Pediatr Blood Cancer 2011;56:279–281

Height Impairment After Lower Dose Cranial Irradiation in ChildrenWith Acute Lymphoblastic Leukemia

Arnold C. Paulino, MD,1,2,3* Pavan Jhaveri, MD,3 Zoann Dreyer, MD,2,3 Bin S. Teh, MD,1,3

and M. Fatih Okcu, MD, MPH2,3

INTRODUCTION

Cranial irradiation is known to cause growth hormone deficiency

and height impairment at doses 18–24 Gy in children with acute

lymphoblastic leukemia (ALL) [1–4]. Recent studies and the

current Children’s Oncology Group (COG) protocols in ALL have

employed doses of 12–12.6 Gy for cranial prophylaxis [5].

Not much is known regarding the effect of 12 or 12.6 Gy cranial

radiotherapy (RT) on height as most if not all reports dealing with

height measurements have used higher doses [6]. The purpose of this

study is to determine whether height impairment is seen in children

receiving cranial RT doses of 12–18 Gy and to analyze whether

height impairment is less with 12–12.6 Gy compared to 18 Gy

cranial RT.

PATIENTS AND METHODS

From 1997 to 2007, 24 children �14 years of age received

cranial RT either as central nervous system (CNS) prophylaxis or

treatment for CNS-positive T-cell or acute pre-B-cell ALL at The

Methodist Hospital. One patient was excluded from the study

because he has attained final height at the time of cranial RT, defined

as the height when there was <2 cm increase over a 1-year period.

None of the patients received radiation elsewhere in the body nor did

any patient receive total body irradiation (TBI). None of the patients

had a previous history of cranial or craniospinal irradiation. There

were 13 girls and 10 boys with a median age of 9.3 years (range,

1.9–14.6 years) at the time of initial diagnosis. Patients were treated

on or according to the following protocols: Pediatric Oncology

Group (POG) 9404 (n¼ 11), Children’s Oncology Group (COG)

AALL0232 (n¼ 4), COG AALL02P2 (n¼ 4), POG 9906 (n¼ 2),

and other (n¼ 2). Dose fractionation schemes for cranial RT

included 18 Gy in 9 fractions (n¼ 8), 18 Gy in 10 fractions (n¼ 5),

12.6 Gy in 7 fractions (n¼ 6), and 12 Gy in 8 fractions (n¼ 4).

Median age at the time of RT for 12 or 12.6 Gy was 8.1 years while

for 18 Gy was 10.6 years. There was no difference in the distribution

of patients in the 12 or 12.6 Gy versus 18 Gy groups according to

age, gender, or length of follow-up (Table I). Fraction size of 1.5 or

1.8 Gy was more common in children irradiated to 12 or 12.6 Gy

compared to 18 Gy (P¼ 0.01, Fisher’s exact test). Patients receiving

cranial RT were matched by age at time of diagnosis (�1 year),

gender, and race/ethnicity to a control group of 23 patients who had

ALL but did not receive cranial RT. Median follow-up for irradiated

patients was 63.5 months while for unirradiated patients was

91 months. It was 64.5 months for 12–12.6 Gy and 63 months for

18 Gy cranial RT.

Statistical Analyses

Standing height was measured at initial diagnosis of ALL and at

regular visits during the follow-up period. Patient height was

converted to a z-score, adjusting for age and sex, using standardized

growth charts developed by the Centers for Disease Control and

Prevention for children in the United States [7]. The z-score

indicates the number of standard deviations the height measurement

is away from the mean for the normal age–sex cohort. The z-score at

initial diagnosis (zi) was compared to the z-score at last follow-up

(zf) using the paired Student’s t-test. The differences in z-scores

(zf� zi) were also compared according to age at diagnosis (<5 vs.

�5 years), gender, use of cranial RT, cranial RT dose (12 or 12.6 Gy

vs. 18 Gy), daily RT dose (1.5 or 1.8 Gy vs. 2 Gy), or length of

follow-up after RT (36–60 months vs. >60 months) using the

unpaired Student’s t-test. All analyses were done using GraphPad

software and a two-sided P-value of <0.05 was considered

statistically significant.

Purpose. The purpose of this study is to determine whether heightmeasurements are affected by cranial radiation doses of 12–18 Gy.Patients and Methods. From 1997 to 2007, 23 children receivedcranial RT for T-cell or pre-B-cell acute lymphoblastic leukemia(ALL). Dose fractionation schemes included 18 Gy in 9 fractions(n¼8), 18 Gy in 10 fractions (n¼5), 12.6 Gy in 7 fractions (n¼6),and 12 Gy in 8 fractions (n¼ 4). These patients were matched andcompared to a control group of 23 patients who had ALL but nocranial RT. Height z-scores at diagnosis and last follow-up werecompared using the paired Student’s t-test. Differences in z-scoresaccording to host and treatment parameters were compared using

the unpaired Student’s t-test. Median follow-up for irradiated patientswas 63.5 months while for unirradiated patients was 91 months.Results. The mean z-scores at initial diagnosis and last follow-upwere 0.14 and �0.48 for patients receiving 12–12.6 Gy (P¼ 0.016),�0.16 and �0.89 for 18 Gy (P¼0.003), and 0.34 and 0.22 for no RT(P¼0.62). For children receiving RT, the mean difference in z-scoresat initial diagnosis and last follow-up was �0.67 while for thosenot receiving RT, it was �0.10 (P¼ 0.043). Conclusion. Childrenreceiving 12–18 Gy cranial RT for ALL were found to have heightimpairment compared to those not receiving RT. Pediatr BloodCancer 2011;56:279–281. � 2010 Wiley-Liss, Inc.

Key words: height; leukemia; pediatric cancer; prophylactic cranial irradiation

� 2010 Wiley-Liss, Inc.DOI 10.1002/pbc.22781Published online 9 September 2010 in Wiley Online Library(wileyonlinelibrary.com).

——————1Department of Radiation Oncology, The Methodist Hospital, The

Methodist Hospital Research Institute, Houston, Texas; 2Division of

Hematology/Oncology, Department of Pediatrics, Texas Children’s

Hospital, Houston, Texas; 3Baylor College of Medicine, Houston,

Texas

Presented in part at the 92nd Annual Meeting of the American Radium

Society from May 1 to 5, 2010 at Cancun, Mexico.

Conflict of interest: Nothing to declare.

*Correspondence to: Arnold C. Paulino, Department of Radiation

Oncology, The Methodist Hospital, 6565 Fannin St., DB1-077,

Houston, TX 77030. E-mail: apaulino@tmhs.org

Received 15 June 2010; Accepted 15 July 2010

RESULTS

The mean z-scores for all irradiated and non-irradiated patients at

initial diagnosis and at last follow-up were 0.15� 0.15 (standard

error of the mean) and �0.24� 0.17, respectively (P¼ 0.007).

For children not receiving RT (n¼ 23), the mean z-scores prior to RT

and at time of last follow-up were 0.34� 0.19 and 0.22� 0.26,

respectively (P¼ 0.62). For children receiving 12 or 12.6 Gy

(n¼ 10), the mean z-scores prior to RT and at the time of last

follow-up were 0.14� 0.38 and �0.48� 0.26, respectively

(P¼ 0.016). For children receiving 18 Gy (n¼ 13), the mean

z-scores prior to RT and at the time of last follow-up were

�0.16� 0.30 and �0.89� 0.25, respectively (P¼ 0.003). The

mean difference in z-scores (zf� zi) for 0, 12 or 12.6, and 18 Gy

were �0.12� 0.23, �0.62� 0.21, and �0.72� 0.20 respectively

(Table II). Analysis of differences in z-scores (zf� zi) revealed that

children receiving cranial RT had height impairment compared to

those not receiving RT (P¼ 0.043). Subgroup analysis of children

receiving cranial RT of 12–12.6 Gy versus 0 Gy (P¼ 0.07) and

18 Gy versus 0 Gy (P¼ 0.22) did not reveal any statistically

significant difference. Analysis of differences in z-scores according

to gender (P¼ 0.50), age at diagnosis (P¼ 0.27), fraction size

(P¼ 0.13), and length of follow-up (P¼ 0.28) were not significant.

The differences in z-scores (zf� zi) according to cranial RT dose

(12 or 12.6 Gy vs. 18 Gy) were not significant (P¼ 0.68). At a mean

follow-up of 79 months, 29 of 46 (63.0%) children have attained

adult height. None of the patients received growth hormone

replacement therapy.

DISCUSSION

Height impairment is a known complication of ALL therapy.

Age�4 years, female gender, and use of cranial RT are well-known

parameters which increase the likelihood of height impairment

[4,6,8–10]. Height deficits are more pronounced in children

receiving cranial doses of 24 Gy compared to 18 Gy. Sklar et al.

[4] studied three groups of ALL patients (0, 18, and 24 Gy cranial

RT) and found that the greatest decrease in final height standard

deviation scores (SDS) was in children receiving 24 Gy followed by

18 Gy. Davies et al. noted similar results. Height impairment was

more common with the 24 Gy dose; in addition girls receiving 24 Gy

had the highest decrease in height SDS [11]. To our knowledge, this

is the first report examining the occurrence of height impairment in

children with ALL receiving 12 or 12.6 Gy cranial RT. Our findings

indicate that even when the cranial dose is lowered to 12 or 12.6 Gy,

there is impairment in standing height as evidenced by lower z-

scores at last follow-up compared to initial diagnosis in this

subgroup. Furthermore, the differences in z-scores (zf� zi) were

statistically the same in children receiving cranial RT doses of 12–

12.6 Gy compared to 18 Gy; however, the patient numbers are small

and this finding should be taken with caution.

It is well known that some investigators have found that children

receiving chemotherapy without cranial RT have some height

impairment [4,6,8,10,12,13] while others have not [14,15]. We did

not find any significant height impairment in the control group

which did not receive cranial RT. Figure 1 shows the differences in

z-scores according to the dose of cranial RT in different reports

[4,8,11,13–15]. In general, one can conclude that the greatest

impairment in height is seen in children receiving 24 Gy followed by

18 Gy. The height impairment observed with 12 or 12.6 Gy is within

the range of height impairment seen in those receiving 18 Gy cranial

RT. We were not able to find differences in height according to

age at RT and gender, possibly because of the small numbers on

patients in this study. Likewise, we were unable to show a difference

according to fraction size, a main determinant of late effects of

radiotherapy [16].

One of the possible limitations of our study is that we did not look

at differences in intensity of chemotherapy which can potentially

impact final height [4,8,17]. Patients who had cranial RT may be

receiving more intensive chemotherapy as they are generally higher

risk. Although it is believed that the intensity of chemotherapy can

affect height, it is less of a determinant compared to the use of cranial

RT 18–24 Gy [6]. In one study of ALL children who received

chemotherapy without cranial RT, only 2 of 235 (0.9%) survivors

were diagnosed with growth failure. Both patients with growth

failure received chemotherapy which included methotrexate,

6-mercaptopurine, vincristine, doxorubicin, cyclophosphamide,

L-asparaginase, dexamethasone, cytarabine, 6 thioguanine, and

intrathecal methotrexate [12]. Another possible limitation is that we

included children up to 14 years of age if they had not attained final

height. One can argue that their height impairment would be less,

but in our series, 5 out of the 12 children from 12 to 14 years of

age had a difference in z-score or (zf� zi) of ��1.0. Finally, some

have reported catch-up growth during the first 1–2 years after

Pediatr Blood Cancer DOI 10.1002/pbc

TABLE I. Characteristics of Children Receiving CranialRadiation Therapy Dose of 12 or 12.6 Gy Versus 18 Gy

Parameter

12 or

12.6 Gy 18 Gy P-valuea

Gender 0.69

Male 5 5

Female 5 8

Age at RT (years) 1.00

<5 3 3

�5 7 10

Fraction size (Gy) 0.01

1.5 or 1.8 10 5

2 0 8

Length of follow-up (months) 0.68

36–60 4 7

>60 6 6

RT, radiation therapy. aFisher’s exact test.

TABLE II. z-Scores According to Dose of Cranial Irradiation for Acute Lymphoblastic Leukemia

z-Score at initial

diagnosis (zi)

z-Score at last

follow-up (zf)

Median follow-up

(months)

Mean difference in

z-scores (zf� zi) P-value

No cranial RT (0 Gy), N¼ 23 0.34� 0.19 0.22� 0.26 91 �0.12� 0.23 0.62

Cranial RT (12 or 12.6 Gy), N¼ 10 0.14� 0.38 �0.48� 0.26 64.5 �0.62� 0.21 0.016

Cranial RT (18 Gy), N¼ 13 �0.16� 0.30 �0.89� 0.25 63 �0.72� 0.20 0.003

280 Paulino et al.

chemotherapy [4,8]. Although this can potentially affect our results,

our median follow-up is 61 and 91 months for irradiated and

unirradiated patients, well beyond the time when catch-up growth

has been described after cessation of chemotherapy. Catch-up

growth has been described 1–2 years after cessation of chemo-

therapy and would usually occur within 5 years after initial ALL

diagnosis [8,18,19].

What are the possible explanations for the decreased height in

children receiving 12–12.6 Gy cranial RT? Growth hormone

deficiency has been described in children as low as 8 Gy in single

and 12 Gy in fractionated doses of TBI [20,21]. The available data

regarding the effect of 12–12.6 Gy RT to the brain are reported

only in children receiving TBI, but the cause of growth impairment

is confounded by exposure of the spine and extremities to RT as

well as the use of intensive chemotherapy. The contribution of

growth hormone deficiency is unclear, and some investigators have

found that irradiation of the skeletal system rather than the brain is

the main determinant of decreased height in survivors receiving

TBI [22]. Others have found that both growth hormone deficiency

and late effects to the bone are responsible for decreased

height [20].

The findings of this study indicate that even with 12–18 Gy

cranial RT, decreased height occurs. Radiation oncologists who treat

children with ALL should include this possibility when they acquire

parents’ informed consent for cranial RT. Whether the height deficit

from 12 to 12.6 Gy is less compared to 18 Gy cranial RT cannot be

answered in this study.

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Pediatr Blood Cancer DOI 10.1002/pbc

Fig. 1. Mean difference in z-scores (zf� zi) according to dose of

cranial irradiation (0, 12, 18, and 24 Gy) as reported in the literature

(b, boys; g, girls).

Height After Cranial Irradiation in ALL 281