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Neuroblastoma

Article  in  Pediatric Blood & Cancer · May 2021

DOI: 10.1002/pbc.28473

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Received: 28 January 2020 Revised: 15 May 2020 Accepted: 18 May 2020

DOI: 10.1002/pbc.28473 Pediatric

Blood &
Cancer The American Society of
Pediatric Hematology/Oncology
SUPPLEMENT ARTICLE

Neuroblastoma

Christine Chung1 Tom Boterberg2 John Lucas3 Joseph Panoff4

Dominique Valteau-Couanet5 Barbara Hero6 Rochelle Bagatell7
Christine E. Hill-Kayser8
1
Department of Radiation Oncology, Diablo Valley Oncology and Hematology, Pleasant Hill, California
2
Department of Radiation Oncology Ghent University Hospital, Gent, Belgium
3
Department of Radiation Oncology St Jude Children’s Research Hospital, Memphis, Tennessee
4
Department of Radiation Oncology, Miami Cancer Institute, Baptist Health, South Florida, Florida
5
Department of Childhood and Adolescent Cancer Gustave Roussy Cancer Campus, Villejuif-Grand, Paris, France
6
Department of Pediatric Hematology and Oncology, University Children’s Hospital, Cologne, Germany
7
Department of Pediatrics, Division of Oncology, Children’s Hospital of Philadelphia and the Perelman School of Medicine, University of Pennsylvania, Philadelphia,
Pennsylvania
8
Department of Radiation Oncology University of Pennsylvania and the Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

Correspondence
Christine E. Hill-Kayser, Associate Professor of Abstract
Radiation Oncology, University of Pennsylva-
nia and the Children’s Hospital of Philadelphia,
The survival of patients with high-risk neuroblastoma has improved significantly
Philadelphia, PA. with the use of intensive multimodality treatment regimens, including chemotherapy,
Email: Christine.Hill@pennmedicine.
upenn.edu
surgery, radiation therapy, myeloablative chemotherapy followed by stem cell rescue,
and immunotherapy. This report summarizes the current treatment strategies used in
the COG and SIOP for children with neuroblastoma. The improved global collaboration
and the adoption of a uniform International Neuroblastoma Risk Group Staging System
will help facilitate comparison of homogeneous pretreatment cohorts across clinical
trials. Future research strategies regarding the indications for and dosages of radiation
therapy to the primary and metastatic sites, and the integration of meta-iodobenzyl
guanidine therapy into the multimodal treatment program, are discussed.

KEYWORDS
autologous stem cell rescue, chemotherapy, immunotherapy, MIBG, neuroblastoma, radiation
therapy, surgery

1 INTRODUCTION system.1 It is the most common extracranial solid tumor in children,

with approximately 700 cases diagnosed per year in the United States
Neuroblastoma is a cancer that arises in cells derived from the neural alone.2 Most children are diagnosed under the age of five years, with
crest, and tumors can develop at any site in the sympathetic nervous a median age at diagnosis of 17 months.3 Clinical symptoms vary

Abbreviations: ASCR, autologous stem rescue; CTV, clinical target volume; HR NBL, high-risk neuroblastoma; IDRFs, image-defined risk factors; IMRT, intensity modulated radiation therapy;
INRGSS, International Neuroblastoma Risk Group Staging System; MIBG, meta-iodobenzyl guanidine; PET, positron emission tomography scan; RT, radiation therapy; TBI, total body irradiation

Pediatr Blood Cancer. 2021;68(Suppl. 2):e28473. wileyonlinelibrary.com/journal/pbc © 2021 Wiley Periodicals LLC S1 of S8
https://doi.org/10.1002/pbc.28473
S2 of S8 CHUNG ET AL .

depending on the location of the primary tumor and may include an TA B L E 1 IDRFs in neuroblastic tumors
abdominal mass, abdominal pain, respiratory distress, or neurological
Ipsilateral tumor extension within two body compartments
symptoms from spinal cord involvement.4,5 Children with metastatic
Neck
disease often appear ill at diagnosis, with fever, bone pain, and weight
Tumor encasing carotid and/or vertebral artery and/or internal jugular
loss. Although in some cases of neuroblastoma, lesions may regress
vein
spontaneously, in others, the disease may behave aggressively, with
Tumor extending to base of the skull
many patients succumbing to recurrent/refractory metastatic disease.
Tumor compressing the trachea
Therapy is stage and risk stratified, and some elements of radiotherapy
may be response adapted. Cervicothoracic junction

Modern protocols, including induction chemotherapy, surgi- Tumor encasing brachial plexus roots
cal resection, high-dose chemotherapy with autologous stem Tumor encasing subclavian vessels and/or vertebral and/or carotid
cell rescue (ASCR), external beam radiotherapy (EBRT), and artery

immunotherapy or differentiating agents, have improved out- Tumor compressing the trachea
comes, with three-year survival rates now exceeding 60%.6 Past Thorax
treatments that used less intensive chemotherapy resulted in Tumor encasing the aorta and/or major branches
four-year survival rates of 10%-15%. This review will focus on cur- Tumor compressing the trachea and/or principal bronchi
rent treatment approaches in high-risk neuroblastoma in North
Lower mediastinal tumor, infiltrating the costovertebral junction
America and Europe, particularly as they pertain to external beam between T9 and T12
radiotherapy. Thoracoabdominal
Tumor encasing the aorta and/or the vena cava
Abdomen/pelvis
2 DIAGNOSIS AND STAGING
Tumor-infiltrating the porta hepatis and/or the hepatoduodenal
ligament
Biopsy of the primary neuroblastoma tumor or a metastatic soft-tissue
Tumor encasing branches of the superior mesenteric artery and the
lesion is generally required to establish the diagnosis, although the
mesenteric root
diagnosis can be made based on bone marrow involvement and ele-
Tumor encasing the origin of celiac axis and/or of the superior
vated urinary catecholamines if the risk of tumor biopsy is deemed mesenteric artery
unacceptable. Anatomic imaging of the primary site is required, as
Tumor invading one or both renal pedicles
well as bone marrow aspirate and biopsies and an iodine-123 meta-
Tumor encasing the aorta and/or the vena cava
iodobenzylguanidine (MIBG) scan. A FDG-PET CT can be used if the
Tumor encasing the iliac vessels
primary tumor is MIBG nonavid.
The staging system currently used worldwide is the International Pelvic tumor across the sciatic notch

Neuroblastoma Risk Group Staging System (INRGSS).7,8 The INRGSS Intraspinal tumor
was developed to facilitate comparison across clinical trials by defin- Extension, regardless of location, provided that more than one-third
ing homogeneous pretreatment patient cohorts. Staging is based on of the spinal canal in the axial plane is invaded and/or the
perimedullary leptomeningeal spaces are not visible and/or the
the presence or absence of imaging-defined risk factors (IDRFs), which
spinal cord signal is abnormal
are defined by the relationship between the tumor and adjacent struc-
Infiltration of adjacent organs/structures
tures. IDRFs were originally intended to indicate surgical risk, but are
Pericardium, diaphragm, kidney, liver, duodeno-pancreatic block and
now considered proxies for biological variables that have not yet been
mesentery
identified (Table 1).
Conditions to be recorded, but not considered as IDRFs
The INRGSS recognizes four stages: localized disease without (L1)
Multifocal primary tumors
and with (L2) IDRFs, metastatic disease (M) and metastatic dis-
ease in very young children that is limited to specific sites (MS) Pleural effusion, with or without malignant cells

(Table 2). The INRG Task Force also developed the INRG Consen- Ascites, with or without malignant cells
sus Pretreatment Classification Schema for pretreatment risk strat-
ification. An analysis of 13 variables in an 8800-patient cohort
revealed 16 combinations of known prognostic factors, including High-risk neuroblastoma is defined as metastatic disease in a
age (< 12 months, 12-18 months, ≥ 18 months), stage, histology child ≥ 18 months or a patient of any age with L2, M, or MS disease with
(category, grade), and molecular characteristics (MYCN amplifica- amplification of the MYCN oncogene. Subsets of patients with other
tion status, chromosome 11q status, tumor cell ploidy) (Table 3). combinations of risk factors may benefit from high-risk therapy when
These factors allowed for the allocation of patients into four outcomes are expected to be suboptimal with intermediate-risk ther-
main prognostic groups (very low, low, intermediate, and high risk) apy; these include some patients < 18 months of age with MYCN non-
(Table 4).7 amplified disease but an 11q aberration.
CHUNG ET AL . S3 of S8

TA B L E 2 INRG staging system chemotherapy, preoperative tumor volume to comprise the radiation
target volume. A uniform expansion is added to this volume to create
INRG
Stage Definition the clinical target volume (CTV). Prior COG protocols used 1.5-2 cm

L1 Localized disease, without imaging-defined risk factors (for margins from the postoperative bed to create the CTV; the current
example, encasement of major blood vessels or COG High-Risk Neuroblastoma study, ANBL1531, uses 1 cm treat-
encroachment into the spinal canal). ment margins. CTV margins may be tailored further at tissue interfaces
L2 Localized disease with imaging-defined risk factors. where invasion or infiltration is unlikely, such as the kidney, liver, and
M Metastatic disease that does not fall into the MS category (for bone.16
example, those aged less than 18 months with bone Considerable uncertainty exists surrounding the use of higher radi-
metastases, and all older patients with distant metastases). ation doses for patients with residual disease after surgical resection.
MS Age less than 18 months with metastatic disease limited to On the COG protocol ANBL 0532, patients with incompletely resected
liver, skin, or bone marrow.
primary neuroblastoma received an additional 14.4 Gy boost to areas
of gross residual disease, for a total dose of 36 Gy; however, analysis of
local control rates compared with historical controls suggested no ben-
3 LOCAL CONTROL: USE OF SURGERY AND efit of this escalated dose, resulting in removal of the “boost” from cur-
EXTERNAL BEAM RADIOTHERAPY TO CONTROL rent COG protocols.17 Some have argued for both higher18 and lower
PRIMARY TUMOR SITE AND PERSISTENT SITES OF doses19 for the cone-down/boost phase of therapy when residual dis-
METASTATIC DISEASE ease is present.
Even modern primary site radiotherapy following ASCR is asso-
3.1 North America ciated with increased risk for acute and late complications. Acute
complications may include nausea, vomiting, weight loss, anorexia,
3.1.1 Surgery radiation dermatitis, diarrhea, esophagitis, and pneumonitis. Late com-
plications may include renal insufficiency, pancreatic endocrine and
Surgical resection remains a mainstay of curative therapy for high-risk exocrine insufficiency, tissue hypoplasia and fibrosis, risk for second
neuroblastoma. In North American paradigms, definitive surgical cancers, and bone deformities. Nonadrenal primary site radiotherapy
resection of the primary tumor is generally undertaken following can lead to hypogonadism, pulmonary fibrosis, and focal nodular
four cycles of chemotherapy. Surgical resection has been demon- hyperplasia of the liver.20-24
strated to improve overall survival relative to biopsy alone9 ; however, Attempts at mitigating the radiation-associated complications have
the importance of gross total resection compared with subtotal included dose reduction and risk stratification, as well as reduction
resection remains unclear. Two recent studies suggested decreased in radiation exposure using proton radiotherapy, CTV volume reduc-
mortality risk and improved event-free survival and freedom from tion, and organ avoidance strategies.19,20,25-27 Early reports on dose
local recurrence when at least 90% of tumor was resected.10,11 reduction suggest that doses as low as 18 Gy might control the pri-
As a result, the American Pediatric Surgical Association concluded mary site when MYCN amplification and residual disease are absent.28
that resection at an experienced center of > 90% of the primary The use of IMRT or proton therapy may reduce bowel and verte-
tumor with preservation of adjacent organs and neurovascular bral body dose, lowering the risk of skeletal deformities and bony
structures is the preferred approach in patients with high-risk hypoplasia.25,29
disease.12

3.1.3 Metastatic site radiotherapy

3.1.2 Primary site radiotherapy
Historically, treatment of metastatic sites has been a topic of relative
Radiotherapy to the primary site and persistent MIBG-avid metastases uncertainty because of the paucity of clinical data. The COG proto-
is recommended following induction chemotherapy, surgical resection, col ANBL1531 mandates focal radiation to ≤ 5 metastatic sites that
and high-dose chemotherapy and ASCR.13 Analyses from Children’s do not completely respond to induction chemotherapy.30 A few retro-
Cancer Group (CCG) trial 3891 suggested that patients receiving a spective cohort studies have evaluated focal metastatic site radiother-
combination of 10 Gy total body irradiation (TBI) and an additional apy. Bradfield et al. reported that one of 21 patients who received RT
boost of 10 Gy to the primary site with focal external beam radio- to initial metastatic sites had local failure at the primary site and an
therapy had improved local control,14 setting the Children’s Oncology irradiated bony metastatic site. Four of 17 patients (24%) developed
Group (COG) standard of focal primary site radiotherapy to 21.6 Gy recurrences at metastatic sites, but not within the treatment field.31
following ASCR. In COG A3973, 21.6 Gy was given to the postinduc- Casey et al. analyzed 159 patients with radiation of 244 metastatic
tion chemotherapy, preoperative primary tumor volume. Retrospective sites. Metastatic sites that cleared with induction chemotherapy had
analysis showed no benefit from radiation of uninvolved lymph nodes improved local control (LC) compared with sites with persistent uptake
(elective lymph node radiation).15 Modern protocols thus use the post- on MIBG scans (LC rate, 92% vs 67%; P < 0.0001). Patients who had LC
S4 of S8 CHUNG ET AL .

TA B L E 3 International neuroblastoma treatment risk groups

INRG Age Histological Grade of tumor Pretreatment

stage (months) classification differentiation MYCN 11q aberration Ploidy risk group
L1/L2 Any GN maturing A Very low
GNB intermixed
L1 Any Any except NA B Very low
GN maturing or Amp K High
GNB intermixed
L2 <18 Any except NA No D Low
GN maturing or Yes G
GNB intermixed Intermediate
≥18 GNB nodular; Differentiating NA No E Low
neuroblastoma Poorly differentiating NA Yes
or undifferentiating
H Intermediate
M <18 NA Hyperdiploid F Low
<12 NA Diploid I Intermediate
12 to < 18 NA Diploid J Intermediate
<18 Amp O High
≥18 P High
MS <18 NA No C Very low
Yes Q High
Amp R High

TA B L E 4 INRG prognostic groups beam radiotherapy do not exist, although supplanting external beam
radiotherapy with use of I-131 MIBG in the setting of diffuse metastatic
Pretreatment Five-year Proportion of
risk group EFS (%) patients (%) disease with an incomplete response is an attractive approach due

Very low >85 28.2 to practical and toxicity concerns associated with delivery. Secondary
analyses of RT response in COG ANBL 0532 should provide additional
Low >75 to ≤85 26.8
valuable data regarding the benefit of treating metastatic sites. Future
Intermediate ≥50 to ≤75 9.0
studies investigating the role of I-131 MIBG compared with EBRT are
High <50 36.1
needed.

at irradiated metastatic sites had improved overall survival compared 3.2 Europe
with those who did not (71% vs 50%; P < 0.0001).32 Gatcombe et al.
reported that only one of six patients had in-field relapse after radi- 3.2.1 Surgery
ation to persistent metastatic disease on postinduction scans.33 Simi-
larly, Polishchuk et al. also found a higher risk of relapses in metastatic The current strategy in most high-risk neuroblastoma treatment
sites with no RT: 3 of 19 (15.8%) after RT, compared with 128 of 506 protocols in Europe involves resection of the primary tumor after
(25.3%) after no-RT to metastatic sites.34 These data, although retro- completion of all induction chemotherapy, rather than following
spective, support continued investigation of the use of RT to control only four to five cycles of systemic treatment as in North Amer-
metastatic disease in patients with high-risk neuroblastoma. In a retro- ican regimens. Thus, surgical intervention occurs at a relatively
spective analysis of three large high-risk neuroblastoma trials, Li et al. later point in the treatment course in the European protocols. Sev-
found that patients who received TBI as part of an older consolidation eral details regarding the role of aggressive surgery in high-risk
model had significantly fewer metastatic relapses in previously MIBG- neuroblastoma remain controversial. Inconsistent documentation of
avid sites compared with patients who did not receive TBI. These surgical approaches and lack of immediate postoperative imaging
authors suggest that I-131 MIBG (systemic radiotherapy) may supplant should be addressed in upcoming trials as in the European Interna-
the use of TBI and improve metastatic site control.13 Direct compar- tional Collaboration for Neuroblastoma Research (SIOPEN) HR-NBL2
isons of I-131 MIBG to consolidative metastatic site-directed external trial.
CHUNG ET AL . S5 of S8

3.2.2 Primary site radiotherapy argument for adding radiotherapy to persistent metastatic sites to
improve outcomes. Randomized trials are needed to more accurately
External beam RT to the primary site has an established role in the define the role of radiotherapy for metastatic sites in neuroblastoma.
treatment of patients with high-risk neuroblastoma based on substan- TBI has been abandoned for the treatment of neuroblastoma in
tial clinical evidence, despite the absence of randomized data. Cur- North America and Europe. Significant long-term side effects after TBI
rently, different international groups use varying RT strategies. The for neuroblastoma included cataracts, hypothyroidism, growth delay,
recently closed SIOPEN High-Risk Neuroblastoma 1 study prescribed and the risk of secondary tumors.38
a dose of 21 Gy in 14 fractions to the presurgical primary tumor vol-
ume, including regional lymph nodes if involved, for all patients. A com-
promise in dose or volume was allowed in cases with very large tumors 4 SYSTEMIC THERAPY
to meet normal tissue tolerances. This dose was given regardless of
the extent of the disease or surgery. Preliminary retrospective results 4.1 North America
presented at ASCO 2018 showed that the five-year EFS for patients
with complete macroscopic excision who received RT was 44% ± 2%, The general treatment paradigm in North America includes five cycles
but 31% ± 6% without RT (P = 0.013).35 The use of radiation was not of six-drug induction therapy utilizing topotecan, cyclophosphamide,
randomized on this trial; however, RT was omitted in some very young cisplatin, etoposide, doxorubicin, and vincristine. Maximal safe resec-
patients or those with very large primary tumors. tion of the primary tumor is undertaken after four cycles of chemother-
The German Pediatric Oncology and Hematology Group (GPOH) apy. Induction chemotherapy is followed by tandem cycles of high-dose
utilized intensified local therapy with RT in metastatic neuroblastoma chemotherapy and ASCR and, finally, immunotherapy, historically con-
patients with unresectable MIBG-avid residual primary tumors on the sisting of alternating cycles of dinutuximab/granulocyte macrophage
GPOH NB97 trial 36 : A retrospective analysis of 110 patients showed colony stimulating factor (GM-CSF) and dinutuximab/interleukin-2
that 13 patients who received RT for local residual disease had a sim- (IL-2). This paradigm results in five-year event-free survival rates of
ilar outcome to 74 unirradiated patients without any MIBG-positive approximately 60%, and has been developed based on results of a
residual (three-year EFS 85% with RT vs 61%, three-year OS 92% with series of clinical trials led by the Children’s Oncology Group.6 Of
RT vs 75%). The outcome was worse in 23 children without EBRT to particular interest is the importance of immunotherapy in improv-
the residual primary (three-year EFS 25%, three-year OS 51%). These ing prognosis—neuroblastoma is one of the few cancers for which
data support the use of EBRT to address residual primary disease in immunotherapy has been demonstrated to provide significant bene-
patients with HR-NB, although the question of the benefit of radiother- fit over conventional chemotherapy alone, and has thus been incorpo-
apy for completely resected disease remains in this population, with rated as part of upfront treatment for the past decade. Permutations
findings limited by small patient numbers and retrospective nature. to the above paradigm currently under investigation include addition
Currently, the GPOH uses primary site EBRT only in patients > 1 year of therapeutic 131 I-MIBG and targeted small molecules based on indi-
old with MIBG-positive residual disease after induction chemother- vidual disease, patient, and tumor characteristics (Figure 1).
apy. In these patients, a total dose of 36 Gy is delivered to the resid- A historic approach is essential to understanding the rationale
ual tumor volume following high-dose chemotherapy and stem cell behind the current complex, multimodality treatment of high-risk neu-
transplantation. Based on the GPOH experience and previous SIOPEN roblastoma. In the 1990s, the CCG trial 3891 investigated (1) the
experience, the current SIOPEN High-Risk Neuroblastoma Study 2 combination of high-dose chemotherapy (HDC)/TBI/ASCR compared
(SIOPEN/HR-NBL2) will investigate whether dose escalation beyond with intensive conventional chemotherapy and (2) the addition of 13-
21 Gy will improve LC and survival for patients with residual disease. cis-retinoic acid after completion of chemotherapy. This trial of 539
Patients with macroscopic residual disease after induction chemother- patients showed improvement in EFS with the HDC regimens and
apy, surgery, high-dose chemotherapy, and ASCR will be randomized to the addition of 13-cis-retinoic acid as continuation therapy; the group
receive 21 Gy to the preoperative tumor volume versus 21 Gy to the that received both interventions achieved a three-year EFS of 55%
preoperative tumor bed + 15 Gy boost to the residual tumor. compared with 18% for those that received neither.39 Subsequently,
COG ANBL0032 demonstrated improvement in two-year EFS from
46% to 66% with the addition of anti-GD2 antibody dinutuximab and
3.2.3 Metastatic site radiotherapy cytokines combined with cis-retinoic acid compared with cis-retinoic
acid alone. COG ANBL0532 demonstrated that the use of tandem
Radiation to a limited number of metastatic sites, in addition to the cycles of HDC with ASCR compared with a single cycle resulted in
primary site, is still controversial. Unlike COG trials, the SIOPEN improved three-year EFS of 63% vs 49%; high-dose regimens in this
strategy is to omit RT for metastatic disease because of a lack of clear study included carboplatin/etoposide/melphalan (CEM) with or with-
supporting data. In a retrospective analysis of SIOPEN data, patients out addition of thiotepa/cyclophosphamide (TC)6 (Figure. 1).
with more than three distinct spots or diffuse disease on MIBG scan Single-agent 131 I-MIBG at doses greater than 12 mCi/kg may result
had a significantly poorer outcome than patients with ≤ 3 distinct in disease response for over 30% of patients with relapsed and refrac-
spots after induction chemotherapy.37 These findings bolstered the tory neuroblastoma, and 131 I-MIBG has been used in the setting
S6 of S8 CHUNG ET AL .

FIGURE 1 Multidisciplinary treatments and HDC and stem cell transplant strategies adopted in recent COG and European protocols

of relapsed/refractory disease for several decades.39,40 Kraal et al. 4.2 Europe

showed that upfront therapy with 131 I-MIBG before systemic therapy
as per the German NB2004-HR protocol was feasible, tolerable, and Strong evidence from randomized trials supports use of several sys-
effective in newly diagnosed high-risk NBL patients.41 temic therapy regimens in the treatment of high-risk neuroblas-
More recently, 131 I-MIBG has been incorporated into pilot trials toma (Figure 1). Alkylating agents, platinum analogues, vinca alka-
after induction therapy in both Europe and the United States: COG loids, epipodophyllotoxins, and anthracyclines are considered standard
ANBL09P1 was a pilot study designating 15 mCi/kg as the appro- agents. Only a few new drugs have been introduced in recent years and
priate dose of this agent when given after completion of induction include topotecan, irinotecan, and temozolomide.46
chemotherapy and prior to ASCR. Earlier administration of 131 I-MIBG
The SIOPEN HR-NBL1 trial compared RAPID COJEC (vincristine,
is being studied in the randomized portion of the COG phase III carboplatin, etoposide, cisplatin, and cyclophosphamide) induction
trial, ANBL1531 (currently open to enrollment). Patients on this chemotherapy with the Memorial Sloan Kettering modified N7 regi-
study whose tumors are found to have aberrations in the ALK gene men (cyclophosphamide, doxorubicin, vincristine, cisplatin, and etopo-
(expected to be approximately 15% of newly diagnosed patients with side). Preliminary results showed no difference in survival and
high-risk disease)42 will receive standard multimodality therapy with metastatic response rates.47 However, RAPID COJEC was less toxic
the addition of the small-molecule ALK inhibitor crizotinib using a dose than the modified N7 regimen, so this regimen was selected to be
previously evaluated in ADVL0912.43 The ANBL1531 study is also the SIOPEN reference induction regimen. In the induction phase of
evaluating different HDC regimens used during consolidation therapy. the German (GPOH) NB2004-HR trial, patients were randomized
This study will randomize patients to receive the TC/CEM tandem reg- between six N5 (cisplatin, vindesine, and etoposide)-N6 (vincristine,
imen (that improved outcomes in the ANBL0532 study compared with dacarbazine, ifosfamide, and doxorubicin) cycles or the experimental
CEM alone) versus a single cycle of HDC busulfan/melphalan (Bu-Mel). induction chemotherapy having two additional topotecan-based cycles
The Bu-Mel conditioning regimen was found to be superior to a single (N8 [topotecan, cyclophosphamide, topotecan, and etoposide]-N5-N6
CEM transplant in European trials44 and found to be safe when used cycles). Final results of the trial are expected in 2020. The GPOH tri-
with U.S. regimens in the ANBL12P1 trial.45 Overall, the goals of the als NB97 and NB2004 utilize therapy with 131 I-MIBG for patients with
open ANBL1531 study are to (1) understand potential for improved residual MIBG-avid disease (either metastatic or at the primary site) at
outcomes based on addition of novel agents to induction regimens the end of induction therapy46 (Figure 1).
and (2) determine the optimal HDC conditioning regimen preceding The benefit of HDC consolidation was demonstrated in three
ASCR. randomized trials.46 Recent COG data also suggested that tandem
CHUNG ET AL . S7 of S8

intensification was feasible and could potentially benefit certain REFERENCES

patients.6 The VERITAS trial by SIOPEN randomizes very-high-risk 1. Maris JM. Recent advances in neuroblastoma. N Engl J Med.
neuroblastoma patients to single HDC with Bu-Mel versus tandem 2010;362:2202-2211.
2. Ward E, DeSantis C, Robbins A, Kohler B, Jemal A. Childhood and ado-
HDC with thiotepa and Bu-Mel, followed by ASCR, with the addition
lescent cancer statistics, 2014. CA Cancer J Clin. 2014;64:83-103.
of a 131 I-MIBG arm26 (Figure 1). 3. Goodman MT GJ, Smith MA, Olshan AF, Sympathetic nervous sys-
tem tumors. Cancer incidence and survival among children and adoles-
cents: United States SEER Program, 1975-1995. Bethesda, MD; 1999.
4. Neuroblastic tumours of adrenal gland and sympathetic nervous sys-
5 FUTURE RESEARCH AND DIRECTIONS
tem. Pathology and Genetics of Tumours of the Nervous System. Lyon:
IARC; 2000:153.
Despite significant progress in the treatment of children with high-risk 5. Angstman KB, Miser JS. Neuroblastoma. Am Fam Physician. 1990;41:
neuroblastoma, many children are not cured with the intensive multi- 238-244.
6. Park JR, Kreissman SG, London WB, et al. A phase III randomized clin-
modality therapy outlined above. In both North America and Europe,
ical trial (RCT) of tandem myeloablative autologous stem cell trans-
future trials will focus on improvements in induction therapy and opti-
plant (ASCT) using peripheral blood stem cell (PBSC) as consolidation
mization of HDC regimens. In North America, ANBL1531 is examining therapy for high-risk neuroblastoma (HR-NB): a Children’s Oncology
the introduction of 131 I-MIBG and crizotinib into induction regimens, Group (COG) study. J Clin Oncol. 2016;34:LBA3-LBA.
and recent data from the St. Jude Children’s Cancer Research Hospital 7. Cohn SL, Pearson AD, London WB, et al. The International Neurob-
lastoma Risk Group (INRG) classification system: an INRG task force
NB2012 trial indicate that immunotherapy can be safely combined
report. J Clin Oncol. 2009;27:289-297.
with induction chemotherapy.48 This approach is currently being stud- 8. Monclair T, Brodeur GM, Ambros PF, et al. The International Neurob-
ied in a multicenter COG pilot. The European SIOPEN HR-NBL2 trial lastoma Risk Group (INRG) staging system: an INRG Task Force report.
will aim to define the most effective chemotherapy induction regimen, J Clin Oncol 2009;27:298-303.
9. Du L, Liu L, Zhang C, et al. Role of surgery in the treatment of patients
comparing head-to-head RAPID COJEC and the GPOH N5-N6 regi-
with high-risk neuroblastoma who have a poor response to induction
mens. Efforts through COG and SIOPEN will also be directed toward chemotherapy. J Pediatr Surg. 2014;49:528-533.
understanding specific uses of tandem and single cycles of HDC using 10. La Quaglia MP. State of the art in oncology: high risk neuroblastoma,
different agents and in the setting of specific consolidation regimens. alveolar rhabdomyosarcoma, desmoplastic small round cell tumor, and
POST-TEXT 3 and 4 hepatoblastoma. J Pediatr Surg. 2014;49:233-240.
Future trials may aim to further individualize induction therapy, poten-
11. von Allmen D, Davidoff AM, London WB, et al. Impact of extent of
tially with inclusion of targeted antibodies with and without immune resection on local control and survival in patients from the COG
modulating cytokines. Increasing numbers of targeted small molecules A3973 study with high-risk neuroblastoma. J Clin Oncol 2017;35:208-
are being developed and tested in preclinical and clinical settings, and 216.
12. Newman EA, Abdessalam S, Aldrink JH, et al. Update on neuroblas-
may also be included in future pilot studies. Newer and potentially
toma. J Pediatr Surg. 2018.
more effective inhibitors of ALK signaling are being evaluated in the 13. Li R, Polishchuk A, DuBois S, et al. Patterns of relapse in high-risk neu-
setting of relapsed disease,49 and may soon be incorporated into front- roblastoma patients treated with and without total body irradiation.
line trials. Because studies have shown that aberrations in components Int J Radiat Oncol Biol Phys. 2017;97:270-277.
14. Haas-Kogan DA, Swift PS, Selch M, et al. Impact of radiotherapy for
of the MAPK signaling pathway are more common in tumors sam-
high-risk neuroblastoma: a Children’s Cancer Group study. Int J Radiat
pled at relapse compared with paired tumors from the same patient Oncol Biol Phys. 2003;56:28-39.
obtained at the time of diagnosis,50 considerable interest exists in 15. Haas-Kogan D, Douglas J, London WB, et al. Extent of lymph node radi-
the development of inhibitors of these molecules for neuroblastoma ation coverage in high-risk neuroblastoma does not affect clinical out-
therapy. come: a report from the COG A3973 study. Int J Radiat Oncol Biol Phys.
2014;90:S114.
Many questions remain regarding the optimal use of external beam
16. Children’s Oncology Group https://childrensoncologygroup.org/
radiotherapy—these include dose to primary site, particularly in the anbl1531. Accessed May 13, 2020.
setting of residual disease after induction chemotherapy and surgical 17. Liu KX, Naranjo A, Zhang FF, et al. Role of radiotherapy dose-
resection, and optimal treatment of persistent metastatic disease sites. escalation for high-risk neuroblastoma with post-surgical primary site
gross residual disease: a report from the COG ANBL0532 study. Int J
As systemic therapy continues to evolve, the role of LC and focused
Radiat Oncol Biol Phys. 2019;105(1):S3.
therapies require continued evaluation, recognizing that this disease 18. Casey DL, Kushner BH, Cheung NV, Modak S, LaQuaglia MP, Wolden
requires aggressive multimodality therapy in order to be cured, but also SL. Dose-escalation is needed for gross disease in high-risk neuroblas-
that optimal therapy may ultimately be highly individualized. toma. Pediatr Blood Cancer. 2018;65:e27009.
19. Lucas JT, Jr. Implications of image-defined risk factors and primary site
response on local control and radiation treatment delivery in the man-
CONFLICTS OF INTEREST agement of high risk neuroblastoma: is there a role for de-escalation
None. of adjuvant primary site radiotherapy. Int J Radiat Oncol Biol Phys. 2019
Mar 15;103(4):869-877.
20. Utriainen P, Vatanen A, Toiviainen-Salo S, Saarinen-Pihkala U, Maki-
ORCID
tie O, Jahnukainen K. Skeletal outcome in long-term survivors of child-
John Lucas https://orcid.org/0000-0002-4139-4160 hood high-risk neuroblastoma treated with high-dose therapy and
Barbara Hero https://orcid.org/0000-0003-4129-890X autologous stem cell rescue. Bone Marrow Transplant. 2017;52:711-
Christine E. Hill-Kayser https://orcid.org/0000-0002-1993-1185 716.
S8 of S8 CHUNG ET AL .

21. Elzembely MM, Dahlberg AE, Pinto N, et al. Late effects in high-risk roblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 tri-
neuroblastoma survivors treated with high-dose chemotherapy and als. Eur J Nucl Med Mol Imaging. 2018;45:292-305.
stem cell rescue. Pediatr Blood Cancer;2018:e27421. 38. Flandin I, Hartmann O, Michon J, et al. Impact of TBI on late effects in
22. Fahy AS, Roberts A, Nasr A, Irwin MS, Gerstle JT. Long term out- children treated by megatherapy for stage IV neuroblastoma. A study
comes after concurrent ipsilateral nephrectomy versus kidney-sparing of the French Society of Pediatric Oncology. Int J Radiat Oncol Biol Phys.
surgery for high-risk, intraabdominal neuroblastoma. J Pediatr Surg. 2006;64:1424-1431.
2019 Aug;54(8):1632-1637. 39. Matthay KK, Villablanca JG, Seeger RC, et al. Children’s Cancer Group.
23. Stone A, Novetsky Friedman D, Worgall S, et al. Long-term pulmonary Treatment of high-risk neuroblastoma with intensive chemotherapy,
outcomes in pediatric survivors of high-risk neuroblastoma. J Pediatr radiotherapy, autologous bone marrow transplantation, and 13-cis-
Hematol Oncol. 2017;39:547-554. retinoic acid. N Engl J Med. 1999;341:1165-1173.
24. Armstrong AE, Danner-Koptik K, Golden S, et al. Late effects in 40. DuBois SG, Matthay KK. Radiolabeled metaiodobenzylguanidine for
pediatric high-risk neuroblastoma survivors after intensive induction the treatment of neuroblastoma. Nucl Med Biol. 2008;35(Suppl 1):S35-
chemotherapy followed by myeloablative consolidation chemother- S48.
apy and triple autologous stem cell transplants. J Pediatr Hematol Oncol. 41. Kraal KC, Bleeker GM, van Eck-Smit BL, et al. Feasibility, toxicity
2018;40:31-35. and response of upfront metaiodobenzylguanidine therapy followed
25. Ng LW, Wong KK, Ally Wu CL, Sposto R, Olch AJ. Dose sculpting inten- by German Pediatric Oncology Group Neuroblastoma 2004 proto-
sity modulated radiation therapy for vertebral body sparing in children col in newly diagnosed stage 4 neuroblastoma patients. Eur J Cancer.
with neuroblastoma. Int J Radiat Oncol Biol Phys. 2018;101:550-557. 2017;76:188-196.
26. Turcotte LM, Whitton JA, Friedman DL, et al. Risk of subsequent neo- 42. Bresler SC, Weiser DA, Huwe PJ, et al. ALK mutations confer differ-
plasms during the fifth and sixth decades of life in the childhood cancer ential oncogenic activation and sensitivity to ALK inhibition therapy in
survivor study cohort. J Clin Oncol. 2015;33:3568-3575. neuroblastoma. Cancer Cell. 2014;26:682-694.
27. Kralik SF, Watson GA, Shih CS, Ho CY, Finke W, Buchsbaum J. 43. Mosse YP, Lim MS, Voss SD, et al. Safety and activity of crizotinib
Radiation-Induced large vessel cerebral vasculopathy in pediatric for paediatric patients with refractory solid tumours or anaplastic
patients with brain tumors treated with proton radiation therapy. Int large-cell lymphoma: a Children’s Oncology Group phase 1 consortium
J Radiat Oncol Biol Phys. 2017;99:817-824. study. Lancet Oncol. 2013;14:472-480.
28. Casey D, Kushner B, Cheung NK, Modak S, La Quaglia M, Wolden S. 44. Ladenstein R, Potschger U, Pearson ADJ, et al. Busulfan and mel-
Local control with reduced-dose radiation therapy for high-risk neu- phalan versus carboplatin, etoposide, and melphalan as high-dose
roblastoma: 3-year results from a prospective trial. Pediatr Blood Can- chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an
cer. 2018;65:S242. international, randomised, multi-arm, open-label, phase 3 trial. Lancet
29. Hattangadi JA, Rombi B, Yock TI, et al. Proton radiotherapy for high- Oncol. 2017;18:500-514.
risk pediatric neuroblastoma: early outcomes and dose comparison. Int 45. Granger M, Yanik GA, Naranjo A, et al. Myeloablative busul-
J Radiat Oncol Biol Phys. 2012;83:1015-1022. fan/melphalan (BuMel) consolidation following induction chemother-
30. DeWitt JC, Mock A, Louis DN. The 2016 WHO classification of cen- apy for patients with high-risk neuroblastoma: a Children’s Oncology
tral nervous system tumors: what neurologists need to know. Curr Opin Group (COG) study. J Clin Oncol. 2016;34:10528.
Neurol. 2017;30:643-649. 46. Amoroso L, Erminio G, Makin G, et al. Topotecan-vincristine-
31. Bradfield SM, Douglas JG, Hawkins DS, Sanders JE, Park JR. Fraction- doxorubicin in stage 4 high-risk neuroblastoma patients failing to
ated low-dose radiotherapy after myeloablative stem cell transplanta- achieve a complete metastatic response to rapid COJEC: a SIOPEN
tion for local control in patients with high-risk neuroblastoma. Cancer. study. Cancer Res Treat. 2018;50:148-155.
2004;100:1268-1275. 47. Garaventa A PU, Valteau-Couanet D, Castel V, Elliot M, Ash S, Chan G.
32. Casey DL, Pitter KL, Kushner BH, et al. Radiation therapy to sites Randomised induction for high-risk neuroblastoma comparing COJEC
of metastatic disease as part of consolidation in high-risk neuroblas- and the N5-MSKCC regimen. J. Clin Oncol. 36(15_suppl):10507-10507.
toma: can long-term control be achieved. Int J Radiat Oncol Biol Phys. 48. Furman WL, Federico SM, McCarville MB, et al. A phase II trial of
2018;100:1204-1209. Hu14.18K322A in combination with induction chemotherapy in chil-
33. Gatcombe HG, Marcus RB, Jr, Katzenstein HM, Tighiouart M, Esi- dren with newly diagnosed high-risk neuroblastoma. Clin Cancer Res.
ashvili N. Excellent local control from radiation therapy for high- 2019;25(21):6320-6328.
risk neuroblastoma. Int J Radiat Oncol Biol Phys. 2009;74:1549- 49. Goldsmith KC, Kayser K, Groshen SG, et al. Phase I trial of lorlatinib
1554. in patients with ALK-driven refractory or relapsed neuroblastoma:
34. Polishchuk AL, Li R, Hill-Kayser C, et al. Likelihood of bone recurrence a New Approaches to Neuroblastoma Consortium Study (Abstract).
in prior sites of metastasis in patients with high-risk neuroblastoma. Int J Clin Oncol. 2020;38(suppl):10504. abstr.
J Radiat Oncol Biol Phys. 2014;89:839-845. 50. Eleved TF, Oldridge DA, Bernard V, et al. Relapsed neuroblas-
35. Holmes K PU, Sarnacki S, Monclair T, Cecchetto G, Gomez Chacon J, tomas show frequent RAS-MAPK pathway mutations. Nat Genet.
et al. Influence of surgical excision on survival in high-risk neuroblas- 2015;47(8):864-871.
toma revisited after introduction of ch14.18/CHO Immunotherapy in
the HR-NBL1/SIOPEN Trial. ASCO2018.
36. Simon T, Hero B, Bongartz R, Schmidt M, Muller RP, Berthold F.
Intensified external-beam radiation therapy improves the outcome of How to cite this article: Chung C, Boterberg T, Lucas J, et al.
stage 4 neuroblastoma in children >1 year with residual local disease.
Neuroblastoma. Pediatr Blood Cancer. 2021;68:(Suppl. 2):
Strahlenther Onkol. 2006;182:389-394.
37. Ladenstein R, Lambert B, Potschger U, et al. Validation of the mIBG e28473. https://doi.org/10.1002/pbc.28473
skeletal SIOPEN scoring method in two independent high-risk neu-

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