Growth in children with poor-risk neuroblastoma after regimens with or without total body irradiation in preparation for autologous bone marrow transplantation

Abstract

Impaired growth after TBI prior to BMT has been a constant finding in children with leukemia. The growth of poor-risk neuroblastoma (NBL) survivors treated with myeloablative preparative regimens and ABMT at the Hospital for Children and Adolescents, University of Helsinki, since 1982 is reported. Two separate groups were analyzed: (1) The TBI- patients (n = 15) were conditioned with high-dose chemotherapy only. They had been treated at the age of 1.0-6.3 (mean 3.0) years and the post-ABMT follow-up time was 1.5-14.5 (mean 7.7) years. (2) The TBI+ patients (n = 16) had received TBI in addition to high-dose chemotherapy. They had been treated at the age of 1.3-4. 8 (mean 3.0) years, and the post-ABMT follow-up time was 1.5-8.0 (mean 4.7) years. The height standard deviation score (SDS) was similar for the two groups at the time of diagnosis, -0.3 +/- 1.2 (mean +/- s.d.), and at the time of ABMT, -0.7 +/- 1.1. After transplantation, the height SDS continued to decrease in the TBI+ group, the mean being -2.0 SDS at 5 years after ABMT. In the TBI-group, the mean height SDS remained within -0.7 to -0.9 to the 10 years of follow-up. Five patients received growth hormone (GH) therapy starting 2-6 years after ABMT. They all had low GH secretion in provocative tests. All showed some response to GH therapy. The mean height SDS increased 0.4 SDS during the 3 years following the start of GH therapy, while in the untreated patients a decrease of 0. 8 SDS during the corresponding time (P = 0.009) was observed. We conclude that NBL patients grow poorly following ABMT when TBI is included in the conditioning regimen, but close to normally when treated without TBI. The need for GH therapy should be evaluated early to avoid an unnecessary decrease in final height.

Full text

Bone Marrow Transplantation, (1999) 24, 1131–1136
1999 Stockton Press All rights reserved 0268–3369/99 $15.00
http://www.stockton-press.co.uk/bmt
Growth in children with poor-risk neuroblastoma after regimens with
or without total body irradiation in preparation for autologous bone
marrow transplantation
L Hovi
1
, UM Saarinen-Pihkala
1
, K Vettenranta
1
, M Lipsanen
1
and P Tapanainen
2
1
Hospital for Children and Adolescents, University of Helsinki, Helsinki; and
2
Children’s Hospital, University of Oulu, Oulu,
Finland
Summary:
Impaired growth after TBI prior to BMT has been a
constant finding in children with leukemia. The growth
of poor-risk neuroblastoma (NBL) survivors treated
with myeloablative preparative regimens and ABMT at
the Hospital for Children and Adolescents, University
of Helsinki, since 1982 is reported. Two separate groups
were analyzed: (1) The TBI
−
patients (n=15) were con-
ditioned with high-dose chemotherapy only. They had
been treated at the age of 1.0–6.3 (mean 3.0) years and
the post-ABMT follow-up time was 1.5–14.5 (mean 7.7)
years. (2) The TBI
+
patients (n=16) had received TBI
in addition to high-dose chemotherapy. They had been
treated at the age of 1.3–4.8 (mean 3.0) years, and the
post-ABMT follow-up time was 1.5–8.0 (mean 4.7)
years. The height standard deviation score (SDS) was
similar for the two groups at the time of diagnosis,
−0.3 ±1.2 (mean ±s.d.), and at the time of ABMT,
−0.7 ±1.1. After transplantation, the height SDS con-
tinued to decrease in the TBI
+
group, the mean being
−2.0 SDS at 5 years after ABMT. In the TBI
−
group,
the mean height SDS remained within −0.7 to −0.9 to
the 10 years of follow-up. Five patients received growth
hormone (GH) therapy starting 2–6 years after ABMT.
They all had low GH secretion in provocative tests. All
showed some response to GH therapy. The mean height
SDS increased 0.4 SDS during the 3 years following the
start of GH therapy, while in the untreated patients a
decrease of 0.8 SDS during the corresponding time
(P=0.009) was observed. We conclude that NBL
patients grow poorly following ABMT when TBI is
included in the conditioning regimen, but close to nor-
mally when treated without TBI. The need for GH ther-
apy should be evaluated early to avoid an unnecessary
decrease in final height.
Keywords: neuroblastoma; growth; growth hormone
therapy; BMT; late effects
Impaired growth after total body irradiation (TBI) prior to
bone marrow transplantation (BMT) has been a finding in
Correspondence: L Hovi, Hospital for Children and Adolescents, Univer-
sity of Helsinki, PL 281, 00029 HYKS, Finland
Received 1 February 1999; accepted 3 June 1999
many studies.
1–7
Usually the impaired growth, as indicated
by decrease in growth velocity or in height standard devi-
ation score (SDS), has been shown to continue for several
years to a variable extent. Type (single vs fractionated) and
dose of TBI and possibly previous central nervous system
irradiation have been factors affecting the outcome. Most
of these studies concern children with leukemia or aplastic
anemia. Neuroblastoma (NBL) is the most common extra-
cranial solid tumor of childhood, and poor-risk NBL
remains today a real therapeutic challenge. High-dose
chemotherapy and autologous BMT (ABMT) have been
used in the treatment of NBL patients from the late 1970s.
These patients differ from leukemia patients in many
respects: they are usually younger, they do not receive
additional central nervous system irradiation except to local
bony metastases, their conventional chemotherapy contains
drugs unusual in the treatment of leukemia, such as cispla-
tin, and their preparative regimen for BMT is different and
it may or may not contain TBI. Further, at transplantation,
autologous rather than allogeneic stem cells are most often
used and, accordingly, graft-versus-host disease (GVHD)
and corticosteroid therapy play no role in NBL. There are
very few reports on post-transplant growth of children with
NBL conditioned with TBI, and even less on those without
TBI. The growth velocity of NBL patients with TBI has
been observed to be less than that of leukemia patients.
8
At the Hospital for Children and Adolescents, University
of Helsinki, patients with poor-risk NBL have been treated
with high-dose chemotherapy and ABMT since 1982.
Before 1987 they did not receive TBI, while it has been
part of the preparative regimen in most patients since that
time. We analyzed long-term post-transplant growth of
NBL survivors treated with and without TBI. Five patients
have received growth hormone (GH) therapy for 2–5 years.
We also report the response to GH in these patients.
Patients and methods
This study includes all patients with poor-risk NBL (stage
IV disease or stage III disease with N-myc amplification)
who have been treated at the Hospital for Children and
Adolescents, University of Helsinki, with myeloablative
preparative therapy and ABMT since 1982 and who have
survived relapse-free for at least 1 year post-transplant. The
patients comprise all long-term survivors of poor-risk NBL
in Finland during the time period. They were both diag-

Growth of transplanted neuroblastoma patients
L Hovi
et al
1132
Table 1 Characteristics of children with poor-risk neuroblastoma, divided in categories according to pre-transplant conditioning regimen
No. Age at ABMT Follow-up time Dose of TBI Local radiotherapy Problems after ABMT Hormone therapy
(years) after ABMT (Gy) after ABMT
(years) Area Dose (Gy)
Non-TBI patients
L-PAM
1 2.7 11.5 —
2 5.2 10.0 —
3 1.5 10.0 —
4 1.7 10.5 —
5 2.0 10.5 neck 20
6 1.6 14.5 liver 4
7 5.8 9.5 —
8 2.4 9.0 mediastinum 24
9 1.0 11.0 liver 7
10 2.8 3.0 — relapse at 4 years
11 1.8 2.5 — relapse at 3 years
12 4.4 1.5 — relapse at 2 years
13 6.3 2.0 — relapse at 2 years
VP-16, carboplatin, thiotepa
14 2.5 1.5 lumbar spine 24 relapse at 2 years
and sacrum
15 1.9 2.0 abdomen 20
TBI
+
patients
VMP +TBI
16 4.8 8.0 12 orbit GH, T4
mandible 32 estradiol
17 3.2 8.0 12 — GH, T4
18 4.0 8.0 12 — GH, T4
19 3.2 7.0 12 — radiation nephritis, carditis GH, T4
20 3.4 1.5 12 — restrictive pulmonary disease,
died at 2 years
21 2.3 7.0 10 mediastinum 16
22 1.3 6.0 10 forehead 20
abdomen 20
23 2.3 6.0 10 — renal insufficiency GH, T4
24 2.0 5.0 10 forehead 6
25 3.9 4.0 10 abdomen 15
26 3.2 4.0 10 orbit 46
neck 30
27 2.1 3.0 10 abdomen 18
28 3.3 3.0 10 orbit 20
lumbar spine 18
29 3.9 2.0 10 abdomen 18
30 3.5 1.5 10 abdomen 15
31 3.2 1.5 10 —
L-PAM =melphalan; VMP =etoposide, melphalan, cisplatin; GH =growth hormone; T4 =thyroxine.
nosed and treated at this hospital (n=25) or they were
referred to this center for evaluation for high-dose therapy
and ABMT (n=6). The post-ABMT follow-up of five
patients took place in the referring hospitals; the others
were mainly followed up at this hospital.
Treatment protocols
Between 1982 and 1986 the conventional chemotherapy for
poor-risk NBL patients was etoposide and cisplatin only.
Surgery was performed early and usually repeated one to
two times. Local irradiation was rarely used. The prepara-
tive treatment for ABMT consisted of high-dose melphalan
(140–180 mg/m
2
, single dose) only.
9
These patients are
included in the TBI
−
group of this study.
In 1987 a new treatment protocol was introduced.
10
All
patients received conventional multiagent chemotherapy
including cyclophosphamide, dacarbazine, vincristine, cis-
platin, doxorubicin and etoposide. Surgery was frequently
performed late. Local irradiaton of 15–20 Gy was delivered
to the tumor bed if tumor was left behind at surgery, and to
bulky bony metastases. The preparative regimen for ABMT
consisted of high-dose chemotherapy (VMP) using etopo-
side (total dose 300 mg/m
2
), melphalan (total dose
210 mg/m
2
) and cisplatin (90 mg/m
2
), and TBI of 10 or
12 Gy given in five to six fractions over 3 days. Two
patients with recurrent metastatic retinoblastoma (RBL)
were treated identically to the NBL patients. All these
patients are included in the TBI
+
group of this study.
During the later time period, two patients with poor-risk,

Growth of transplanted neuroblastoma patients
L Hovi
et al
1133
stage III NBL were treated as the other poor-risk NBL
patients, but they were conditioned for ABMT with chemo-
therapy including etoposide (total dose 750 mg/m
2
), car-
boplatin (total dose 1500 mg/m
2
) and thiotepa (total dose
900 mg/m
2
). Full tumor dose radiotherapy was adminis-
tered to the field of bulky primaries, but no TBI was given.
These patients are included in the TBI
−
group of this study.
TBI
−
patients
Fifteen children (9 boys, 6 girls) had high-dose chemo-
therapy without TBI prior to ABMT at ages 1.0 to 6.3
(mean 3.0) years (Table 1). Poor-risk NBL was diagnosed
at 0.1–5.7 (mean 2.3) years. With two exceptions, patients
in this group were treated between 1982 and 1986 and the
post-ABMT follow-up was 1.5 to 14.5 (mean 7.7) years.
The age of the patients at the time of this study was 3.9 to
16.1 (mean 10.2) years. Local irradiation of 4–24 Gy to the
tumor bed or metastases was delivered in six patients. None
had irradiation to the skull area.
TBI
+
patients
Sixteen children (9 boys, 7 girls) received VMP+TBI prior
to ABMT at ages between 1.3 and 4.8 (mean 3.0) years
(Table 1). Malignancy (NBL =14, RBL =2) had been diag-
nosed at 1–3.9 (mean 2.5) years. The post-ABMT follow-
up was 1.5–8.0 (mean 4.7) years. The age of the patients
at the time of this study was 4.3 to 12.8 (mean 6.4) years.
Local irradiation prior to ABMT was delivered in 10
patients, 5 to the area of cranium in doses of 6, 20, 20, 32
and 46 Gy, and 7 to the tumor bed in doses of 15–20 Gy.
The dose of TBI was 10 Gy in 11 patients and 12 Gy in
5 patients.
Post-transplant follow-up
All patients had repeat post-transplant evaluations at 1 to 2
month intervals during the first year. The interval increased
during the subsequent years but they continued to be seen
at least once a year. Patients underwent physical examin-
ation and appropriate testing for detection of recurrent dis-
ease. Patients with medical problems were treated accord-
ingly. Heights were carefully measured at each check-up
by an experienced nurse using a wall-mounted stadiometer.
Relative heights in SDS were estimated from national Finn-
ish growth charts.
11
Thyroid function of the irradiated
patients was assessed at 1 to 2 yearly intervals by measur-
ing serum thyroid stimulating hormone and thyroxine lev-
els. GH secretion was evaluated, when clinically indicated,
by using insulin-arginine provocative tests. Four patients
with height SDS below −2 and one with a decrease of
height SDS of 1.6 were considered GH-deficient because
their maximal GH responses to both stimuli were ⬍10
␮
g/l.
They had received GH therapy for 2–5 years starting 2–6
years after ABMT (Table 2).
Statistical methods
The significance of differences between the groups was cal-
culated by the paired or unpaired two-tailed t-test or by
Table 2 The growth (cm/year) and height SDS of GH treated patients
before GH, at GH start, and during ongoing GH replacement
No. −1AtGH+1+2+3+4+5
year start year years years years years
16 cm/year 4.0 8.5 6.5
SDS −0.4 −0.4 −0.1 0.0
17 cm/year 3.9 6.7 6.9 5.5 5.8 3.3
SDS −2.0 −2.2 −2.0 −1.8 −1.6 −1.6 −1.5
18 cm/year 4.1 6.2 4.7 4.1 3.0 3.1
SDS −2.4 −2.8 −2.5 −2.4 −2.4 −2.4 −2.6
19 cm/year 3.0 6.6 5.7 5.0 3.5 3.0
SDS −3.2 −4.0 −3.8 −3.8 −3.7 −3.6 −3.8
23 cm/year 3.1 5.1 6.6 6.9 6.5
SDS −3.2 −3.3 −3.9 −3.6 −3.0 −2.8
analyses of variance with repeated measures. The corre-
lations between age at transplant and growth was evaluated
by multiple regression analyses.
Results
The mean height SDS of the patients treated with TBI
decreased continuously over several years after ABMT,
whereas the mean height SDS of the patients treated with-
out TBI showed neither decrease nor catch-up after
ABMT (Figure 1).
Growth before ABMT
At diagnosis, the height SDS (mean ±s.d.) for all patients
was −0.3 ±1.2 and the two groups, TBI
+
and TBI
−
, were
similar. At the time of ABMT, the height SDS
had decreased to −0.7 ±1.1 (P=0.004), again with no
difference between the groups (Figure 1).
Growth after ABMT
After transplantation, the height SDS continued to decrease in
patients in the TBI
+
group (Figure 1). Their mean height SDS
decreased during the first year after ABMT from −0.6 to −1.2
2
1
0
–1
–2
–3
Dg ABMT 1 2 3 4 5 6 7 8 9 10
Years after transplantation
Height SDS
n
= 15 TBI–
TBI+
n
= 16
(
n
= 5)
(
n
= 3)
P
= 0.03
**
P
= 0.04
Figure 1 Height SDS (mean ±s.d.) before and after ABMT in total body
irradiated (full circle) and non-irradiated (open circle) NBL patients.

Growth of transplanted neuroblastoma patients
L Hovi
et al
1134
and further to −2.0 at 5 years after ABMT. The decrease was
statistically significant between the following time points:
ABMT–1 year (P=0.005), 1–2 years (P=0.03), 2–3 years
(P=0.011), and 3–4 years (P=0.034); patients on growth
hormone therapy are excluded.
In the TBI
−
group, the mean height SDS remained within
−0.7 to −0.9 to the 10 years of follow-up. The height SDS
in the TBI
−
group was significantly higher than in the TBI
+
group at 5 and 6 years after ABMT (Figure 1).
Effect of TBI dose
During the first 2 years after ABMT, the height SDS of the
patients with 12 Gy of TBI decreased 1.0 SDS, compared
to 0.6 SDS in those with 10 Gy (NS).
Of the patients followed over 2 years after ABMT, all
four who had received 12 Gy, but 1/9 10 Gy, subsequently
received GH therapy.
Neither age at ABMT nor sex correlated with decrease
in height SDS.
The patients on GH therapy
Five patients received GH therapy starting 2–6 years after
ABMT (Table 2). Their age was 2.3 to 4.8 years at ABMT
and 4.3 to 10.5 years when GH therapy was started. Patient
16 had retinoblastoma and had received local radiotherapy
of 32 Gy to the left orbit and mandibular angle. No other
patient had any extra radiotherapy in addition to TBI.
Patient 23 had severe renal insufficiency after ABMT due
to a fungal infection in his remaining kidney. Extirpation
of his abdominal neuroblastoma had included nephrectomy.
The remaining kidney was subsequently removed 1 year
after ABMT and he received peritoneal dialysis until a kid-
ney transplant 2.3 years after ABMT, 3 months after start-
ing GH therapy (Figure 2).
All these five patients had biochemical evidence of GH
deficiency tested with the insulin-arginine provocative test
where their maximal GH peak was ⬍10
␮
g/l. Their pre-
treatment growth velocity was 3.0–4.1 cm/year. They
2
1
0
–1
–2
–3
–4
Dg ABMT 1 2 345678
Years after transplantation
Height SDS
GH
GH
GH
GH
GH
*
Figure 2 Height SDS before and after ABMT of NBL patients with TBI
as part of the preparative regimen. The start of growth hormone therapy
is shown with an arrow and development of height SDS during therapy
with hatched line. * =kidney transplantation (see text).
received recombinant hGH at a dose of 0.1 IU/kg/day. Dur-
ing the first GH year, all showed a modest response to GH
therapy with a mean growth of 6.6 cm. The response, how-
ever, decreased with prolonged treatment. During the fourth
GH year the mean growth was only 4.7 cm (Table 2,
Figure 2). During the first 3 GH years, the mean height SDS
of the patients increased 0.4 SDS while it simultaneously
decreased 0.8 SDS in the nonsubstituted patients in the
TBI
+
group (P=0.009). During the fifth year of GH ther-
apy, the growth velocity was no better than before GH.
All five patients were also receiving thyroxine replacement
because of subclinical hypothyroidism.
Discussion
Our results indicate that the growth of poor-risk NBL
patients, who had received a TBI containing preparative
regimen prior to ABMT, was subnormal several years fol-
lowing transplantation. No patient demonstrated spon-
taneous catch-up growth during the follow-up period. In
contrast, the growth of the TBI
−
patients was not impaired
following ABMT.
Age and height SDS of the two patient groups did not
differ at the time of diagnosis or at ABMT justifying the
assumption that the patient groups were comparable even
though the patients were mainly treated in different time
periods and the conventional chemotherapy was different.
The loss of height SDS during therapy before ABMT was
similar and the mean height SDS of the total group was
−0.7 at ABMT.
The growth of children with leukemia or aplastic anemia
has been shown to be normal or only slightly impaired fol-
lowing BMT when chemotherapy only has been included
in the conditioning regimen.
5,12
We could not find corre-
sponding information on children with NBL who are usu-
ally younger during therapy and have conventional chemo-
therapy different from that of the hematology patients. In
this study with several years of follow-up, the mean height
SDS of the TBI
−
patients decreased 0.4 SDS before and
0.3 SDS following ABMT. The growth of the two children
treated after 1987 with more intensive chemotherapy was
comparable but their follow-up time is still short. Our find-
ings support the data of close to normal growth of children
treated with cytostatic chemotherapy even when very high
doses with ABMT support have been used.
The growth of children with leukemia and aplastic
anemia treated with TBI has been shown to be
impaired for several years following BMT especially if the
patients have received previous central nervous system
irradiation.
1,2,5–7,13–15
In a 6-year follow-up study of 32
long-term survivors of cancer, all treated with TBI and
BMT, Willi et al
8
observed that the 11 patients with NBL
continued to grow poorly, whereas a comparison group of
21 patients with leukemia had essentially normal growth 2
years after the procedure and even showed some catch-up
growth in years 4 to 6. Our results on the growth of NBL
patients treated with TBI are in accordance with their study.
According to our preliminary report on patients treated with
TBI and BMT, the growth of NBL patients was more
impaired than that of leukemia patients.
4
However, after a

Growth of transplanted neuroblastoma patients
L Hovi
et al
1135
longer follow-up and a larger group of NBL patients, the
difference between NBL and leukemia patients is no longer
significant. No catch-up growth is seen in either group
(Figure 3).
Several reasons for the poor growth after TBI and BMT
have been proposed. A significant incidence of GH
deficiency in leukemia patients treated with TBI has been
reported.
1,6,7,15,17–19
Olshan et al
20
studied GH secretion of
six transplanted NBL patients and showed GH deficiency
in three patients; only one child had completely normal GH
secretion. However, the response to GH therapy in three
GH-deficient NBL patients was poor, suggesting a state of
relative GH resistance. The direct effects of irradiation on
the epiphyses or other soft tissues have been proposed to
be one reason for poor growth in GH-treated transplant
patients.
17
The GH status of our patients was not systematically
evaluated, but only when clinically indicated and start of
GH therapy was considered. Five patients, all with GH
deficiency based on subnormal responses in provocative
tests, received GH therapy starting 2–6 years after ABMT.
They all showed some response to GH therapy with
increasing growth velocities. In three, some catch-up
growth was shown which did not occur in any patient in
the TBI
+
group not receiving GH. The modest response to
GH therapy in our patients was in accordance with the
finding of the previously reported NBL patients and clearly
poorer than the growth response of GH deficient non-tumor
patients.
20
Despite the suboptimal response, our results sug-
gest that treating GH-deficient transplanted NBL patients
with substitute hormone therapy might be useful in increas-
ing the final height although this has not yet been reached.
Investigation of GH status and start of therapy should not
be unnecessarily delayed if the best possible growth result
is to be obtained. This is especially important in short
children whose height expectancy is low even without
malignant disease.
TBI has been widely used in poor-risk NBL patients as
part of the preparative regimen before ABMT. However,
TBI may not be necessary in all patients, and is not used
in all contemporary programs. The superiority of high-dose
2
1
0
–1
–2
–3
Dg ABMT 1 2 4 6 8 103579
Years after transplantation
Height SDS
ALL, TBI+
NBL, TBI+
NBL, TBI–
Brain tumors
Figure 3 Mean height SDS before and after ABMT in total body
irradiated and non-irradiated NBL patients, as compared with children
with ALL who received TBI preparative for allogeneic BMT
4
or with
children with brain tumors who were treated in this same hospital and
received cranial doses of 16–56 Gy.
16
chemotherapy with ABMT compared with conventional
chemotherapy in the treatment of high-risk NBL patients
was confirmed in a randomized Childrens Cancer Group
study with a 3-year event-free survival of 34% in the
ABMT group. The preparative regimen did not include
TBI.
21
In three non-randomized trials using TBI along with
high-dose chemotherapy as preparative therapy for ABMT,
a disease-free survival (DFS) of 34–49% has been
reported.
22–24
In our older series without TBI, a 2.8-year
survival of 54% was reported,
9
and even if updated now,
and the patients retrospectively staged to III (regional
lymph node metastases only) excluded, the very-long-term
survival of 36% is reached in this very small group of
patients. In our later cohort including TBI we have pub-
lished a 53% 4-year DFS post-transplant,
10
meaning today
a 6-year DFS because no further relapses have occurred.
We have advocated stratifying patients according to early
response to therapy. Prompt ‘in vivo purging’ of bone mar-
row was a favorable prognostic factor resulting in 100%
survival, and in these children TBI could probably be
omitted.
In conclusion, our program for poor risk NBL including
multi-agent chemotherapy and TBI peparative for ABMT
results in good long-term survival figures (53% 6-year
DFS) at the expense of impaired growth. This finding dic-
tates: (1) search for equally effective regimens without TBI;
(2) recognition of the problem, careful follow-up of
patients, and early institution of GH replacement therapy
in order to avoid unnecessary decrease of the final height.
Acknowledgements
This study was supported by a grant from the Nona and Kullervo
Va
¨re Foundation.
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