survival and late effects in children with stage 4 neuroblastoma

Pediatr Blood Cancer 2011;57:629–635

Survival and Late Effects in Children With Stage 4 Neuroblastoma

Thomas Perwein, MD,* Herwig Lackner, MD, Petra Sovinz, MD, Martin Benesch, MD, Sandrin Schmidt, MD,Wolfgang Schwinger, MD, and Christian Urban, MD

INTRODUCTION

Neuroblastoma (NB) is the most common extracranial solid

tumor in pediatric patients accounting for approximately 8% of

all malignancies in children under 15 years [1–3]. Median age at

diagnosis is 18 months and about 75% of NBs occur before the age

of 5 years [2]. In approximately half of all cases metastases can be

found at diagnosis and about 15% of all oncological deaths in

childhood are due to NB [3,4]. Outcome of metastatic disease

remains poor: only about 40% of children with stage 4 NB are

alive after 5 years, despite intensive multimodality therapy [4–8].

Reported 5-year survival without recurrence or progression of dis-

ease is about 35% [5–8]. Mass screening programmes have not

reduced mortality [9,10]. However, the use of modern multimodal-

ity therapy regimens including intensive induction, myeloablative

high-dose chemotherapy, and autologous stem-cell transplantation

as well as 13-cis-retinoic acid and targeted immunotherapy may

lead to improvements in prognosis and, therefore, cause more long-

term survivors [5,11,12]. The young age of patients with stage 4

NB and the need of an aggressive therapy as well as the underlying

disease can lead to long-term sequelae in different organs. These

late effects may affect the children’s ability to meet expected mile-

stones of development and thus severely interfere with quality of

life. The most frequently reported long-term sequelae are endo-

crine deficits such as hypothyroidism, growth hormone (GH)

deficiency/diminished growth and gonadal damage, as well as

sensorineural hypacusis, musculoskeletal changes, dental and vis-

ual problems, and second neoplasms [7,12–25]. The aim of this

retrospective study is to give an overview of survival in children

with stage 4 NB treated at our clinic and to describe the spectrum

of late effects seen in survivors.

PATIENTS AND METHODS

Patients

Inclusion criteria comprised all patients diagnosed and treated

with stage 4 NB between 1984 and 2009 at the Division of Paedi-

atric Haematology/Oncology, Medical University of Graz, Austria.

Survivors had to have finished therapy before September 2009 and

to be seen regularly within our tumor follow-up programme. A

total of 31 patients fulfilled these criteria, 16 of whom were alive

after completed therapy and were subsequently followed up at our

outpatient clinic. Patient characteristics are listed in Table I.

Median duration of treatment of the 16 survivors was 12 months

(range: 0.8–21.4). Table II provides a general view of treatment of

survivors.

Methods

Medical records were reviewed retrospectively for information

on tumor, treatment, and long-term sequelae. A late effect was

defined as a persistent change most probably caused by the tumor

or therapy and still existing at the time of the last visit (after being

seen in at least two visits), or still needing therapy or being cured

by causal therapy (e.g., surgery). Survivors had been included in a

detailed follow-up programme after completed therapy since Jan-

uary 1990, as previously described [20,26]. Additional examin-

ations specific to NB survivors contained detection of urine

catecholamines and neuron-specific enolase (NSE), local CT/

MRI, as well as regular 99Tc-bone scintigraphies and 123I-MIBG-

scans. All follow-up examinations were conducted or coordinated

in the division’s outpatient clinic. Identified late effects were fur-

ther retrospectively classified and graded according to the Com-

mon Terminology Criteria for Adverse Events (CTCAE), Version

3.0 [27]. Some late effects that could not explicitly be found in

these criteria were graduated as follows: Mild changes detected by

Background. Treatment of metastatic neuroblastoma (NB)demands aggressive oncological therapy, which may cause long-term sequelae in survivors. The aim of this retrospective single centerstudy is to give an overview of survival in children with stage 4 NBand to describe the spectrum of late effects seen in survivors. Pro-cedure. Medical records of 31 patients with stage 4 NB treatedbetween 1984 and 2009, who were included in a follow-up pro-gramme, were reviewed for information on tumor, treatment and lateeffects. Results. Five-year overall survival was 54.3 � 9% and 5-yearevent-free survival was 44.9 � 9%. Patients diagnosed after 1996had a significantly better survival rate than those diagnosed before(74 � 11.2% vs. 33.3 � 12.2%, P ¼ 0.011). In 15 of the 16 survi-vors (93.8%), numerous late effects were detected. The most com-mon long-term sequelae were renal changes in 10 patients (62.5%)

and endocrine disturbances in 9 patients (56.3%), including hypo-thyroidism with need of substitution in 50%, GH deficiency in37.5% and hypogonadism in 12.5%. Sensorineural hearing lossoccurred in 37.5% of survivors. Further observed late effects werehepatobiliary changes (31.3%), musculoskeletal problems, and pul-monary abnormalities (each 25%), as well as neurologic changes(18.8%), dental defects (12.5%), and unilateral blindness (6.3%).Second neoplasms appeared in 3 patients, 1 of whom died of hep-atocellular carcinoma following infection with hepatitis B. Con-clusions. More than 50% of children with stage 4 NB may survive.The high incidence of severe long-term sequelae underlines theimportance of careful follow-up in order to detect and treat lateeffects early enough. Pediatr Blood Cancer 2011;57:629–635.� 2011 Wiley-Liss, Inc.

Key words: children; late effects; neuroblastoma; survival

Division of Paediatric Haematology/Oncology, Medical University of

Graz, Graz, Austria

Conflicts of interest: nothing to report.

*Correspondence to: Thomas Perwein, MD, Division of Paediatric

Haematology/Oncology, Department of Paediatrics and Adolescent

Medicine, Medical University of Graz, Auenbruggerplatz 30, A-8036

Graz, Austria. E-mail: [email protected]

Received 16 August 2010; Accepted 21 December 2010

� 2011 Wiley-Liss, Inc.DOI 10.1002/pbc.23036Published online 11 February 2011 in Wiley Online Library(wileyonlinelibrary.com).

diagnostic methods but clinically remaining unremarkable were

classified as grade 1. Moderate damages needing any further inter-

vention (e.g., drug therapy) or remaining symptomatic without

interfering with activities of daily life were given grade 2. Severe

late effects needing a more aggressive therapy with hospitalization

(e.g., surgery) or being a persistent handicap with reduction of

quality of life were classified as grade 3. Psychologic issues were

not explicitly investigated in this study, so information was based

on what providers noted in the medical charts. Median cumulative

doses (MCD) of chemotherapeutic agents were calculated

TABLE I. Clinical Characteristics of the 31 Patients With Stage 4 NB

Characteristics No. (%) Median (range) Survivors Dead

Total 31 (100) 16 15

Sex

Male 22 (71) 12 (75) 10 (67)

Female 9 (29) 4 (25) 5 (33)

Age at diagnosis (months) 21.5 (1–127.5) 21 (2–128) 35 (1–108)

<18 months 10 (32) 5 (31) 5 (33)

�18 months 21 (68) 11 (69) 10 (67)

Year of diagnosis

�1996 15 (48) 4 (25) 11 (73)

>1996 16 (52) 12 (75) 4 (27)

MYCN-amplification 12/26 (46) 7/15 (47) 5/11 (46)

Deletion of 1p 9/23 (39) 7/14 (50) 2/9 (22)

Raised urine catecholamines 30/31 (97) 15/16 (94) 15/15 (100)

VMA 25/30 (83) 42.5 (2.1–373) 13/16 (81) 12/14 (86)

HVA 28/30 (93) 62.8 (5.5–456) 15/16 (94) 13/14 (93)

Dopamine 16/20 (80) 2.71 (0.8–25.6) 10/14 (71) 6/6 (100)

Ferritin �92 ng/mla 17/23 (74) 244.5 (31.2–5,020) 5/10 (50) 12/13 (92)

LDH �587 U/La 16/30 (53) 822.5 (180–6,000) 8/15 (53) 8/15 (53)

NSE �100 mg/L 19/29 (66) 150.2 (8.9–449) 9/15 (60) 10/14 (71)

Localization of primary

Adrenal 18 (58)

Retroperitoneum 3 (10)

Mediastinum 2 (6.5)

Thoracoabdominal 5 (16)

Pelvic 1 (3)

Unknown primary 2 (6.5)

Localization of metastases

Bone marrow 26 (84)

Skeleton 23 (74)

Lymph nodes 23 (74)

Liver 7 (23)

Peritoneum 4 (13)

Pleura 2 (6.5)

Kidney 1 (3)

Testes 1 (3)

Lung 1 (3)

Orbita 1 (3)

Treatment protocols

Sidney-Faber (modified) 1 (3)

NB-A-87 5 (16)

NB-A-89 1 (3)

NB-92 2 (6.5)

A-NB-94 11 (35.5)

NB 99 3 (10)

HR-NBL1/ESIOP 8 (26)

Treatment modalities

Chemotherapy 31 (100)

Surgery 27 (87)

Irradiation (local/TBI) 13 (42)

Transplantation (BM/PBSC) 23 (74)

Othersb 17 (55)

VMA, vanillyl mandelic acid; HVA, homovanillic acid; LDH, lactate dehydrogenase; NSE, neuron-specific enolase; TBI, total body irradiation;

BM, bone marrow; PBSC, peripheral blood stem cells. aLimit values refer to median values published by the INRG Task Force [6].b13-cis-Retinoic acid, GD2 antibodies, 131I-MIBG.

630 Perwein et al.

Pediatr Blood Cancer DOI 10.1002/pbc

according to the effectively given doses in mg/m2 body surface, a

Cisplatin-equivalent was calculated using the cumulative dose of

Cisplatin in mg/m2 plus 25% of the cumulative dose of Carbopla-

tin, as previously described [22]. Statistical analysis and demon-

stration of overall (OS) and event-free survival (EFS) was done

using the Kaplan and Meier method, comparison of survival rates

was performed using the log-rank test. Height standard deviation

scores (SDS) were referred to international data of the WHO.

Comparison of SDS was carried out using the t-test for paired

samples. The Mann–Whitney U-test was used for non-parametric

data. A P-value of �0.05 was chosen to indicate statistical

significance.

RESULTS

Survival

Of 31 patients, 16 survived. Five-year OS was 54.3% (�9

SEM), as shown in Figure 1. Median follow-up from diagnosis

was 4.3 years (range: 0.4–23.2). Nine patients died of disease

recurrence, 5 patients died of therapy-refractory NB progression,

1 patient was lost to follow-up after 6.6 years, but known to have

died. Five-year OS of the patients diagnosed before or in 1996

(Group A; n ¼ 15), compared with the rate of those diagnosed and

treated after 1996 (Group B; n ¼ 16) was 33.3 � 12.2% versus

74 � 11.2% (P ¼ 0.011; Fig. 2). There was no significant differ-

ence in survival of patients having received high-dose chemother-

apy with autologous stem-cell transplantation and those who had

TABLE II. Treatment of the 16 NB Survivors

Treatment modality No. of patients (%) Median cumulative dose (range)

Chemotherapy 16 (100)Etoposide 15 (94) 2,159 mg/m2 (600–2,943)

Vincristine 15 (94) 7.8 mg/m2 (6.3–12.7)

Cyclophosphamide 15 (94) 5,078 mg/m2 (2,929–12,444)

Carboplatin 14 (87.5) 1,542 mg/m2 (800–6,083)

Melphalan 13 (81) 139 mg/m2 (120–220)

Cisplatin 11 (69) 320 mg/m2 (271–605)

Doxorubicin 9 (56) 216 mg/m2 (108–280)

Busulfan 4 (25) 319 mg/m2 (88–503)

Thiotepa 2 (12.5) 631 mg/m2 (595–667)

Nitrogen Mustard 2 (12.5) 22.5 mg/m2 (21–24)

Dacarbazine 2 (12.5) 3,066 mg/m2 (2,171–3,960)

Irinotecan 1 (6) 1,125 mg/m2

Topotecan 1 (6) 2.9 mg/m2

Teniposide 1 (6) 525 mg/m2

Ifosfamide 1 (6) 16,500 mg/m2

Irradiation 8 (50)Local 7 (44) 21 Gy (19.5–51)

TBI 1 (6) 12 Gy

Surgery 15 (94)Laparotomy 12 (75)

Thoracotomy 3 (19)

Adrenalectomy 6 (37.5)

Nephrectomy 1 (6)

Transplantation 13 (81)Autologous BM 2 (12.5) 3.6 � 108 MNC/kg (0.4–6.9)

Autologous PBSC 11 (69) 8.8 � 106 CD34þ/kg (4.7–40.7)

Others

13-cis-Retinoic acid 9 (56)131I-MIBG 1 (6)

GD2 antibody 4 (25)

Total numbers of patients receiving a special category of treatment are written in bold font. TBI, total body irradiation; BM, bone marrow; PBSC,

peripheral blood stem cells.

Fig. 1. Overall survival of the 31 patients with stage 4 NB

(54.3 � 9%).

Outcome in Children With Stage 4 NB 631


not. Likewise, there was no significant difference in children being

1 year of age or older who obtained Rapid COJEC-induction and

those who had another induction therapy. Five-year EFS was

44.9 � 9% (Fig. 3). Median survival time without recurrence of

disease was 2.3 years (range: 0.4–23.3). Two of 12 patients

(16.7%) suffering disease recurrence survived.

Long-Term Sequelae

Median age of the 16 survivors at last follow-up was 10.5 years

(range: 6.1–30). Median follow-up time was 7.4 years (range: 1.5–

22.7). In 15 of the 16 survivors (93.8%), one or more tumor- or

therapy-related long-term sequelae occurred. Median number of

late effects per patient was 5 (range: 1–9). In 13 patients (81.3%)

one or more mild changes (grade 1) were noted, 14 (87.5%) had

one or more moderate long-term effects (grade 2). Fifty percent of

the survivors (n ¼ 8) suffered from severe long-term compli-

cations (grade 3 or higher), one patient died of second neoplasm

(grade 5). Detected long-term effects are listed in Table III.

Endocrine

Primary hypothyroidism was found in 8 survivors (50%), all of

them needing thyroid replacement therapy. Median time of occur-

rence was 9 months after therapy (range: 0–163). Median number

of diagnostic 123I-MIBG scans (after protection with potassium

iodide) was 10 in survivors with hypothyroidism (range: 3–14)

as well as 10 in survivors with normal thyroid function (range:

0–14). GH deficiency occurred in 6 patients (37.5%) within a

median time of 11.5 months after therapy (range: 0–134), with

one child needing GH substitution after total body irradiation

(TBI). One patient (6.3%) remained too short for age (�2 SDS).

All 16 survivors were analyzed for body height (Fig. 4). There was

a significant difference between mean SDS for height and age at

diagnosis and after completion of therapy of 1.4 � 0.24 (95% CI:

0.89–1.9; P ¼ 0.000). Mean SDS at diagnosis and at the last

examination also differed significantly, with 1.23 � 0.31 SDS

(95% CI: 0.57–1.88; P ¼ 0.001). Two survivors (12.5%) had

hypogonadism with raised gonadotropin levels. There was one

case of missing puberty out of 6 survivors who had already reached

the appropriate age (males: 14.5 years, females: 13 years). Further-

more, there was one boy (6.3%) with precocious puberty needing

therapy with a GnRH-analogon.

Sensory

Sensorineural hypacusis was detected in 6 children (37.5%),

requiring hearing aids in 2 and cochlear implant in 1. Hearing loss

occurred after a median time of 3.2 months after therapy (range: 0–

15). All 6 patients received cisplatin (MCD: 332 mg/m2; range:

312–605) plus carboplatin (MCD: 2,281 mg/m2; range: 1,435–

3,000). The MCD of the ‘‘cisplatin-equivalent’’ was significantly

higher in children with hearing loss (MCD: 1,007 mg/m2; range:

672–1,096) than in those with normal hearing (MCD: 362 mg/m2;

range: 200–2003; P ¼ 0.011). One patient (6.3%) had an atrophy

of the optic nerve with total unilateral amaurosis caused by tumor

compression.

Neurologic/Psychologic

Persistent neurologic late effects were seen in 3 survivors

(18.8%), including 1 Horner’s syndrome after tumor resection in

the cervico-thoracal region, diffuse asymptomatic EEG-changes in

2 patients, and unilateral abducens palsy caused by tumor com-

pression in 1. In two children (12.5%) psychologic late effects were

noted (disorder of social development and behavioral problems

indicating psychotherapeutic rehabilitation in one patient and

severe disorder of speech development due to bilateral hypacusis

in another one).

Musculoskeletal

Four survivors (25%) had at least one change concerning the

musculoskeletal system (1 tibia epiphysiolysis because of meta-

stasis, 1 scoliosis, 1 femoral exostosis, 1 osteochondroma of the

scapula, 1 asymmetric pectus carinatum, and 1 unspecific chronic

myositis). Median time of occurrence was 6.8 years after com-

pletion of therapy (range: 3–8). None of these patients underwent

irradiation or thoracotomy.

Fig. 2. Comparison of OS rates of Group A (time of diagnosis

�1996; n ¼ 15) and Group B (time of diagnosis >1996; n ¼ 16):

33.3 � 12.2% versus 74 � 11.2% (P ¼ 0.011).

Fig. 3. Event-free survival of the 31 patients with stage 4 NB

(44.9 � 9%).

632 Perwein et al.


Hepatobiliary

In 5 children (31.3%) hepatobiliary changes were found. Three

had cholecystolithiasis (1 needing cholecystectomy). One patient

became infected with hepatitis B during NB therapy in the 1980s,

which became chronic leading to liver cirrhosis and finally to

hepatocellular carcinoma and death. Four of the 5 children with

liver changes had abdominal irradiation (MCD: 23 Gy; range:

19.5–44.8) and all were given cyclophosphamide (MCD:

6,260 mg/m2; range: 3,940–9,600).

Renal

Persistent renal changes were detected in 10 patients (62.5%), 5

of whom had a total function loss of one kidney caused by the

primary tumor and the therapy, respectively. All 10 children had a

primary localized in the abdomen and all underwent laparotomy

and received cyclophosphamide (MCD: 5.9 g/m2; range: 2.9–

12.4). Nine were given cisplatin (MCD 320 mg/m2; range: 271–

605). All 7 survivors with local abdominal irradiation (MCD:

21 Gy; range: 19.5–44.8) developed renal late effects.

TABLE III. Frequency and Severity of Long-term Sequelae in the 16 NB Survivors

Late effects No. (%) Grade 1–2 (n) Grade �3 (n)

Endocrine 9 (56.3)Primary hypothyroidism 8 (50) 8 0

Growth hormone deficiency 6 (37.5) 6 0

Short stature 1 (6.3) 1 0

Primary hypogonadism 2 (12.5) 0 2

Precocious puberty 1 (6.3) 1 0

Sensory 7 (43.8)Sensorineural hypacusis 6 (37.5) 3 3

Unilateral blindness 1 (6.3) 0 1

Neurologic 3 (18.8)Horner’s syndrome 1 (6.3) 1 0

EEG changes 2 (12.5) 2 0

Abducens palsy 1 (6.3) 1 0

Psychologic 2 (12.5)Disorder of social development 1 (6.3) 1 0

Disorder of speech development 1 (6.3) 0 1

Musculoskeletal 4 (25)Osteochondroma/exostosis 2 (12.5) 2 0

Epiphysiolysis/leg length discrepancy 1 (6.3) 1 0

Scoliosis 1 (6.3) 1 0

Thoracic deformation 1 (6.3) 1 0

Muscle pain/unspecific myositis 1 (6.3) 1 0

Soft tissue 1 (6.3)Seroma 1 (6.3) 1 0

Hepatobiliary 5 (31.3)Cholelithiasis 3 (18.8) 2 1

Hepatitis B/cirrhosis 1 (6.3) 0 1

Parenchyma alterations (FNH, fibrosis) 4 (25) 4 0

Renal 10 (62.5)Hypertension 1 (6.3) 1 0

Unilateral loss of function/shrunken kidney 5 (31.3) 5 0

Parenchyma alterations/small kidney 3 (18.8) 3 0

St.p. nephrectomy 1 (6.3) 1 0

Dental 2 (12.5)Agenesis 2 (12.5) 0 2

Root stunting 1 (6.3) 1 0

Crossbite 1 (6.3) 1 0

Pulmonary 4 (25)Obstruction 1 (6.3) 1 0

Parenchyma alterations 3 (18.8) 3 0

Laboratory 2 (12.5)Chronic thrombocytopenia 1 (6.3) 1 0

Raised ferritin levels 1 (6.3) 1 0

Second neoplasms 3 (18.8)Benigna 3 (18.8) 1 2

Malignb 1 (6.3) 0 1

Total numbers of patients with one or more late effects of one category are expressed in bold font. EEG, electroencephalogram; FNH, focal

nodular hyperplasia. aColon polypes, thyroid adenoma, fibroma. bHepatocellular carcinoma.



Second Neoplasms

In 3 of the long-term survivors (18.8%), secondary tumors

occurred within a median time of 10 years after therapy (range:

4.4–19.7). In 2 cases there were benign changes and 1 patient had

both a benign tumor and a malignancy. Benign tumors were

multiple subcutaneous fibromas in one patient (without neurofibro-

matosis) and 3 different colon polypes after abdominal irradiation

with 25.6 Gy in another patient needing resection. The third patient

had a thyroid adenoma and multiple cysts after TBI with 12 Gy,

needing resection. This patient also developed hepatocellular car-

cinoma following hepatitis B, finally leading to death 18 years after

completion of NB therapy.

DISCUSSION

Our study gives an overview of the situation of young patients

treated with stage 4 NB at our department within the last 25 years.

The results are comparable with those of previous studies on this

subject. Due to the small number of patients and the study’s retro-

spective character, results of this work should be regarded and

interpreted with reservation. Five and 10-year OS in our study

was 54% and 5 and 10-year EFS was 45%, rates being similar to

those reported in recent studies [11,12]. Thus, more than a half of

patients with metastatic NB may survive. Our work also shows that

survival could be improved over the past decade. It is of note that

only 2 out of 12 children (16.7%) with recurrence survived. These

results emphasize the importance of modern multimodality treat-

ment including differentiation and eradication therapy [5].

Tumor- and therapy-related long-term sequelae were present in

almost all patients with half of them (8 patients) suffering from

severe chronic health problems (grade �3), of whom 1 even died.

We identified a wide range of late effects, which compare to the

reported spectrum of late effects in NB survivors so far [7,12–25].

Persisting renal damages, also mentioned in other studies [12–

14], were the most prevalent late effects in our patients. It should be

of interest that in all of our survivors having received abdominal

irradiation renal late effects were found, as well as in the majority

of those having had abdominal primary localization and laparot-

omy and in most of those having received cyclophosphamide and/

or cisplatin, possible causes also being described elsewhere

[12,14,28].

Endocrine disturbances were detected in 56.3% of our survivors

with hypothyroidism being the most common endocrine late effect

(50%), within the previously described range of 24–60% [12–

14,18,19]. Primary hypothyroidism occurred after diagnostic use

of radiolabeled MIBG, despite protection of the thyroid gland with

potassium iodide, as reported by van Santen et al. [29]. The median

number of scans did not differ in the two groups with and without

hypothyroidism in our cohort. Thus, radioiodide damage of the

thyroid rather seems to be caused by an insufficient prophylaxis,

either because of individually different mechanisms of iodide

uptake and storage, or lack of compliance. Irradiation of the thy-

roid gland was not a reason in our study except for one case with

TBI. Other factors, such as young age of patients or some chemo-

therapeutic agents may also favor development of hypothyroidism

[18,29,30].

The rate of children with GH deficiency in this cohort also lies

within the published range of 10–54% [12–14,19]. However, none

of our children had cranial irradiation, a cause identified by Lav-

erdiere et al. [15], except for one patient with TBI being the only

one requiring GH substitution. Growth of NB patients can be

affected by different factors (e.g., GH deficiency, irradiation, che-

motherapy, hypothyroidism). NB survivors have presented dimin-

ished height SDS in many studies [12–14,19,31,32]. In this work,

the retrospective growth analysis before and after therapy and in

the course of follow-up also showed significant differences in the

mean SDS for height and age. The decrease between baseline SDS

at diagnosis and SDS at end of therapy was greater than that

between diagnosis and last follow-up visit. This leads to the

assumption that growth recovered at least in some of our patients.

Furthermore, it has to be mentioned that only in one case height

SDS was not normal at the last visit.

Primary hypogonadism has been reported before [12–

14,18,19], and also was a problem in our cohort. However, neither

of the two children (12.5%) in our study had received radiation

therapy. Possible causes are chemotherapeutic agents like alkylat-

ing agents [28]. One of 6 survivors having already reached the

appropriate age for puberty needed hormone replacement therapy

because of missing puberty. It remains to be seen in how many of

the other survivors gonadal damages will become present once

having reached pubertal age.

A well known problem seen in NB survivors is irreversible

hearing loss [12–14,19,21,23] which occurred in six children in

our cohort, who had received significantly higher MCDs of

platinum compounds than those showing normal audiograms.

Therefore, our findings support the results of numerous studies

describing the ototoxicity of cisplatin and carboplatin [13–15,21–

23]. The influence of other potentially ototoxic substances like

aminoglycosides or diuretics was not investigated in this study.

High-grade hypacusis in young children has substantial effects

on speech development, cognitive performance, and quality of life

[24]. Severe disturbance of speech development in one of our

survivors with hypacusis underlines the importance of early detec-

tion in order to face such problems adequately.

Psychologic late effects were noted in two of our patients

(12.5%). However, as psychological issues were not explicitly

Fig. 4. Standard deviation scores (SDS) for height and age of the 16

NB survivors at diagnosis (Time Point 1; median 1.6; range: �0.61 to

3.54), completion of therapy (Time Point 2; median 0.28; range: �1.2

to 0.94) and at the last follow-up examination (Time Point 3; median

0.19; range: �2 to 2.44).

634 Perwein et al.


examined, they may be underrepresented in this study. Many late

effects are likely to impede developmental progress and activities

of daily life (e.g., affection of fertility, physical differences leading

to exclusion by peers or disability to participate in sports or other

socially normative activities), thus causing severe distress. There-

fore, more systematic clinical attention to document and under-

stand the predictors of quality of life and psychological distress in

childhood cancer survivors, for example, by providing question-

naires and stronger involvement of psychologists in follow-up

examinations, is needed in future studies.

Blindness was previously described in NB survivors [7,14,15].

In one of our survivors (6.3%), unilateral amaurosis occurred as a

result of tumor compression of the optic nerve. Due to the tendency

of NB to metastasize to the orbital region, patients with stage 4 NB

are likely to suffer damages of the optic nerve. Laverdiere et al.

[15] reported that NB survivors have a near sevenfold elevated risk

for blindness.

Finally, in 3 of our NB survivors (18.8%) second neoplasms

occurred after 10 years, comprising 2 patients with benign tumors

and 1 with both a benign thyroid adenoma and a secondary malig-

nancy (hepatocellular carcinoma after hepatitis B). This patient

died of secondary cancer 18 years after NB therapy.

In conclusion, survival rates of patients with stage 4 NB have

improved over the past decades, with more than a half of patients

surviving by now. However, an inacceptably high number of

survivors of stage 4 NB faces severe health complications.

Therefore, it is of utmost importance to include these patients in

detailed follow-up programmes. Only by intensive multidiscipli-

nary tumor follow-up and a profound knowledge of possible long-

term effects early detection of emerging problems can be guaran-

teed. Thus, we can face late effects adequately and optimize

the long-term care for survivors, for the purpose of an improved

quality of life.

REFERENCES

1. Deutsches Kinderkrebsregister. Jahresbericht. 2008. Available at: http://

www.kinderkrebsregister.de (accessed October 20, 2009).

2. Brodeur GM. Neuroblastoma: Biological insights into a clinical enigma.

Nat Rev Cancer 2003;3:203–216.

3. Maris JM, Hogarty MD, Bagatell R, et al. Neuroblastoma. Lancet

2007;369:2106–2120.

4. Graf N. Neuroblastoma. In: Sitzmann FC, editor. Padiatrie, 3rd edition.

Stuttgart: Thieme; 2007. pp. 504–507.

5. Matthay KK, Villablanca JG, Seeger RC, et al. Treatment of high-risk

neuroblastoma with intensive chemotherapy, radiotherapy, autologous

bone marrow transplantation, and 13-cis-retinoic acid. N Engl J Med

1999;341:1165–1173.

6. Cohn SL, Pearson ADJ, London WB, et al. The International Neuroblas-

toma Risk Group (INRG) classification system: An INRG task force

report. J Clin Oncol 2009;27:289–297.

7. Escobar MA, Grosfeld JL, Powell RL, et al. Long-term outcomes in

patients with stage IV neuroblastoma. J Pediatr Surg 2006;41:377–381.

8. De Bernardi B, Nicolas B, Boni L, et al. Disseminated neuroblastoma in

children older than one year at diagnosis: comparable results with three

consecutive high-dose protocols adopted by the Italian Co-Operative

Group for Neuroblastoma. J Clin Oncol 2003;21:1592–1601.

9. Kerbl R, Urban CE, Ambros IM, et al. Neuroblastoma mass screening in

infancy: Insights into the biology of neuroblastic tumors. J Clin Oncol

2003;21:4228–4234.

10. Woods WG, Gao R-N, Shuster JJ, et al. Screening of infants and mortality

due to neuroblastoma. N Engl J Med 2002;346:1041–1046.

11. George RE, Li S, Medeiros-Nancarrow C, et al. High-risk neuroblastoma

treated with autologous peripheral-blood stem cell-supported transplan-

tation: Long-term survival update. J Clin Oncol 2006;24:2891–2896.

12. Trahair TN, Vowels MR, Johnston K, et al. Long-term outcomes in chil-

dren with high-risk neuroblastoma treated with autologous stem cell trans-

plantation. Bone Marrow Transplant 2007;40:741–746.

13. Hobbie WL, Moshang T, Carlson CA, et al. Late effects in survivors of

tandem peripheral blood stem cell transplant for high-risk neuroblastoma.

Pediatr Blood Cancer 2008;51:679–683.

14. Laverdiere C, Cheung N-KV, Kushner BH, et al. Long-term complications

in survivors of advanced stage neuroblastoma. Pediatr Blood Cancer

2005;45:324–332.

15. Laverdiere C, Liu Q, Yasui Y, et al. Long-term outcomes in survivors of

neuroblastoma: A report from the Childhood Cancer Survivor Study. J Natl

Cancer Inst 2009;101:1131–1140.

16. Garaventa A, Gambini C, Villavecchia G, et al. Second malignancies in

children with neuroblastoma after combined treatment with 131I-metaio-

dobenzylguanidine. Cancer 2003;97:1332–1338.

17. Paulino AC, Mayr NA, Simon JH, et al. Locoregional control in infants

with neuroblastoma: Role of radiation therapy and late toxicity. Int J

Radiat Oncol Biol Phys 2002;52:1025–1031.

18. van Santen HM, de Kraker J, Vulsma T. Endocrine late effects from multi-

modality treatment of neuroblastoma. Eur J Cancer 2005;41:1767–1774.

19. Flandin I, Hartmann O, Michon J, et al. Impact of TBI on late effects in

children treated by megatherapy for stage IV neuroblastoma. A study of

the French Society of Pediatric Oncology. Int J Radiat Oncol Biol Phys

2006;64:1424–1431.

20. Lackner H, Benesch M, Schagerl S, et al. Prospective evaluation of late

effects after childhood cancer therapy with a follow-up over 9 years. Eur J

Pediatr 2000;159:750–758.

21. Kushner BH, Budnick A, Kramer K, et al. Ototoxicity from high dose use

of platinum compounds in patients with neuroblastoma. Cancer 2006;107:

417–422.

22. Parsons SK, Neault MW, Lehmann LE, et al. Severe ototoxicity following

carboplatin-containing conditioning regimen for autologous marrow trans-

plantation for neuroblastoma. Bone Marrow Transplant 1998;22:669–674.

23. Simon T, Hero B, Dupuis W, et al. The incidence of hearing impairment

after successful treatment of neuroblastoma. Klin Padiatr 2002;214:149–

152.

24. Gurney JG, Tersak JM, Ness KK, et al. Hearing loss, quality of life, and

academic problems in long-term neuroblastoma survivors: A report from

the Children’s Oncology Group. Pediatrics 2007;120:1229–1236.

25. Neve V, Foot ABM, Michon J, et al. Longitudinal clinical and functional

pulmonary follow-up after megatherapy, fractionated total body irradia-

tion, and autologous bone marrow transplantation for metastatic neuro-

blastoma. Med Pediatr Oncol 1999;32:170–176.

26. Lackner H, Moser A, Sovinz P, et al. Langzeitbetreuung junger Erwachs-

ener nach Krebserkrankung im Kindesalter—Wohin fuhrt der Weg? Wien

Klin Wochenschr 2007;119:361–364.

27. National Cancer Institute. Cancer Therapy Evaluation Program. Common

Terminology Criteria for Adverse Events v3.0 (CTCAE). Available at:

http : //ctep.cancer.gov/protocolDevelopment /electronic_applications/

docs/ctcaev3.pdf (accessed October 14, 2009).

28. Dickerman JD. The late effects of childhood cancer therapy. Pediatrics

2007;119:554–568.

29. van Santen HM, de Kraker J, van Eck BLF, et al. High incidence of thyroid

dysfunction despite prophylaxis with potassium iodide during 131I-meta-

iodobenzylguanidine treatment in children with neuroblastoma. Cancer

2002;94:2081–2089.

30. Lackner H, Urban C, Sovinz P, et al. Hypothyroidism after treatment of

metastatic neuroblastoma. Pediatr Blood Cancer 2010;55:768. published

online in Wiley InterScience (http://www3.interscience.wiley.com): DOI:

10.1002/pbc.22593.

31. Giorgiani G, Bozzola M, Locatelli F, et al. Role of busulfan and total body

irradiation on growth of prepubertal children receiving bone marrow trans-

plantation and results of treatment with recombinant human growth hor-

mone. Blood 1995;86:825–831.

32. Kushner BH, Wolden S, LaQuaglia MP, et al. Hyperfractionated low-dose

radiotherapy for high-risk neuroblastoma after intensive chemotherapy and

surgery. J Clin Oncol 2001;19:2821–2828.



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