Pediatr Blood Cancer 2008;51:275–279

Neuropsychological Outcome Following Intensity-Modulated RadiationTherapy for Pediatric Medulloblastoma

Neelam Jain, PhD,1* Kevin R. Krull, PhD,1,2 Pim Brouwers, PhD,2,3

Murali M. Chintagumpala, MD,2,3 and Shiao Y. Woo, MD4

INTRODUCTION

Surgery, cranial irradiation, and chemotherapy are all vital

components in the treatment of medulloblastoma, the most frequent

malignant brain tumor of childhood. Using a combination of these

modalities, cure rates approach 80% [1]. However, these high

cure rates are achieved at the cost of delivering higher doses of

chemotherapy and craniospinal radiation, further increasing the

likelihood of central nervous system (CNS) morbidities, partic-

ularly sensorineural hearing loss (SNHL) and neurocognitive

abnormalities.

Neurocognitive Abnormalities

Longitudinal studies of children treated for malignant posterior

fossa tumors, including medulloblastoma, have consistently

documented significant neurocognitive deficits that tend to be

progressive and to be related to age at treatment as well as to type of

treatment [2]. In addition to declines in global intelligence, specific

deficits in memory, visuospatial abilities, reading [3], and arithmetic

have also been reported [4–6]. Moreover, some of the neuro-

cognitive deficits, particularly those in the language domains, may

be partially related to hearing loss.

Hearing Loss

Radiation-induced SNHL usually develops within 6–12 months

after the completion of radiation treatment [7]. SNHL has been

shown to be a dose-related phenomenon [8], affecting the higher

hearing frequencies in 25–50% of patients following doses of

50–60 Gy [9–11]. Although the mechanism remains unproven,

SNHL is thought to be attributed to radiation-induced changes in the

cochlea itself or in the surrounding vasculature [12,13].

Platinum-based agents play an important role in the chemo-

therapy regimens for medulloblastoma, and cisplatin-induced

hearing loss in children is well documented [14–16]. The

ototoxicity is typically bilateral, irreversible, and directly related

to cumulative cisplatin dose. Hearing loss first occurs in the higher

frequencies, and continued exposure eventually affects the lower

frequencies used in speech. The known risk factors for cisplatin

ototoxicity are young age at treatment and prior cranial irradiation

[14]. Unfortunately, the vast majority of medulloblastoma patients

share these risk factors.

Ototoxicity has been shown to be more significant when radio-

therapy and cisplatin chemotherapy are used in combination. Cranial

irradiation before chemotherapy enhances and potentiates cisplatin

ototoxicity [17–20]. With cisplatin alone, there is a negligible risk of

hearing loss at cumulative doses of 90–360 mg/m2; however, this risk

increases to 60–80% when cisplatin is combined with prior cranial

irradiation [14]. This degree of hearing loss may significantly impact

the child’s developing cognitive abilities and quality of life.

Intensity-modulated radiation therapy (IMRT) is a relatively

new technology that uses inverse planning and computer-controlled

radiation deposition [21]. The chief advantage of IMRT is its ability

to precisely deliver radiation to the target tissue with relative sparing

of the surrounding tissues. In the case of posterior fossa tumors the

surrounding tissue includes the cochlea and eighth cranial nerve.

This targeted delivery of radiation enables escalation of dose to the

tumor, thus potentially providing better disease control while

simultaneously minimizing treatment-related morbidity. Compared

Background. Combined cisplatin chemotherapy and cranialirradiation for treatment of medulloblastoma in children can causesignificant ototoxicity and impair cognitive function and quality oflife. We have previously demonstrated the conformal technique ofintensity-modulated radiation therapy (IMRT) to reduce ototoxicity,however, it has been suggested that IMRT may increase risk ofcognitive deficits compared to conventional radiation therapy (CRT).This study compared the impact of the two treatments on measuresof neurocognitive functioning. Procedure. Twenty-five pediatricpatients with medulloblastoma were treated either with CRT orIMRT. In addition they received neurocognitive assessments toevaluate long-term functional outcome. Statistical analyses between

the two groups were conducted to compare levels and profilesof performance on tests not confounded with hearing loss.Results. When compared to CRT, children treated with IMRT didnot perform more poorly on any of the measures. Both groups’ meanperformance was significantly lower than published norms onseveral of the measures employed. Conclusion. The benefit ofreduced ototoxicity with IMRT does not appear to be at the cost of adecline in nonverbal intellectual abilities, visual-spatial skills,processing speed, or fine motor dexterity when compared to CRTin children with medulloblastoma. Pediatr Blood Cancer 2008;51:275–279. � 2008 Wiley-Liss, Inc.

Key words: CNS tumors; late effects of treatment; neuropsychology; radiation oncology

� 2008 Wiley-Liss, Inc.DOI 10.1002/pbc.21580

——————1Learning Support Center for Child Psychology, Texas Children’s

Hospital, Houston, Texas; 2Department of Pediatrics, Baylor College

of Medicine, Houston, Texas; 3Texas Children’s Cancer Center, Texas

Children’s Hospital, Houston, Texas; 4Department of Radiation

Oncology, M.D. Anderson Cancer Center, University of Texas,

Houston, Texas

Neelam Jain’s and Kevin R. Krull’s present address is Department of

Epidemiology and Cancer Control, St. Jude Children’s Research

Hospital, Memphis, TN.

Pim Brouwer’s present address is Division of AIDS & Health and

Behavior Research, NIMH, Bethesda, MD.

*Correspondence to: Neelam Jain, St. Jude Children’s Research

Hospital, Department of Epidemiology and Cancer Control, 332 N

Lauderdale St. MS # 735, Memphis, TN 38105-2794.

E-mail: neelam.jain@stjude.org

Received 29 November 2007; Accepted 4 March 2008

to conventional radiation therapy (CRT), however, the redistribution

of the radiation dose with IMRT leads to other brain areas now

receiving low dose exposure. With posterior fossa tumors this

includes exposure to medial-temporal brain regions, which are

involved in spatial organization, memory, and aspects of processing

speed.

In an earlier article [22], we demonstrated that the conformal

technique of IMRT reduced the rate of ototoxicity in children with

medulloblastoma by decreasing the radiation dose delivered to the

auditory apparatus. Recently, it has been questioned whether this

redistribution may be associated with an increased risk of cognitive

impairment [23]. It is plausible that children treated with IMRT

would demonstrate larger deficits in neurocognitive abilities due to

the fact that the radiation dose they received was distributed more

intensely to medial brain areas in order to spare the auditory nerve.

The purpose of the current study was to compare a group of

children treated with IMRT to a group treated with CRT to

investigate whether the benefit of reduced ototoxicity was

associated with an increase in neurocognitive dysfunction, due to

greater medial-temporal radiation exposure. This study focused on

nonverbal measures of neurocognitive functioning to reduce the

possible confounding effect of differential hearing loss in the IMRT

and CRT groups on development of age-appropriate expressive and

receptive language skills.

METHODS

Subjects

Ninety-six percent (25/26) of the children who participated in the

original ototoxicity study [22] completed neuropsychological

evaluations following surgical resection of their tumor and the

completion of all chemotherapy and radiation therapy. Demo-

graphic information for the study sample can be found in Table I.

Each child underwent at least one neuropsychological evaluation

and the results of the most recent evaluations were used in the

analyses. The difference in age at treatment between the groups was

significant [F(1, 23)¼ 4.35, P< 0.05]. However, there was no

significant group difference with respect to age at the time of the

neuropsychological evaluations or with respect to time between the

end of treatment and the evaluation. Detailed treatment-based data

can be found in Table II as well as in the original article [22].

Neuropsychological Assessment

All children were administered a protocol driven comprehensive

battery of standardized neuropsychological measures following the

completion of their treatment regimen. The evaluation included the

assessment of intellectual abilities, visual-motor integration, and

fine motor dexterity.

All children completed a standardized measure of Global Mental

Ability consisting of either the Wechsler Adult Intelligence Scale—

Third Edition (WAIS-III; [24]), the Wechsler Intelligence Scale for

Children—Third Edition (WISC-III; [25]), the Differential Abilities

Scale (DAS; [26]), or the Leiter International Performance Scale—

Revised (Leiter-R; [27]). The specific measure used was based upon

the age of the child at the time of the evaluation and whether or not

their communication abilities appeared compromised as a result of

hearing loss. Overall nonverbal functioning was evaluated with the

Global Index of Visuo-Spatial Abilities (GIVSA), which was

defined as either the Performance Intelligence Quotient (PIQ) of the

WAIS-III or WISC-III, the Spatial Cluster from the DAS, or the

Brief IQ from the Leiter-R. Similarly, a Global Index of Verbal

Abilities (GIVA) defined as the Verbal Intelligence Quotient (VIQ)

of the WAIS-III/WISC-III or the Verbal Cluster from the DAS and a

Global Index of Mental Abilities (GIMA) defined as either the Full

Scale Intelligence Quotient (FSIQ) from the WAIS-III/WISC-III,

the General Conceptual Ability score from the DAS, or the FSIQ

from the Leiter-R were calculated as previously described [28].

Given that the cognitive measures used are standardized with a mean

of 100 and a standard deviation of 15, the nonverbal, verbal, and

overall intelligence standard scores for each child were grouped

together to create the GIVSA, GIVA, and GIMA variables.

Spatial organizational skills were assessed with the Beery Test

of Visual Motor Integration—Fourth Edition (VMI; [29]), which

requires the child to copy 27 geometric designs of increasing

complexity. Processing speed was assessed with the Coding and

Symbol Search subtests from the WISC-III/WAIS-III. Fine motor

speed was assessed using the Purdue Pegboard Test [30]. This task

requires a child to place pegs in holes on a board as quickly as

possible using first their dominant hand and then their nondominant

hand. Fine motor dexterity was assessed using the Grooved

Pegboard Test [31], which requires children to place grooved pegs

into matching holes as quickly as possible using their dominant and

nondominant hands, independently.

The relationships between type of treatment, age at diagnosis,

age at testing, time since diagnosis, and the various neuro-

psychological measures were examined using Pearson product-

moment or bi-serial correlations. T-tests were used to compare

differences in level and profile of performance between the two

treatment groups.

RESULTS

All analyzed neuropsychological scores (see Table III) were

based on age-corrected standard scores with a mean of 100 and a

standard deviation (SD) of 15. There was no significant difference

(P> 0.50, h2¼ 0.00) in overall neurocognitive functioning as

reflected by the GIMA scores between children treated with IMRT

and children treated with CRT. The mean nonverbal GIVSA score

for the IMRT Group was not statistically significantly different from

the mean of the CRT Group [t(20)¼ 0.84, P> 0.40, h2¼ 0.03].

There was no significant difference (P> 0.70, h2¼ 0.01) between

the groups for the verbal GIVA scores for the IMRT group and the

CRT group.

Further group analyses on tasks assessing visual-spatial abilities

were conducted to ascertain possible differences on functions not

confounded with language skills. The IMRT group’s performance

Pediatr Blood Cancer DOI 10.1002/pbc

TABLE I. Demographic Data for Total Study Sample

IMRT CRT

Male/female 13/2 8/2

Risk status 11 Standard, 4 high 4 Standard, 6 high

Age at diagnosisa 92.07 (34.74) 64.90 (26.93)b

Age at evaluationa 141.80 (48.10) 142.90 (48.93)

Time between diagnosis

and evaluationa49.73 (44.60) 78.00 (46.83)

aAll means (standard deviations) for ages presented in months;bIndependent-samples T-test P< 0.05.

276 Jain et al.

on the VMI, a measure of visual-spatial ability, was not significantly

higher than the score for the CRT group [t(21)¼ 1.71, P< 0.11,

h2¼ 0.12] even though the difference was in the moderate to large

effect size range, likely due to the small sample size [32]. Both

groups did show a deficit on this test compared to the standardization

sample (IMRT t(12)¼�3.86, P< 0.01; CRT t(9)¼�7.59,

P< 0.01).

On the Purdue Pegboard Test no significant differences in fine

motor speed were evident (all P’s> 0.50) in dominant hand (DH) or

nondominant hand (NDH) functioning. Both groups performed

significantly below established norms (IMRT DH t(7)¼�4.80,

P< 0.01, IMRT NDH t(6)¼�3.67, P< 0.05; CRT DH t(7)¼�5.87, P< 0.01, CRT NDH t(7)¼�7.08, P< 0.01). On the

Grooved Pegboard test, there were again no significant differences

(P’s> 0.50) between the groups for either hand. However, both

groups scored well below established norms on this measure (IMRT

DH t(10)¼�2.70, P< 0.05, IMRT NDH t(9)¼�3.13, P< 0.05;

CRT DH t(4)¼�1.94, P¼ 0.12, CRT NDH t(4)¼�4.17,

P< 0.05).

Processing speed was assessed with the Coding and Symbol

Search subtests from the WISC-III/WAIS-III. No significant

differences in performance between the groups were evident

(P> 0.30) and both groups performed significantly below

established norms on the Coding subtest (IMRT t(10)¼�4.56,

P< 0.01; CRT t(4)¼�4.64, P< 0.05). Similarly, no significant

differences in performance were noted between the groups

(P< 0.10) on the Symbol Search subtest and the CRT group

performed more poorly than establish norms on this measure

(t(4)¼�7.07, P< 0.01).

Finally, exploratory analyses were carried out to determine if

there were any consistent relationships between the neuropsycho-

logical variables and disease and treatment variables. Correlation

coefficients between GIVSA and age at diagnosis (r¼ 0.18), time

between diagnosis and testing (r¼ 0.10), and age at the time of the

evaluation (r¼ 0.25) did not reach significance for the IMRT group.

In the CRT group the correlation between GIVSA and age at

diagnosis (r¼ 0.69) approached statistical significance at (P< 0.10)

suggesting that treatment at an earlier age was associated with lower

GIVSA scores [33]. This age at treatment effect is also observed in

the correlation for the VMI with the overall group; of the ten

outcome measures only the VMI was significantly correlated with

age at diagnosis (r¼ 0.45, P< 0.05). The correlations between

Pediatr Blood Cancer DOI 10.1002/pbc

TABLE II. Treatment Data for Total Study Sample in Order of Treatment Administration

IMRT CRT

Standard

Peripheral blood stem cell harvest Prior to beginning CRT —

CRT 23.4 GY 23.4–24 GY

Posterior fossa boost 12.6 GY (1.8 GY/day) 30.6–32.4 GY

Tumor bed boost 19.8 GY (1.8 GY/day) —

Chemotherapy Dose intensified (over 4 cycles) Conventional doses (several cycles)

Peripheral stem cell infusion Delivered in between each dose of chemotherapy —

High

Peripheral blood stem cell harvest Prior to beginning CRT —

CRT delivered by conventional parallel-opposed

beams

— 35.2–36 GY

Posterior fossa boost delivered by conventional

parallel-opposed beams

— 18–19.8 GY

Chemotherapy Topotecan (2 courses) Conventional doses (several cycles)

CRT 36 GY —

Tumor bed boost 19.8 GY (1.8 GY/day) —

Chemotherapy Dose intensified (over 4 cycles) —

Peripheral stem cell infusion Delivered in between each dose of chemotherapy —

TABLE III. Neurocognitive Data for Total Study Sample

IMRTa CRTa

Measure

GIMA 83.9 (20.9, 49–122) 83.8 (19.4, 49–112)

GIVSA 88.1 (20.7, 47–127) 80.6 (19.4, 50–104)

GIVA 85.4 (18.8, 58–113) 88.4 (19.5, 56–119)

VMI 85.2 (13.8, 63–114) 76.4 (9.8, 64–99)

Purdue DH 72.5 (16.2, 44–91) 72.5 (13.2, 48–88)

Purdue NDH 68.3 (22.9, 40–105) 66.0 (13.6, 43–87)

Grooved Peboard DH 79.0 (25.8, 40–110) 71.6 (32.7, 40–121)

Grooved Pegboard NDH 70.9 (29.4, 40–105) 63.2 (19.7, 40–83)

Coding 80.0 (14.5, 55–95) 72.0 (13.5, 60–95)

Symbol search 92.0 (16.7, 60–115) 75.0 (7.9, 65–85)

aAll means (standard deviations, range).

Neuropsychological Outcome in Medulloblastoma 277

GIVSA and the time between diagnosis and testing (r¼�0.31) and

age at the time of the evaluation (r¼ 0.23) did not reach significance.

DISCUSSION

IMRT treatment for posterior fossa tumors in children has been

associated with significant improvements in disease outcome and

reduction in ototoxicity [22]. The current investigation suggests

that these improvements have not been at an apparent cost in

neurocognitive functioning. In our sample children treated with

IMRT were not found to perform significantly worse than children

treated with CRT on neuropsychological measures. Furthermore,

both groups demonstrate significant delays when compared

to standardization samples. This finding is consistent with the

literature that reports neurocognitive changes in children treated for

medulloblastoma as early as two years post-diagnosis [34].

Neuropsychological measures, such as the ones used in our

study, have been demonstrated to be sensitive to the effects of

cranial radiation (2). Specifically, a number of studies have shown a

relation between radiation variables and neurocognitive develop-

ment [35] even in studies with small sample sizes [36]. Cranial

irradiation as treatment for childhood cancer has been associated

with cognitive decline and deficits, specifically in domains of

nonverbal functioning [37] including PIQ, visual-motor integration,

visual memory, fine motor skills, and executive functioning

[35,38,39]. Longitudinal assessments have demonstrated a consis-

tent decline in intelligence and children under the age of seven were

found to show greater declines in nonverbal intellectual abilities

than older children [33,40].

Differences in neurocognitive functioning between the IMRT

and CRT groups could be expected because of differences in the

radiation fields. To spare the eighth cranial nerve to reduce the

degree of SNHL with IMRT, the medial temporal lobes, including

the hippocampus and entorhinal cortex receive slightly more

radiation than with CRT [22,23]. These structures are highly

susceptible to radiation associated injury of microvasculature as

well as neuroprogenitor cells [41]. Damage to these medial temporal

structures can result in both specific and/or general neurocognitive

deficits. However, we were unable to document such a differential

negative effect for the IMRT group, using measures that are very

sensitive to abnormalities in these areas.

Differences in neurocognitive outcome may also be related to

maturational differences in the development of cognitive skills, with

treatment-related neurocognitive deficits emerging at varying times

during the process of brain maturation. It is important to consider not

only the age at diagnosis but also the maturational level (i.e., time of

evaluation) when evaluating children who have experienced brain

insults such as cranial radiation [42].

As expected, the children with medulloblastoma performed

below the levels expected on the basis of their socioeconomic and

psychosocial background on most of the neuropsychological

measures administered. The specific etiology of this deficit is hard

to determine. The independent contribution of hearing loss, which

may have a significant functional impact on neurocognitive

function, cannot be separated in this patient population from the

possible neuropathological sequelae of surgery, radiation therapy,

and chemotherapy or from the consequences of the tumor itself.

Limitations in this study include a small sample size, lack of

randomization resulting in differences in some demographic

variables, and lack of a consistent neuropsychological testing

battery which consequently required adapted methodology and did

not enable assessment of all relevant domains (e.g., memory). Since

CRT is no longer the standard of care, a comparison between CRT

and IMRT using a randomized design is not feasible and one will

need to rely on historic data for comparisons. The current study

attempted to make optimal use of the data that was available, but the

limitations need to be recognized.

In conclusion, significant improvements in the treatment of

pediatric brain tumors has resulted in increasing rates of long-term

survival and cure and subsequent treatment modifications have

resulted in the reduction of toxicities. In that vein, IMRT was

successfully adapted to reduce ototoxicity associated with treatment

for medulloblastoma, but this adaptation could have caused

different neurotoxicities which would be reflected in neurocognitive

deficits. The current study did not find evidence for differential

neurocognitive deficits in the IMRT treated group. Thus, the benefit

of reduced ototoxicity with IMRT does not seem to be at the cost of

compromising nonverbal intellectual abilities, visual-spatial skills,

processing speed, or fine motor dexterity when compared to CRT in

children with medulloblastoma.

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Neuropsychological Outcome in Medulloblastoma 279