intermittent admissions, and therefore, not attending their regular school. Hence, there is a need for future studies focusing on academic achievement as well as intervention. Hospital-based educational activities and intervention stimulating the cognition can help these children resume their routine and academic activities at the earliest.

The present study implicates that combined use of CRT and HD-MTX had an immediate effect on the neurocognitive functions among children with ALL. Cognitive rehabilitation is vital to improve their overall level of cognitive functioning and quality of life. Involving parents and teachers in the recovery process is crucial. The current study has focused on the short-term cognitive effects of CNS prophylaxis treatment and this can be expanded to look into the long term effect.

The present study supports the need for continued evaluation of neurocognitive functioning in Indian children with ALL, who are receiving CNS prophylactic therapy to identify potential neurocognitive sequelae of treatment. Prevention of neurocognitive sequelae through rehabilitative measures and continuation of school and pharmacotherapy for these children is recommended.

ACKNOWLEDGMENT

Footnotes