Endocrine late sequelae in long-term survivors of childhood non ...

original article
Endocrine late sequelae in long-term survivors of
childhood non-Hodgkin lymphoma
Annals of Oncology
doi:10.1093/annonc/mdr511
M. van Waas 1 , S. J. C. M. M. Neggers 1,2 , M. L. te Winkel 1 , A. Beishuizen 1 , R. Pieters 1 &
M. M. van den Heuvel-Eibrink 1 *
1 2
Department of Pediatric Oncology/Hematology, Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam; Section of Endocrinology, Department of Medicine,
Erasmus University Medical Centre, Rotterdam, The Netherlands
Received 12 July 2011; revised 30 August 2011; accepted 23 September 2011
Background: Aim of this study was to investigate the long-term endocrine effects of treatment of childhood
non-Hodgkin lymphoma (NHL).
Patients and methods: A single-center cohort of 84 survivors (22 females) was included in this retrospective study.
Median age was 21 years (9–40 years) and time after cessation of therapy 12 years (4–30 years). Height, weight,
percentage fat, lean body mass (LBM), bone mineral content (BMC), bone mineral density of total body (BMDTB) and
bone mineral density of lumbar spine (BMD LS) were measured. Thyroid-stimulating hormone (TSH), free thyroxin (fT4),
insulin-like growth factor-1 (IGF-1), inhibin B and anti-müllerian hormone (AMH) levels were measured. Results were
compared with Dutch controls.
Results: Height was lower in survivors [mean standard deviation score (SDS) 20.36, P = 0.002], but further analysis
showed that shorter stature was already present at diagnosis (mean SDS 20.28, P = 0.023). Body mass index,
percentage fat, BMC, BMDTB and BMD LS were not different from controls. LBM was lower in survivors (mean
SDS 20.47, P = 0.008). TSH, fT4 and IGF-1 were normal in all survivors. Three of 20 adult females had low AMH levels
and 23 of 42 adult males had low inhibin B levels.
Conclusions: Twelve years after cessation of treatment, NHL survivors did not develop adiposity, osteoporosis or
thyroid disease. Male survivors may be at risk for infertility.
Key words: anthropometry, bone mineral density, endocrine sequelae, fertility, late effects, non-Hodgkin lymphoma
introduction
Annals of Oncology Advance Access published November 2, 2011
Six percent of children with a malignancy suffer from non-
Hodgkin lymphomas (NHLs) [1]. Currently, the 5-year survival
for childhood NHL is 80%. Because of this high survival rate
and since treatment is administered in a growing and
developing individual, long-term side-effects are an important
issue. Treatment of NHL consists of intensive chemotherapy, in
rare cases combined with radiotherapy. Treatment schedules
involve high doses of corticosteroids, which may cause reduced
bone mineral density, osteoporosis and obesity [2]. Both
normal and decreased bone mineral density (BMD) have been
reported in long-term survivors of other malignancies treated
with chemotherapy including corticosteroids [3–9]. In
addition, altered body composition, especially obesity, was
observed during and after treatment of acute lymphoblastic
leukemia (ALL) [10–19]. Other endocrine or metabolic
sequelae that have been described in NHL and ALL survivors
are growth hormone deficiency, hypothyroidism, insulin
resistance and dyslipidemia [18–20]. Moreover, infertility or
*Correspondence to: Dr M. M. van den Heuvel-Eibrink, Department of Pediatric
Oncology/Hematology, Erasmus Medical Center-Sophia Children’s Hospital, Room Sp-
2568,
PO Box 2060, 3000 CB Rotterdam, The Netherlands. Tel: +31-0-10-7036782;
Fax: +31-0-10-7036801; E-mail: m.vandenheuvel@erasmusmc.nl
impaired reproductive outcome has been described in survivors
of childhood cancer [21–25].
So far, studies on endocrine long-term effects in survivors of
childhood NHL are scarce and often limited by small sample
sizes or by the fact that data of NHL survivors have been
combined with that of survivors of other malignancies [20,
26–31]. Therefore, we investigated endocrine late sequelae after
childhood NHL in a single-center cohort.
patients and methods
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com
patients
We identified all survivors who were alive and ‡4 years after cessation of
therapy on 1 January 2009 and were treated for childhood non-B-NHL, Bcell
type lymphoma (B-NHL) or large-cell anaplastic lymphoma
(LCAL) at the Erasmus Medical Centre-Sophia Children’s Hospital from
1975 to 2003. Survivors that visited the Late Effects Registration (LATER)
outpatient clinic were eligible for analysis. The local ethical committee
approved the study and consent according to the Helsinki Declaration
was obtained [32]. Outpatient clinic visits and performance of dualenergy
X-ray absorptiometry (DXA) scans took place from July 2003
to November 2008. As they received similar treatment regimens, the
LCAL survivors will be analyzed together with the B-NHL group.
Baseline characteristics and treatment details of survivors are summarized
in Table 1.
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original article
Table 1. Baseline characteristics of NHL survivors
NHL survivors Non-B-NHL B-NHL + LCAL
N (male/female) 84 (62/22) 32 (22/10) 52 (40/12)
Age at follow-up (years) a
21 (9–40) 23 (9–37) 20 (10–40)
Age at diagnosis (years) a
8 (2–16) 8 (2–16) 8 (2–16)
Duration of treatment
13 (1–38) 24 (4–38) 6 (1–28)
(months) a
Follow-up time (years) a
Specification of
12 (4–30) 14 (4–25) 9 (5–30)
chemotherapy n (%) TCD (mg/m 2 ) n (%) TCD (mg/m 2 ) n (%) TCD (mg/m 2 )
Methotrexate 79 (94) 15 000 (1500–30 000) 31 (97) 6900 (1500–20 000) 48 (92) 15 000 (1500–30 000)
Vincristine 78 (93) 11 (2–141) 32 (100) 18 (7–141) 46 (88) 9 (2–25)
Cytarabine 76 (90) 1800 (1000–42 500) 28 (88) 3000 (1200–9800) 45 (87) 1800 (1000–42 500)
Corticosteroids b
71 (85) 3413 (710–28 670) 30 (94) 4407 (1840–26 490) 39 (75) 1418 (700–28 670)
Anthracyclines 65 (77) 180 (60–480) 29 (91) 280 (160–480) 36 (69) 180 (60–480)
Cyclophosphamide 69 (82) 5500 (360–16 200) 18 (56) 3000 (2000–6000) 51 (98) 5800 (360–16 200)
Ifosfamide 9 (11) 12 000 (4000–16 000) 1 (3) 4000 (NA) 8 (15) 120 000 (6000–16 000)
Busulfan 1 (1) 480 (NA) 0 NA 1 (2) 480 (NA)
Melphalan 1 (1) 140 (NA) 0 NA 1 (2) 140 (NA)
a Median (range).
b TCD prednisone plus TCD dexamethasone (dexamethasone was converted to prednisone using factor 6.67).
NHL, non-Hodgkin lymphoma; LCAL, large-cell anaplastic lymphoma; TCD, total cumulative doses; NA, not applicable.
anthropometry
Height was measured using a Harpenden stadiometer and compared with
Dutch normative values [33]. Height of survivors of other ethnicities
was compared with normative values for these ethnicities [34, 35]. No data
on target height were available. Weight was measured on a standard clinical
balance. Body mass index (BMI) was calculated as weight (kg)/[height
(m)] 2 . BMI of survivors

Annals of Oncology original article
results
patients
Ninety-two long-term NHL survivors were identified, of whom
84 visited the outpatient clinic and could be analyzed (Figure 1).
Sixty-two males and 22 females were identified, consistent with
the incidence of NHL (NHL occurs two to three times as often
in males as in females). Thirty-two of the 84 survivors were
diagnosed non-B-NHL, 46 B-NHL and 6 LCAL. Seventy-six
survivors were Dutch, 4 Moroccan, 3 Turkish and 1 Asian.
Median age at diagnosis was 8 years (range 2–16 years) and at
follow-up 21 years (range 9–40 years). Thirty-six subjects
(6 females) were aged

original article
Table 3. Determinants of height in NHL survivors
Variable Height (SDS)
ß P value 95% CI
All survivors a
Age at follow-up 0.01 0.556 20.02 to 0.04
Sex (male) 0.26 0.319 20.25 to 0.77
Type of NHL b
Survivors with a DXA scan available
0.13 0.582 20.33 to 0.59
c
Age at follow-up 0.24 0.815 20.03 to 0.04
Sex (male) 0.00 0.303 20.23 to 0.72
Type of NHL 0.16 0.482 20.30 to 0.62
LBM 0.68

Annals of Oncology original article
able to assess these dynamic tests. It should, moreover, be
considered that these tests are more invasive for the survivors,
time consuming and therefore expensive.
Adiposity has been frequently reported not only in leukemia
but also in lymphoma survivors [11, 30, 31]. In the present
study, we found normal BMI and normal percentage fat in
NHL survivors. Hypothyroidism, which can contribute to
obesity and is reported in survivors, especially after local
radiotherapy [49–51], did not occur in this group of survivors.
In patients treated for childhood cancer, treatment can have
a deleterious effect on the acquisition of peak bone mass,
subsequently increasing the risk of fractures at an older age.
Reduced BMD has been described in adolescent and adult NHL
survivors after stem-cell transplantation [52] and in childhood
NHL survivors after chemotherapy combined with cranial
radiotherapy [9, 29]. In our study, which is the largest cohort of
long-term childhood NHL survivors, BMD TB and BMD LS were
within the normal range. BMD LS was still normal after
correction for bone size (BMAD LS). This was in concordance
with the findings in long-term survivors of childhood ALL [9].
When interpreting these results, one should consider the
retrospective nature of this study and the small sample sizes of
the subgroups. However, as the majority of our NHL survivors
were treated with chemotherapy only, these results seem
comprehensible.
Infertility has been frequently reported in childhood cancer
survivors [21–23]. Additionally, low AMH or inhibin B levels,
which are fertility markers, have been reported [24, 25].
Notorious for causing infertility are abdominal radiotherapy
and alkylating chemotherapeutic agents, like cyclophosphamide
[21, 22]. Moreover, cytarabine has been described to contribute
to gonadal damage in survivors of adult acute myeloid
leukemia [53]. However, this was not confirmed in female
childhood cancer survivors [21] and in male childhood cancer
survivors, even a reversed effect was described [22]. In the
present study, 3 of 20 adult female survivors had abnormal
AMH levels. Two of three received both cyclophosphamide and
cytarabine; however, none of them received cranial or
abdominal radiotherapy. Interestingly, inhibin B levels were
low in 55% of adult male survivors. High FSH levels in these
survivors confirm that this is not a problem of pituitary or
hypothalamus but of local origin. After correction for age at
diagnosis and total cumulative dose of alkylating agents,
cytarabine had a significant negative effect on inhibin B levels in
adult males. Although groups are small and results should
therefore be interpreted with caution, this effect seems
substantial and has not been reported previously. Our results
contradict those of Green et al. [22], which may be due to
differences in reported outcomes (siring a pregnancy versus
fertility markers). Inhibin B is a relatively new fertility marker
but has been shown to be the most reliable serum marker
for spermatogenesis [43, 54–57]. Prospective studies are needed
to confirm these data, preferably with larger cohorts and
including both inhibin B measurements and sperm analysis.
In conclusion, long-term childhood NHL survivors,
especially males, have a shorter stature that seems to be
determined by height at diagnosis and not by treatment-related
side-effects. Otherwise, this study shows that long-term
childhood NHL survivors do not seem to be at risk for
endocrine late sequelae like osteoporosis, obesity and
hypothyroidy. However, especially males might be at risk for
gonadal damage, which may be related to the cumulative dose
of cytarabine. To evaluate gonadal damage both in male and
female NHL survivors, prospective studies of larger cohorts are
required.
acknowledgements
The authors would like to thank Wim C. J. Hop from the
Department of Biostatistics for his valuable suggestions and
comments and Manita M. M. P. G. M. van Baalen from the
Department of Pediatric Oncology for helping recruiting data.
Authorship—MMvdH-E was the principal investigator and
takes primary responsibility for the paper. MvW participated in
the statistical analysis. SJCMMN, RP and MH coordinated the
research. MvW, SJCMMN and MMvdH-E wrote the paper.
SJCMMN, MtW, AB, RP and MMvdH-E were involved in
drafting and revising the article.
funding
KiKa (Kinderen Kankervrij; 2009-030); Kinderoncologisch
Centrum Rotterdam.
disclosure
The authors declare no conflict of interest.
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