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Divisions of Endocrinology (W.X., T.M.) and Neurology and Oncology (A.J.), Department of Pediatrics, University of Pennsylvania, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104
Address all correspondence and requests for reprints to: Thomas Moshang, Jr., M.D., Division of Endocrinology, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, Pennsylvania 19104. E-mail: moshang{at}e-mail.chop.edu.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Although there are previous reports of significantly impaired heights post CSRT for medulloblastoma, the long-term follow-up data concerning adult height, and especially sitting height, are scarce. In some studies, the sample size was too small to demonstrate statistical power (12, 19, 20). Some studies reported the absolute height impairment without consideration for familial determinants (20, 21, 22). Adult height outcome, as assessed from a variety of childhood cancer survivors (9, 17, 21, 22) or, alternatively, medulloblastoma survivors from multiple centers (23), increases the chance of introducing variations in oncology therapy, hormonal therapy, and auxological assessments. Because adult height is known to be dependent on but not limited to age and the dose of irradiation, chemotherapy, and GHRT, the above concerns might explain the wide range of adult Z-scores achieved from -2.9 to -5 SD score (SDS) below the normal mean for standing adult height (12, 19, 20).
To determine the adult standing height and sitting height of medulloblastoma survivors in a relatively large number of patients, to elucidate the impact of GHRT at the dose of 0.3 mg/kg·wk on the height outcome, if any, and to compare the height status to their midparental height and to those previously reported studies, we retrospectively reviewed the experience of treating GH deficiency (GHD) secondary to CSRT for medulloblastoma in Children’s Hospital of Philadelphia (CHOP) after synthetic recombinant human GH (rhGH) became available.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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All children diagnosed with medulloblastoma and treated with CSRT and chemotherapy from 1981–1996 at CHOP were reviewed. The outcome data were obtained from GH treatment registries and tumor registries approved by the Institutional Review Board (IRB) of CHOP. Subjects included in the study were those who reached adult height (i.e. the height velocity for the preceding year was less than 1 cm/yr) and whose bone ages were greater than 16 yr in males and greater than 14 yr in females. There were a total of 51 patients (36 males and 15 females) who achieved adult or near adult height (those children with the above criteria but whose GHRT was not yet discontinued). The age range was 13.1–27.5 yr. The mean age of their last clinical visit was 17.95 ± 3.4 yr. The mean age at diagnosis and treatment for medulloblastoma was 7.2 ± 3.0 yr (range, 1.58–11.58 yr).
Oncology treatment
Regardless of tumor stages, the majority (n = 44) had received standard doses of CSRT at 23–39 Gy. There were seven very young children (mean age, 3.96 ± 1.2 yr) who were diagnosed with medulloblastoma between 1987 and 1990 and were treated with a lower dose of CSRT at 18 Gy on an institutional pilot treatment protocol (24, 25). The adjuvant chemotherapy consisted of vincristine, lomustine, and cis-diamminedichloroplatinum and was similar for all patients, with some variations in number of cycles. The low-dose CSRT pilot treatment protocol was approved by the IRB at CHOP and at the Hospital of the University of Pennsylvania.
Anthropometrics
Besides regular oncology follow-up, endocrine clinic visits were available to all of the patients to assess endocrine complications if applicable. Biannual follow-up was made in those patients with endocrine dysfunction. At each endocrine visit, anthropometrics was performed in the endocrinology clinic by trained observers to determine standing height and erect sitting height, using both a standing and sitting Harpenden stadiometer. In those patients receiving only oncology follow-up visits, trained observers obtained yearly standing heights using a stadiometer. Midparental height was obtained by historical report. All raw data of standing height and sitting height were transformed to SDS. The standing height SDS were calculated using U.S. population data provided by the Centers for Disease Control and Prevention/National Center for Health Statistics. The sitting height SDS were calculated by using values for the population means and SD from the published data of Dangour et al. (26).
GHD
The diagnosis of GHD was based clinically upon decelerating growth velocity and biochemically upon failure to respond appropriately to two separate GH secretagogues (peak GH serum concentration < 8 µg/liter), or alternatively low IGF-I in association with abnormal overnight neurosecretory GH profiles (mean serum GH value < 2.5 µg/liter and no more than two peaks of serum GH concentration of 8 µg/liter or greater) (27). GHD was diagnosed in 35 of 44 children who received the standard dose of CSRT, with incident rate of 79.5%. Three GHD patients chose not to be treated with rhGH (group G1). There were five GHD patients treated with GHRT whose clinical information was unavailable for evaluation. Therefore, the subset of GHD patients who received a standard dose of CSRT and treatment with rhGH was limited to 27 individuals (21 males and six females) and comprised group G2. Although there were nine patients (all treated with standard dose of CSRT) who were not GHD, final height was only available for five of these patients (group G3). Among the seven very young patients treated with a lower dose of CSRT, six were GHD and received rhGH. These six subjects were group G4 in this study. The stratification of the four groups is summarized in Table 1
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There were a total of 33 patients in groups G2 (n = 27) and G4 (n = 6) who were treated with GHRT at a dose of 0.3 mg/kg·wk. The average time interval between medulloblastoma therapy and initiation of GHRT was 3.91 ± 1.24 yr. In the children treated with low-dose CSRT, the mean age of starting GHRT was 10.89 ± 2.4 yr, with a mean duration of treatment of 6.05 ± 2.2 yr. In group G2, the mean age for initiation of GHRT was 11.28 ± 2.3 yr with a mean duration of treatment of 6.1 ± 2.4 yr. Those patients that were thyroid or adrenal insufficient were treated with physiological hormone replacement. Four (three males and one female) required gonadal steroid replacement for hypogonadotropic hypogonadism. Six children in group G2 and one in group G4 were treated with long-acting GnRH agonist therapy at a dose of 7.5 mg im every 4 wk, concomitant with rhGH therapy because of early puberty. The adult heights and sitting heights of the children treated as well with GnRH agonist therapy were evaluated separately but were not different from their respective groups.
Statistical analysis
The height measurement at the last clinic visit was used for all subjects. Paired t test was applied when final standing height was compared with their midparental height. Statistical comparisons were also made among the mean adult standing height, midparental height within each group, and between the groups, using one-way ANOVA, post tested with Newman-Keuls multiple column pair comparisons. Data for mean sitting height were compared with the gender-specific normal population data, between groups G2 and G4, and previous reports (12, 17, 19, 20), using t test. The effect of age at onset of CSRT, age at initiation of GHRT, and the duration of GHRT as to adult standing and sitting height outcome was determined by linear regression analysis. The significant level for all comparisons was 0.05.
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Results |
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The adult heights achieved in all of the medulloblastoma patients were impaired with a mean SDS of -1.78 ± 1.01, irrespective of CSRT dose, GHD diagnosis, or rhGH therapy. The patients were significantly shorter than their parents (P < 0.0001). However, the overall adult heights of the patients were taller than adult heights previously reported (Table 2) (6, 9, 12, 20).
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. No differences were observed among the midparental heights in all four groups (P = 0.97). Not surprisingly, the adult height of group G1 (nontreated GHD) was extremely impaired (mean height SDS, -3.23 ± 1.3) and was clearly shorter than the mean parental height. With GHRT, group G2 was much taller (mean height SDS, -1.86 ± 0.8) than group G1 but still significantly shorter than midparental height (P < 0.001). The adult height achieved with GHRT in group G2 was not different from non-GHD patients (group G3), whose mean height SDS was -1.55 ± 1.2. Although group G3 was not statistically different from midparental height, they were shorter, and this nonstatistical difference may reflect the small number (n = 5) in this group. The tallest heights achieved were in those young patients who received low-dose CSRT (mean height SDS, -1.01 ± 1.1). This group was statistically taller than group G2 and not significantly different from group G3 and midparental height. As noted in Table 2
, the 27 patients comprising group G2 who were treated similarly in terms of CSRT and chemotherapy to previously reported studies but were treated with higher doses of rhGH were significantly taller than the outcomes previously reported of medulloblastoma patients also treated with GHRT (P < 0.0001). Of note, the 21 individuals in group G2 without the diagnosis of precocious puberty achieved even better adult height outcome (SDS, -1.75 ± 0.77) when the six patients who received GnRH agonist therapy were removed from the cohort (SDS, -2.24 ± 0.73), although this difference was not statistically significant (Fig. 2).
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The sitting heights were available for 35 patients (two in group G1, 26 in group G2, two in group G3, and five in group G4), and the results are shown in Fig. 3. Compared with the general population, the sitting heights were impaired in all of the children (total group mean SDS, -2.96; P < 0.0001). In groups G2 and G4, the mean sitting height SDS were -3.3 ± 1.43 and -1.62 ± 1.16, respectively. Similar to the comparison of standing adult height outcome, the sitting height of group G4 was significantly taller than that of group G2 (P = 0.021). As well, group G4, but not G2, had significant improvement in sitting height in comparison to the sitting height SDS of -3.4 reported by Adan et al. (19) (P = 0.027). Therefore, higher dosing of rhGH and reduced CSRT doses improved sitting height, although sitting height SDS was still short in comparison to the normal population. Although limited to two patients, the sitting height SDS for group G3 (non-GHD patients) was -2.0. The adult stature in the entire group G3 was shorter than midparental height and not different from group G2, whose spinal growth was impaired despite rhGH treatment. These observations suggest that despite GH sufficiency in group G3, the loss of stature in comparison to midparental height is due to CSRT injury to spinal growth.
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When the age at onset of CSRT and chemotherapy and height outcome was analyzed, the linear regression was positively correlated in group G2, as shown in Fig. 4. The adult standing height and sitting height correlated with the age at irradiation in group G2 with standing height [
2 = 0.3457; P = 0.0013 (n = 27)] and sitting height [2 = 0.288; P = 0.0047 (n = 26)]. The younger the patients were when diagnosed and treated with CSRT, the shorter the adult height and sitting height achieved. This finding is similar to previous reports (11, 12, 13, 16). However, in group G4, despite the young age when treated with CSRT, the lower dose of radiation permitted a better response to rhGH with a better adult height outcome. In both GHRT groups, G2 and G4, there were no correlations in terms of adult height and sitting height outcome with age at initiation of GHRT or duration of therapy (data not shown). However, the age range for each group was limited to a relatively narrow range, as was the duration of treatment.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The present study evaluated a larger number of patients and compared the height outcomes among those with and without GHD and those treated and not treated with GHRT in the context of target genetic height. The analysis of these patients demonstrates that adult heights are generally reduced, regardless of GH status, rhGH therapy, or CSRT dose. The mean standing height in the cohort studied is significantly less than expected, based upon midparental height. The height SDS in the non-rhGH intervention groups of -3.23 for group G1 (non-GHRT) and -1.55 for group G3 (non-GHD) are almost identical to that reported by Sulmont et al. (9). However, there is a great difference in adult height outcome in individuals with rhGH intervention. In contrast to previous reported final height SDS of -2.9 to -5 (6, 9, 12, 20), the patients in this study are much taller (SDS, -1.86 for group G2 and -1.01 for group G4). Although the number of patients in group G1 (non-GHRT but GHD) in our study is small, the outcome is similar to the outcome data as reported by Sulmont et al. (9) and indicate that height outcome is severely impaired in GHD medulloblastoma patients when not treated with rhGH.
In general, a lower dose of rhGH is more commonly administered in Europe, as seen in Sulmont et al. (0.3–0.4 IU/kg·wk), Ogilvy-Stuart et al. (0.5 IU/kg·wk), Adan et al. (0.4–0.6 IU/kg·wk), and Ranke et al. (0.58 IU/kg·wk) (9, 12, 19, 23). This is equivalent to approximately 0.15 mg/kg·wk, based upon the conversion of 1 mg of rhGH being approximately equivalent to 3 IU. The patients in this study were treated at a dose of 0.3 mg/kg·wk. A recently reported dose response study of rhGH in children with GHD demonstrated that a dose of 0.05 mg/kg·d (0.35 mg/kg·wk) significantly improved growth velocity over 2 yr, compared with similar children randomized to receive 0.025 mg/kg·d (0.15 mg/kg·wk) (28). The result of the study supports the use of a higher dose of rhGH in medulloblastoma patients as documented in the present study. Whether an even higher dose of GH treatment (0.7 mg/kg·wk) during puberty, as used in a study of children with isolated GHD (29), would even further promote better adult height in children treated with CSRT and chemotherapy is yet to be evaluated.
Spinal irradiation is an important factor for the poor height outcome in children surviving medulloblastoma. Disproportionate growth is well documented to occur after CSRT (17, 20). There is specific loss in the upper segment and a reduced response to rhGH. Davies et al. (18) postulated that much of the height loss could be corrected if final heights were calculated with a compensatory allowance for the short spine. Both longitudinal and cross-sectional studies demonstrated an age-dependent restriction on spinal growth (16, 17). In several studies, there was catch-up growth with GHRT during the first 3 yr in prepubertal children treated with CSRT. The growth velocity was comparable to that of age-matched children with idiopathic GHD (6, 9, 30), indicative of normal spinal growth response to GHRT during the prepubertal years with loss of spinal growth during puberty (6, 8, 18). The sitting height results of the present study in those children receiving standard doses of CSRT are comparable to previously reported SDS of -3.3 to -3.4 (19, 22). Sitting height impairment (similar to standing height) is age-dependent, with a positive linear correlation between the onset of CSRT and final sitting height (2 = 0.288; P = 0.0047) as seen in Fig. 3. Thus, although the higher dose of rhGH used in this study and conventionally used in the United States improves adult standing height, it does not improve sitting height. Because much of the loss in spinal growth is during puberty, it is of interest but clearly speculative as to whether the higher dose of 0.7 mg/kg·wk during puberty as shown in the Mauras et al. study (29) might overcome the injurious effects of CSRT on the spine.
The sitting height in patients irradiated at a lower dose of CSRT (group G4) is greater and significantly different from that incurred in patients irradiated at conventional dose. Nevertheless, despite the lower dose of CSRT, these children still demonstrated a lower adult sitting height in comparison to the general population. This finding is most likely reflective of the increased sensitivity of young children to radiation injury.
In conclusion, the combination of CSRT and chemotherapy for medulloblastoma has a significant impact on linear growth and sitting heights. The present report confirms that rhGH treatment is important in GHD medulloblastoma survivors to improve adult height. Untreated, the children will survive to be very short adults. Furthermore, this study indicates that the dose of rhGH should be 0.3 mg/kg·wk to achieve an adult height within the normal range for the general population. Unfortunately, rhGH treatment, even at this dose, does not improve spinal growth. In other words, the children will be taller as adults but with disproportionately shorter spines. The best results in terms of adult height and sitting height were in those children treated with a lower dose of CSRT (although very young when diagnosed). Clearly, if neurooncologists decide that lower doses of CSRT can afford good survival rates, almost normal adult stature might be possible.
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Acknowledgments |
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Footnotes |
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Abbreviations: CHOP, Children’s Hospital of Philadelphia; CSRT, craniospinal radiation therapy; GHD, GH deficient or deficiency; GHRT, GH replacement therapy; rh, recombinant human; SDS, SD score(s).
Received April 9, 2003.
Accepted June 14, 2003.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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, M). SDS was -3.23 for group G1 (
, n = 3), -1.86 for group G2 (
, n = 27), -1.55 for group G3 (
, n = 5), and -1.01 for group G4 (•, n = 6). The bars represent mean. *, P < 0.05. NS, Not significant.
, n = 6) and -1.76 for NP (
