SIOPPODC adapted risk stratification and treatment guidelines: Recommendations for neuroblastoma in low and middleincome settings



# Introduction
Neuroblastoma is the most common extracranial solid tumor in childhood in high-income countries (HIC), where it accounts for 10% of pediatric cancers [bib_ref] Trends in cancer incidence among children in the US, Gurney [/bib_ref]. However, in low-and middle-income countries (LMIC) with population-based registries, it accounts for only 1-3% of cancers, and in most LMIC its true incidence is unknown [bib_ref] The international incidence of childhood cancer, Parkin [/bib_ref] [bib_ref] International variations in the incidence of neuroblastoma, Stiller [/bib_ref] [bib_ref] Paediatric cancer in low-income and middle-income countries, Magrath [/bib_ref]. The limited available data suggest that in LMIC, late diagnosis, lack of access to accurate staging, risk stratification, optimal treatment, and abandonment lead to survival rates much lower than those in HIC [bib_ref] International variations in the incidence of neuroblastoma, Stiller [/bib_ref] [bib_ref] Neuroblastoma in Costa Rica: The experience with 76 cases treated at the..., Lobo-Sanahuja [/bib_ref] [bib_ref] Clinico-pathologic characteristics and treatment outcomes in children with neuroblastoma at the Kenyatta..., Kitonyi [/bib_ref] [bib_ref] Neuroblastoma in southern Africa: Epidemiological features, prognostic factors and outcome, Hesseling [/bib_ref] [bib_ref] Neuroblastoma in southern Brazil: An 11-year study, Parise [/bib_ref] [bib_ref] Neuroblastoma management in Chinese children, Li [/bib_ref]. With the Pediatric Oncology in Developing Countries (PODC) committee of the International Society of Pediatric Oncology (SIOP) working group for adapted treatment regimens, we developed these recommendations for adapted management of neuroblastoma.
This manuscript focuses on neuroblastoma, since general principles of adapted therapy have been previously reported [bib_ref] Treatment strategies and regimens of graduated intensity for childhood acute lymphoblastic leukemia..., Hunger [/bib_ref] [bib_ref] Committee S-PG-IRGW. SIOP-PODC recommendations for graduated-intensity treatment of retinoblastoma in developing countries, Chantada [/bib_ref] [bib_ref] Clinical guidelines for the management of children with Wilms tumour in a..., Israels [/bib_ref] [bib_ref] Recommendations for supportive care of children with cancer in a low-income setting, Israels [/bib_ref]. Optimizing treatment in LMIC at centers with variable capabilities and infrastructure requires adapting diagnostic methods, risk stratification, and therapy for children with neuroblastoma based on available resources [bib_ref] Treatment strategies and regimens of graduated intensity for childhood acute lymphoblastic leukemia..., Hunger [/bib_ref] [bib_ref] Committee S-PG-IRGW. SIOP-PODC recommendations for graduated-intensity treatment of retinoblastoma in developing countries, Chantada [/bib_ref] [bib_ref] Clinical guidelines for the management of children with Wilms tumour in a..., Israels [/bib_ref] [bib_ref] Recommendations for supportive care of children with cancer in a low-income setting, Israels [/bib_ref]. In [fig_ref] TABLE I: Resource Settings for Neuroblastoma Diagnosis, Staging, and Risk Stratification Pediatr Blood Cancer... [/fig_ref] , we defined each setting based on the minimal required resources to facilitate appropriate diagnosis and risk-stratified, intensity-adapted treatment. We have used the terminology ''Setting 1'' to represent centers with minimal resources, but with access to care and treatment with curative intent, while ''Setting 4'' represents centers with state-of-the-art diagnostic and treatment capability for highrisk neuroblastoma. Many countries, especially low-income countries (LIC), have extreme heterogeneity in resources available where some privately-funded centers may represent Setting 3, while nearby institutions may be Setting 1. A consistent approach to diagnosis and treatment that is adapted to local conditions and resource availability will improve the care of children in LMIC.

# Methods
A Global Neuroblastoma Network (GNN) subcommittee of pediatric oncologists from LMIC and HIC reviewed published evidence about treatment strategies for low-risk, intermediate-risk, and high-risk neuroblastoma and applied these strategies during weekly online Global Neuroblastoma Network (GNN) case discussions held via www.Cure4Kids.org. The subcommittee consensus recommendations are based on review of published evidence (using PubMed 1 ) for neuroblastoma diagnostics, risk assessments, prognostic markers, and treatment strategies combined with expert opinion about neuroblastoma and healthcare delivery in LMIC. The draft was reviewed by peers in HIC and LMIC and presented to a broad group of pediatric solid tumor experts via web conferences of the SIOP PODC working group on adapted treatment regimens, the annual SIOP meeting, and the GNN weekly online multidisciplinary conferences.
Neuroblastoma is the most common extracranial solid tumor in childhood in high-income countries (HIC), where consistent treatment approaches based on clinical and tumor biological risk stratification have steadily improved outcomes. However, in lowand middle-income countries (LMIC), suboptimal diagnosis, risk stratification, and treatment may occur due to limited resources and unavailable infrastructure. The clinical practice guidelines outlined in this manuscript are based on current published evidence and expert opinions. Standard risk stratification and treatment explicitly adapted to graduated resource settings can improve outcomes for children with neuroblastoma by reducing preventable toxic death and relapse. Pediatr Blood Cancer 2015;62:1305-1316.

## Diagnosis
The diagnosis of neuroblastoma is based on pathology with immunohistochemistry (IHC) complemented by urine catecholamines. In all settings, physical examination, basic laboratory, radiographic, and pathologic evaluation should be performed [fig_ref] TABLE I: Resource Settings for Neuroblastoma Diagnosis, Staging, and Risk Stratification Pediatr Blood Cancer... [/fig_ref]. Neuroblastoma should be suspected in children with cervical, mediastinal, paraspinal, abdominal or pelvic masses, and the diagnosis made by either biopsy of the primary tumor or by identification of characteristic tumor cells in the bone marrow. The presence of hypertension may suggest neuroblastoma or Wilms tumor. Elevated urine catecholamines, including urine homovanillic acid (HVA), vannilylmandelic acid (VMA), strongly suggest the diagnosis, and is helpful to distinguish among small round blue cell tumors [bib_ref] The international neuroblastoma pathology classification (the shimada system), Shimada [/bib_ref]. Conversely, if urine catecholamines are not available or are non-diagnostic, neuroblastoma can be differentiated from other small round blue cell tumors using IHC staining for tyrosine hydroxylase, CD56, and synaptophysin. Alternative diagnosis should be considered for IHC positive staining for leukocyte common antigen CD45 in lymphoma, CD99 in Ewing sarcoma, and desmin and myogenin in rhabdomyosarcoma [bib_ref] Immunohistochemical findings in embryonal small round cell tumors with molecular diagnostic confirmation, Sebire [/bib_ref]. In Setting 1, IHC is usually not available, and the treating doctor will have to rely on a combination of the pathologic appearance and typical clinical features (e.g., age at diagnosis, symptoms, sites of disease, sites of metastases, lack of response to glucocorticoid therapy).

## Staging and response evaluation
Accurate staging and response evaluation are essential for determining treatment and prognosis [fig_ref] TABLE I: Resource Settings for Neuroblastoma Diagnosis, Staging, and Risk Stratification Pediatr Blood Cancer... [/fig_ref]. In all settings, bilateral bone marrow aspirate and biopsy should be performed to detect bone marrow metastases, which occur in 70% of metastatic neuroblastoma patients [bib_ref] Metastatic sites in stage IV and IVS neuroblastoma correlate with age, tumor..., Dubois [/bib_ref]. Radiologic and surgical staging depend on locally available resources: Advance imaging, including magnetic resonance imaging (MRI), 123 I-metaiodobenzylguanidine ( 123 I-mIBG) scans, and 18 FDG-PET have increased the accuracy of diagnosis and staging and facilitate local control with surgery and radiotherapy, but due to high cost, are inconsistently available in LMIC [bib_ref] 123I-MIBG versus 18F-FDG: Which is better, or which can be eliminated?, Sharp [/bib_ref] [bib_ref] Criteria for evaluation of disease extent by (123)I-metaiodobenzylguanidine scans in neuroblastoma: A..., Matthay [/bib_ref]. Surgical staging of the primary tumor is according to the International Neuroblastoma Staging System (INSS-Supplemental Appendix I) [bib_ref] Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to..., Brodeur [/bib_ref]. The recent International Neuroblastoma Risk Group (INRG-Supplemental Appendix I) staging system is a simpler, radiologic staging, which is not influenced by degree of resection [bib_ref] Pearson AD, Force IT. The International Neuroblastoma Risk Group (INRG) staging system:..., Monclair [/bib_ref].

## Setting 1
Staging and response assessment depend on imaging studies and bilateral bone marrow biopsy with simple hematoxylin and eosin staining to document presence of disease [fig_ref] TABLE I: Resource Settings for Neuroblastoma Diagnosis, Staging, and Risk Stratification Pediatr Blood Cancer... [/fig_ref]. Plain radiographs and abdominal ultrasound can document the extent of thoracic and abdominal disease [bib_ref] Treatment of localised resectable neuroblastoma. Results of the LNESG1 study by the..., Bernardi [/bib_ref] , but are suboptimal for staging and pre-operative planning due to their lack of sensitivity to detect small metastatic lesions in lymph nodes or lungs. Evaluation for bone disease should include bone radiographs (e.g., a skeletal survey), with the understanding that plain radiographs are less sensitive (26% lesions identified) than bone scan (59% lesions identified) to detect skeletal involvement [bib_ref] Radionuclide skeletal survey in neuroblastoma, Howman-Giles [/bib_ref] [bib_ref] Radiographic and scintigraphic skeletal imaging in patients with neuroblastoma: Concise communication, Baker [/bib_ref].

## Setting 2
Computerized tomography (CT) of neck, chest, abdomen, and pelvis with intravenous contrast combined with 99m Tc phosphonate nuclear imaging provides greater sensitivity of anatomic location, associated radiologic risk factors for surgery, and metastasis [fig_ref] TABLE I: Resource Settings for Neuroblastoma Diagnosis, Staging, and Risk Stratification Pediatr Blood Cancer... [/fig_ref]. CT is more sensitive for bone involvement than plain radiographs. If spinal involvement is suspected, magnetic resonance imaging (MRI), if available, should be obtained to assess invasion of the neural foramina and spinal cord compression.

## Setting 3
In Setting 3, the neuroblastoma staging and risk classification should include CT of neck, chest, abdomen, and pelvis with intravenous contrast; MRI of sites with suspected spinal involvement and sites where tumor extent is not well defined by CT; and 123 I-mIBG scans, or 18 FDG-PET [fig_ref] TABLE I: Resource Settings for Neuroblastoma Diagnosis, Staging, and Risk Stratification Pediatr Blood Cancer... [/fig_ref]. 123 I-mIBG, which is taken up via the norepinephrine transporter in 90% of patients with neuroblastoma [bib_ref] Criteria for evaluation of disease extent by (123)I-metaiodobenzylguanidine scans in neuroblastoma: A..., Matthay [/bib_ref] is the most sensitive and specific test for metastatic disease in bone or soft tissue. An 18 FDG-PET scan is also sensitive, but less specific than mIBG for neuroblastoma but can be used in patients whose tumors are 123 I-mIBG negative or when 123 I-mIBG scans are unavailable [bib_ref] 123I-MIBG versus 18F-FDG: Which is better, or which can be eliminated?, Sharp [/bib_ref].

## Risk stratification
In the past two decades, risk stratification using clinical and tumor biological features has facilitated intensity-adjusted neuroblastoma therapy with resultant improvements in outcomes and decreased complications in HIC [bib_ref] Treatment of localised resectable neuroblastoma. Results of the LNESG1 study by the..., Bernardi [/bib_ref] [bib_ref] Significance of MYCN amplification in international neuroblastoma staging system stage 1 and..., Bagatell [/bib_ref] [bib_ref] Outcome after reduced chemotherapy for intermediate-risk neuroblastoma, Baker [/bib_ref] [bib_ref] Biologic variables in the outcome of stages I and II neuroblastoma treated..., Perez [/bib_ref] [bib_ref] New definition of low-risk neuroblastoma using stage, age, and 1p and MYCN..., Simon [/bib_ref]. Established prognostic markers utilized over the past two decades include clinical features such as stage, age, serum lactate dehydrogenase (LDH), serum ferritin; tumor histological classification; and tumor biologic features of MYCN gene amplification status, DNA ploidy and segmental chromosomal aberrations [bib_ref] International consensus for neuroblastoma molecular diagnostics: Report from the International Neuroblastoma Risk..., Ambros [/bib_ref] [bib_ref] Segmental chromosomal alterations have prognostic impact in neuroblastoma: A report from the..., Schleiermacher [/bib_ref] [bib_ref] The International Neuroblastoma Risk Group (INRG) classification system: An INRG Task Force..., Cohn [/bib_ref].
Histologic classification according to International Neuroblastoma Pathology Classification (INPC) could be helpful in all settings to guide risk stratification [bib_ref] The international neuroblastoma pathology classification (the shimada system), Shimada [/bib_ref]. Unfortunately, INPC has been underutilized in LMIC due to shortages of trained pathologists familiar with pediatric malignancy and INPC. Fluorescent in situ hybridization (FISH) or RT-PCR for tumor MYCN gene amplification is desirable, but are most essential in risk stratification for children with stage 4 tumor in patients <18 months of age, and for all stage 3 tumors. DNA ploidy is most helpful in infants without MYCN amplified disease, who have stage 4 or 4 S disease, as patients with diploid tumors have significantly lower survival, and may require more intensive therapy [bib_ref] Hyperdiploidy plus nonamplified MYCN confers a favorable prognosis in children 12 to..., George [/bib_ref] [bib_ref] Prognostic value of the stage 4S metastatic pattern and tumor biology in..., Taggart [/bib_ref].

## Prognosis
In HIC, children with localized disease and favorable biology tumors (INSS 1, 2, and 4 S or INRG L1, and MS) have an overall survival (OS) of 96% with surgery alone, or in some cases observation only [bib_ref] Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to..., Brodeur [/bib_ref] [bib_ref] Pearson AD, Force IT. The International Neuroblastoma Risk Group (INRG) staging system:..., Monclair [/bib_ref] [bib_ref] Treatment of localised resectable neuroblastoma. Results of the LNESG1 study by the..., Bernardi [/bib_ref] [bib_ref] The International Neuroblastoma Risk Group (INRG) classification system: An INRG Task Force..., Cohn [/bib_ref] [bib_ref] Outcome after surgery alone or with restricted use of chemotherapy for patients..., Strother [/bib_ref] [bib_ref] A prospective study of expectant observation as primary therapy for neuroblastoma in..., Nuchtern [/bib_ref]. In the intermediate risk group, comprising of infants with metastatic disease or infants and children with unresectable (INSS 3 or INRG L2) disease without tumor MYCN amplification, the OS remains greater than 90% when treated with 3-6 months of outpatient chemotherapy of moderate intensity [bib_ref] Outcome after reduced chemotherapy for intermediate-risk neuroblastoma, Baker [/bib_ref]. Yet in LMIC, survival rates even for localized disease is usually lower [bib_ref] Neuroblastoma in Costa Rica: The experience with 76 cases treated at the..., Lobo-Sanahuja [/bib_ref] [bib_ref] Clinico-pathologic characteristics and treatment outcomes in children with neuroblastoma at the Kenyatta..., Kitonyi [/bib_ref] [bib_ref] Neuroblastoma in southern Africa: Epidemiological features, prognostic factors and outcome, Hesseling [/bib_ref] perhaps due to inaccurate staging or risk stratification. Lack of access to biologic risk classification may lead to over-treatment and higher risk of death from aggressive surgical, toxicity, or treatment abandonment. Treating high-risk disease, comprised mainly of children >18 months with stage 3 and 4
Pediatr Blood Cancer DOI 10.1002/pbc disease and any stage with MYCN amplified tumors is challenging even in HIC, with OS of 40% using modern protocols in settings with excellent supportive care [bib_ref] Outcomes of the POG 9340 /9341/9342 trials for children with high-risk neuroblastoma:..., Zage [/bib_ref] [bib_ref] Disseminated neuroblastoma in children older than one year at diagnosis: Comparable results..., Bernardi [/bib_ref] [bib_ref] Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: Results of German..., Simon [/bib_ref] [bib_ref] Long-term results for children with high-risk neuroblastoma treated on a randomized trial..., Matthay [/bib_ref] [bib_ref] High-dose rapid and standard induction chemotherapy for patients aged over 1 year..., Pearson [/bib_ref]. Due to economic, social, and health system factors, high-risk patients typically form a greater proportion of patients diagnosed with neuroblastoma in LMIC than HIC. In LMIC, especially in Setting 1 centers, high risk patient are often not treated with curative intent, since expected survival rates would be <10% [bib_ref] Neuroblastoma in Costa Rica: The experience with 76 cases treated at the..., Lobo-Sanahuja [/bib_ref] [bib_ref] Clinico-pathologic characteristics and treatment outcomes in children with neuroblastoma at the Kenyatta..., Kitonyi [/bib_ref].

## Adapted risk stratification
Guidelines for risk stratification are shown in [fig_ref] TABLE I: Resource Settings for Neuroblastoma Diagnosis, Staging, and Risk Stratification Pediatr Blood Cancer... [/fig_ref]. Age and stage continue to be the strongest clinical prognostic factors for neuroblastoma. Age <18 months implies favorable disease, even in the presence of metastases, provided there is no tumor MYCN gene amplification [bib_ref] The International Neuroblastoma Risk Group (INRG) classification system: An INRG Task Force..., Cohn [/bib_ref] [bib_ref] Favorable prognosis for patients 12 to 18 months of age with stage..., Schmidt [/bib_ref]. In Setting 3, where INPC classification may be performed, toddlers age 12-18 months with stage 4 disease with Unfavorable Histology (if available) and/or diploidy/hypodiploidy should be considered to have high-risk disease even without MYCN amplification. However, toddlers with stage 3 disease without MYCN amplification should still be treated on the intermediate risk protocol, as the benefit of transplant is not clearly defined [bib_ref] Significance of clinical and biologic features in Stage 3 neuroblastoma: A report..., Meany [/bib_ref]. Children !18 months of age with stage 4 disease should be treated as high-risk, without further need for biologic or clinical markers [bib_ref] The International Neuroblastoma Risk Group (INRG) classification system: An INRG Task Force..., Cohn [/bib_ref].
One significant limitation in LMIC is the inability to assess MYCN amplification in some centers, despite the fact that it is present in approximately 25% of patients [bib_ref] The International Neuroblastoma Risk Groups (INRG): A preliminary report, Castleberry [/bib_ref] and is critical to differentiate between intermediate and high-risk disease for patients <18 months with stage 4 disease, and for all patients with stage 3 disease [bib_ref] The International Neuroblastoma Risk Group (INRG) classification system: An INRG Task Force..., Cohn [/bib_ref]. Although MYCN amplification in stage 1, 2, and 4 S tumors could potentially change the risk group, it is uncommon in this group [bib_ref] Significance of MYCN amplification in international neuroblastoma staging system stage 1 and..., Bagatell [/bib_ref]. When MYCN assessment is not available, we would consider use of serum LDH and serum ferritin as surrogate markers for MYCN amplification in INSS stage 3 and 4 disease. In Children's Cancer Group Study 3891, 70 eligible newly diagnosed patients with Evans stage 3 disease were evaluated for ferritin as a prognostic marker, demonstrating 5-year EFS 38 AE 9% for patients with ferritin >143 ng/ml versus 78 AE 8% for those with ferritin <143 ng/ml [bib_ref] Significance of clinical and biologic features in Stage 3 neuroblastoma: A report..., Meany [/bib_ref] [bib_ref] Outcome of high-risk stage 3 neuroblastoma with myeloablative therapy and 13-cis-retinoic acid:..., Park [/bib_ref]. A review of INRG database identified 1483 INSS stage 3 patients, of which ferritin was known in 666 patients, and LDH in 959 patients. Five-year EFS associated with ferritin <96 ng/ml versus !96 ng/ml was 77 AE 3% versus 61 AE 4%, respectively (P 14 <0.0001), while the 5-year EFS for patients with LDH <580 U/L versus !580 U/L was 78 AE 2% versus 67 AE 3%, respectively (P 14 <0.0001) [bib_ref] Significance of clinical and biologic features in Stage 3 neuroblastoma: A report..., Meany [/bib_ref]. Therefore, any patient with stage 3 disease and those <18 months with stage 4 disease whose LDH and/or ferritin exceed this threshold may be stratified as high-risk [bib_ref] Prognostic value of the stage 4S metastatic pattern and tumor biology in..., Taggart [/bib_ref] [bib_ref] Significance of clinical and biologic features in Stage 3 neuroblastoma: A report..., Meany [/bib_ref] [bib_ref] Outcome of high-risk stage 3 neuroblastoma with myeloablative therapy and 13-cis-retinoic acid:..., Park [/bib_ref] [bib_ref] Serum lactate dehydrogenase in childhood neuroblastoma. A Pediatric Oncology Group recursive partitioning..., Shuster [/bib_ref] [bib_ref] Neuroblastoma a single institution's experience with 128 children and an evaluation of..., Lau [/bib_ref]. If we had to determine a single marker, LDH would be arbitrarily used, as that has the most literature support. The reported threshold at which elevated LDH serves as a prognostic marker varies from >580 IU/L to >1000 IU/L [bib_ref] Significance of clinical and biologic features in Stage 3 neuroblastoma: A report..., Meany [/bib_ref] [bib_ref] Prognostic value of ferritin, neuron-specific enolase, lactate dehydrogenase, and urinary and plasmatic..., Cangemi [/bib_ref] ; therefore, we recommend the intermediate level of 750 IU/L to intensify therapy in LMIC when MYCN status is unknown. The reported threshold at which elevated ferritin has been shown to affect outcome has varied, from >92 ng/ml to >142 ng/ml [bib_ref] The International Neuroblastoma Risk Group (INRG) classification system: An INRG Task Force..., Cohn [/bib_ref] [bib_ref] Prognostic value of ferritin, neuron-specific enolase, lactate dehydrogenase, and urinary and plasmatic..., Cangemi [/bib_ref] [bib_ref] Prognostic importance of serum ferritin in patients with Stages III and IV..., Hann [/bib_ref] ; therefore we recommend considering a pre-treatment ferritin !120 ng/ml to intensify therapy in LMIC when MYCN status is unknown. For both ferritin and LDH, we chose to use an intermediate rather than the highest value as the proposed threshold, acknowledging differences in laboratory ranges while noting that the largest INRG analysis used the lower value. LDH and ferritin assessments are of uncertain prognostic significance in patients with INSS 1, 2, or 4 S tumors, and therefore not recommended for changing the risk category in those patients [bib_ref] Treatment of localised resectable neuroblastoma. Results of the LNESG1 study by the..., Bernardi [/bib_ref] [bib_ref] Significance of MYCN amplification in international neuroblastoma staging system stage 1 and..., Bagatell [/bib_ref] [bib_ref] New definition of low-risk neuroblastoma using stage, age, and 1p and MYCN..., Simon [/bib_ref] [bib_ref] The International Neuroblastoma Risk Group (INRG) classification system: An INRG Task Force..., Cohn [/bib_ref] [bib_ref] Outcome after surgery alone or with restricted use of chemotherapy for patients..., Strother [/bib_ref].

## Treatment guidelines
Treatment guidelines according to risk group and setting are outlined in [fig_ref] TABLE I: Resource Settings for Neuroblastoma Diagnosis, Staging, and Risk Stratification Pediatr Blood Cancer... [/fig_ref].

## Low risk disease
In patients with INSS 1 and 2 tumors, the outcome is excellent, with >95% 3 year OS [bib_ref] Biologic variables in the outcome of stages I and II neuroblastoma treated..., Perez [/bib_ref] [bib_ref] Results of pediatric oncology group protocol 8104 for infants with stages D..., Strother [/bib_ref]. Regardless of setting, surgical resection is sufficient for asymptomatic patients whose tumor is largely (>50%) resected, even if some residual tumor remains. Patients with tumor resection can be monitored without further therapy, with ultrasound or CT every 3 months for the 1st year and then every 6 months until 2 years after diagnosis [bib_ref] Biologic variables in the outcome of stages I and II neuroblastoma treated..., Perez [/bib_ref]. Perinatal adrenal neuroblastoma (Very Low Risk-VLR) patients, with small adrenal masses detected before birth or within the first six post-natal months, have an especially favorable outcome with >95% 4 year OS, without any surgical or medical intervention [bib_ref] A prospective study of expectant observation as primary therapy for neuroblastoma in..., Nuchtern [/bib_ref]. We recommend monitoring these patients with ultrasonography and physical exam every 6-8 weeks, until the mass resolves, or until significant growth warrants surgical resection. Occasionally, these patients will progress to INSS 4 S, but they can be safely observed as long as they remain asymptomatic [bib_ref] Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or..., Nickerson [/bib_ref] [bib_ref] Localized infant neuroblastomas often show spontaneous regression: Results of the prospective trials..., Hero [/bib_ref].
Infants with stage 4 S asymptomatic disease have an overall 5 years survival 100% for those patients that did not require chemotherapy [bib_ref] Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or..., Nickerson [/bib_ref]. For patients with symptomatic stage 4 S neuroblastoma with hepatic dysfunction, coagulopathy, respiratory compromise, or renal impairment, we recommend treatment with intermediate risk therapy. Infants younger than 3 months with hepatomegaly even without symptoms deserve prompt intermediate risk treatment until symptoms abate due to the higher risk of death at this age [bib_ref] Prognostic value of the stage 4S metastatic pattern and tumor biology in..., Taggart [/bib_ref] [bib_ref] Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or..., Nickerson [/bib_ref].

## Intermediate risk disease
There have been significant advances in the therapies for children with intermediate risk neuroblastoma, allowing deintensification of therapy while maintaining survival. Children with stage 3 intermediate risk neuroblastoma or infants with stage 4 were treated in the 1990s with cisplatin, etoposide, doxorubicin, and cyclophosphamide over 9 months, with a 4-year EFS of 100% for favorable stage 3 [bib_ref] Successful treatment of stage III neuroblastoma based on prospective biologic staging: A..., Matthay [/bib_ref] and 3-year EFS >93% for infants with INSS 4, MYCN-Non amplified disease [bib_ref] Biologic factors determine prognosis in infants with stage IV neuroblastoma: A prospective..., Schmidt [/bib_ref]. The poor prognostic indicators identified in the infant group were diploid and/or MYCN-amplified tumors [bib_ref] Hyperdiploidy plus nonamplified MYCN confers a favorable prognosis in children 12 to..., George [/bib_ref] [bib_ref] Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood..., Look [/bib_ref]. A French cooperative trial showed that INSS 3 infants without MYCN gene amplification had a 94 AE 5% EFS with moderate-intensity chemotherapy [bib_ref] Localised and unresectable neuroblastoma in infants: Excellent outcome with low-dose primary chemotherapy, Rubie [/bib_ref]. A large INRG report showed that patients with INSS stage 3 tumors without MYCN amplification had an 81% 5-year EFS [bib_ref] Significance of clinical and biologic features in Stage 3 neuroblastoma: A report..., Meany [/bib_ref].
Therapy has since been modified to shorten the course of treatment, substitute carboplatin for cisplatin, and decrease the cumulative doses of active agents by 60% in an effort to decrease toxicities, hospital stay, and costs, while maintaining survival outcomes, with 88% 3-year EFS and 96% OS [bib_ref] Outcome after reduced chemotherapy for intermediate-risk neuroblastoma, Baker [/bib_ref]. In settings where [bib_ref] Outcome after reduced chemotherapy for intermediate-risk neuroblastoma, Baker [/bib_ref]. We recommend dose reduction as outlined in [fig_ref] TABLE I: Resource Settings for Neuroblastoma Diagnosis, Staging, and Risk Stratification Pediatr Blood Cancer... [/fig_ref] according to availability of resources given the typically favorable outcome and potential need to conserve blood products.
Aggressive surgery may cause significant morbidity in patients with intermediate risk neuroblastoma. Of 235 children with intermediate risk group on the COG A3961 trial, 28% had surgical complications including major hemorrhage, vascular and renal injuries, and intra-operative need for organ resection [bib_ref] Outcome after reduced chemotherapy for intermediate-risk neuroblastoma, Baker [/bib_ref]. Subsequent pilot investigations showed that intermediate risk patients will often mature without progression despite residual unresected tumor [bib_ref] The significance of serial histopathology in a residual mass for outcome of..., Marachelian [/bib_ref]. Given the high survival rate for the intermediate group regardless of resection extent [bib_ref] Prognostic importance of serum ferritin in patients with Stages III and IV..., Hann [/bib_ref] , we recommend chemotherapy for 4-8 cycles depending on control of metastases and tumor reduction with conservative surgery performed if needed to achieve >50% primary tumor response. Radiation therapy is not recommended even in the setting of residual disease. Patients can be monitored with ultrasound or CT every 3-months for the 1st year and then every 6 months until 2 years after diagnosis.

## High risk disease
Despite numerous advances and multimodal therapies in the treatment of children with neuroblastoma, those with high-risk disease continue to be our greatest challenge. The incorporation of three distinct phases of therapy has improved outcome for high-risk neuroblastoma: intensive induction treatment, myeloablative chemotherapy with autologous hematopoietic stem cell rescue, and treatment of MRD [bib_ref] Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation,..., Matthay [/bib_ref] [bib_ref] Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma, Yu [/bib_ref] [bib_ref] Long-term results and risk profiles of patients in five consecutive trials (1979-1997)..., Berthold [/bib_ref]. The goal of induction therapy is to achieve maximum reduction of tumor burden, including reduction of metastatic bone marrow, and bone disease within a timeframe that will minimize the risk of developing resistant tumor clones and clinical progression. Subsequently, potentially resistant residual tumor is treated with high-dose myeloablative therapy followed by autologous hematopoietic stem cell transplantation (ASCT), which has been shown to significantly improve EFS [bib_ref] Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation,..., Matthay [/bib_ref]. The relapse rate of greater than 40% even after such therapies has led to post-transplant treatment for MRD-positive patients using isotretinoin and monoclonal anti-GD2 antibodies [bib_ref] Long-term results for children with high-risk neuroblastoma treated on a randomized trial..., Matthay [/bib_ref] [bib_ref] Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation,..., Matthay [/bib_ref] [bib_ref] Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma, Yu [/bib_ref].
Due to the lack of transplant expertise, reduced access to blood products and pheresis, and difficulty supporting patients through the period of myelosuppression, few Setting 1 centers in LMIC have attempted curative treatment of high-risk neuroblastoma, and have commonly prescribed palliative care. Furthermore, the cost of isotretinoin and lack of access to monoclonal anti-GD2 antibody impede effective MRD treatment in some LMIC. However, a coordinated treatment approach based on resource capabilities can improve outcome for these children progressively, and will eventually lead to overall improvement in supportive care and therapy of childhood cancer. We propose a graduated intensity plan for high-risk patients in different LMIC settings [fig_ref] TABLE I: Resource Settings for Neuroblastoma Diagnosis, Staging, and Risk Stratification Pediatr Blood Cancer... [/fig_ref].

## Induction and local control
No single chemotherapy induction regimen has proven to be superior for induction response and EFS in high-risk neuroblastoma. All regimens reported to date employ multi-agent chemotherapy with a platinum agent, alkylator therapy such as cyclophosphamide, topoisomerase therapy, usually with etoposide or less frequently, doxorubicin, and vincristine. Initial reports suggested that increasing dose intensity might improve response rate, but this has not been borne out in single arm trials which all showed response rates from 70 to 80% [bib_ref] Long-term results for children with high-risk neuroblastoma treated on a randomized trial..., Matthay [/bib_ref] [bib_ref] Results of induction chemotherapy in children older than 1 year with a..., Valteau-Couanet [/bib_ref] [bib_ref] Feasibility of a tandem autologous peripheral blood stem cell transplant regimen for..., Granger [/bib_ref] [bib_ref] N7: A novel multi-modality therapy of high risk neuroblastoma (NB) in children..., Cheung [/bib_ref]. The dose-intensive rapid COJEC [bib_ref] Randomized Trial of prophylactic granulocyte colony-stimulating factor during rapid COJEC induction in..., Ladenstein [/bib_ref] did show an improvement in EFS compared in a randomized trial to OPEC-OJEC, though the 3-year EFS of 31% was not better than that reported with other North American and European regimens [bib_ref] High-dose rapid and standard induction chemotherapy for patients aged over 1 year..., Pearson [/bib_ref].
Given the increased need for supportive care with more intensive regimens and without significant benefit expected for patients without the option of myeloablative therapy, we have recommended induction regimens in Setting 1 using a regimen with low dose metronomic oral cyclophosphamide 25 mg/m 2 daily (max 50 mg) or oral etoposide 50 mg/m 2 /day for palliation of pain and improvement of quality of life, High Risk Setting 1 (HR-1) [bib_ref] A phase I study of zoledronic acid and low-dose cyclophosphamide in recurrent/refractory..., Russell [/bib_ref] [bib_ref] A phase II trial of a multi-agent oral antiangiogenic (metronomic) regimen in..., Robison [/bib_ref]. An alternate approach non-curative therapy would entail administering 1-2 cycles of intermediate risk chemotherapy and local radiation to the primary tumor bed (dosing per Tables III and V) to allow for some tumor reduction, pain relief and improved quality of life. Aggressive pain management is strongly recommended, as end-oflife bone pain can be significant [bib_ref] Pain management in children with advanced cancer and during end-of-life care, Friedrichsdorf [/bib_ref].
For Setting 2, we recommend either the same regimen used for intermediate risk patients, [fig_ref] TABLE I: Resource Settings for Neuroblastoma Diagnosis, Staging, and Risk Stratification Pediatr Blood Cancer... [/fig_ref] , for 8 cycles or modified-Pediatric Oncology Group (POG) 9341 induction regimen, [fig_ref] TABLE I: Resource Settings for Neuroblastoma Diagnosis, Staging, and Risk Stratification Pediatr Blood Cancer... [/fig_ref] [bib_ref] Outcome after reduced chemotherapy for intermediate-risk neuroblastoma, Baker [/bib_ref] [bib_ref] Outcomes of the POG 9340 /9341/9342 trials for children with high-risk neuroblastoma:..., Zage [/bib_ref]. For Setting 3, we suggest the modified-POG 9341 induction regimen, which is more intensive than prior French CAdO-PE [bib_ref] NB87 induction protocol for stage 4 neuroblastoma in children over 1 year..., Coze [/bib_ref] , and has fewer reported acute toxicities than N7 [bib_ref] N7: A novel multi-modality therapy of high risk neuroblastoma (NB) in children..., Cheung [/bib_ref] or the SIOPEN rapid COJEC [bib_ref] High-dose rapid and standard induction chemotherapy for patients aged over 1 year..., Pearson [/bib_ref]. It optimizes platinum, uses less doxorubicin, and has shorter hospitalization (primarily given in a day hospital) and higher response rate than the CCG 3891 protocol [bib_ref] Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation,..., Matthay [/bib_ref]. This protocol is currently being used in Morocco for high-risk patients and has been tolerable in >60 patients without toxic death. An alternative option is to administer the OPEC-OJEC regimen that incorporates more carboplatin but avoids doxorubicin; although response rates are lower than those reported for POG 9341 [bib_ref] High-dose rapid and standard induction chemotherapy for patients aged over 1 year..., Pearson [/bib_ref]. Surgery to resect the primary tumor is recommended after the 4th or 5th induction cycle in patients, whose metastases have responded significantly to chemotherapy, including either a complete metastatic response or a partial response (PR) and fewer than six residual bone metastases that might be treated with radiotherapy. In a review of patients with high risk neuroblastoma on the CCG A3891 trial, a statistically significant improvement was noted in patients with stage 4 neuroblastoma achieving complete remission after surgery with a 5 year EFS 26% AE 4% versus 19% AE 3% [bib_ref] Efficacy of complete resection for high-risk neuroblastoma: A Children's Cancer Group study, Adkins [/bib_ref] although there are conflicting evidence as to the benefit of complete resection when radiotherapy is also incorporated [bib_ref] Role of surgery in the treatment of patients with high-risk neuroblastoma who..., Du [/bib_ref] [bib_ref] Role of surgery in the treatment of patients with stage 4 neuroblastoma..., Simon [/bib_ref]. Given the minimal likely benefit, we recommend avoiding mutilating surgery likely to risk major complications in LMIC and instead using radiation therapy to control unresectable primary tumor and residual bone metastases.
The decision to proceed to a more intensive consolidation should be based on the response to induction chemotherapy. Multiple analyses of myeloablative regimens show that the outcome is significantly better for patients who have achieved at least a partial response at the end of induction [bib_ref] The prognostic impact of functional imaging with (123)I-mIBG in patients with stage..., Schmidt [/bib_ref] , and preferably a good partial response in metastases as manifested by a low MIBG Curie score [bib_ref] Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4..., Yanik [/bib_ref]. Doses are adjusted to mg/kg for infants <10 kg. For Setting 1, it is recommended to reduce the dose so that only 80% of indicated dose is given, to reduce the likelihood of fever and neutropenia or platelet requirements. d After 4 cycles, evaluate for surgery, obtain CBC, creatinine, urinalysis CT, mIBG. The goal of therapy is to achieve resolution of metastases and primary tumor response of >50% with chemotherapy and surgery.
Pediatr Blood Cancer DOI 10.1002/pbc

## Consolidation
The recommended consolidation for curative intent is myeloablative therapy with ASCT, based on three randomized trials [bib_ref] Long-term results for children with high-risk neuroblastoma treated on a randomized trial..., Matthay [/bib_ref] [bib_ref] Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation..., Berthold [/bib_ref] [bib_ref] High dose melphalan in the treatment of advanced neuroblastoma: Results of a..., Pritchard [/bib_ref].
Preliminary results from the European SIOP-EN HR NBL-1 randomized phase III trial comparing busulfan and melphalan (Bu/ Mel) versus carboplatin, etoposide, and melphalan (CEM) as a preparative regimen for autologous transplant, showed improved survival in patients treated on the Bu/Mel arm [bib_ref] Final Results from the HR-NBL1/SIOPEN trial favour Busulphan-Melphalan as Superior Myeloablativ Therapy..., Ladenstein [/bib_ref] [bib_ref] Long-term results of the combination of the N7 induction chemotherapy and the..., Valteau-Couanet [/bib_ref] [bib_ref] Busulfan and melphalan as consolidation therapy with autologous peripheral blood stem cell..., Soni [/bib_ref]. Due to its lesser toxicity and apparently better EFS, we recommend that Setting 3 centers with transplant capabilities utilize either BuMel, (Supplemental Appendix II), or consider melphalan alone (180 mg/ m 2 ), as this is the active agent that has been the backbone of almost all neuroblastoma transplant regimens, and was successful in the first randomized trial [bib_ref] High dose melphalan in the treatment of advanced neuroblastoma: Results of a..., Pritchard [/bib_ref]. One caveat for those utilizing the Bu/Mel regimen is the higher risk of sinusoidal obstructive syndrome (SOS), which may be more severe in LMIC where options for potential prophylaxis or treatment such as defibrotide are not readily available [bib_ref] Busulfan pharmacokinetics following intravenous and oral dosing regimens in children receiving highdose..., Veal [/bib_ref].
We recommend that high-risk patients in Setting 1 continue on their same palliative chemotherapy used in induction for a total of 12 months. In Setting 2, a tolerable consolidation therapy would be 4 cycles of modified POG 9341 regimen [fig_ref] TABLE I: Resource Settings for Neuroblastoma Diagnosis, Staging, and Risk Stratification Pediatr Blood Cancer... [/fig_ref] , the French CAdO/CE regimen for 2 cycles each [bib_ref] Unresectable localized neuroblastoma: improved survival after primary chemotherapy including carboplatin-etoposide. Neuroblastoma Study..., Rubie [/bib_ref] or cyclophosphamide/ topotecan for 6 cycles at 3-4-week intervals (Supplemental Appendix III) followed by radiation therapy to the primary tumor bed and residual bone metastases [bib_ref] NB87 induction protocol for stage 4 neuroblastoma in children over 1 year..., Coze [/bib_ref]. For Setting 3, if resources are available for ASCT, then a peripheral blood stem cell (PBSC) harvest could be performed after 2-5 cycles of induction. An earlier timing of apheresis generally leads to improved feasibility in obtaining sufficient PBSC numbers. If apheresis is not available, autologous bone marrow could be collected and stored providing that metastases have cleared. If resources to conduct ASCT are not available, then a consolidation using outpatient-based cyclophosphamide/topotecan for 6 cycles at 3-4 week intervals should be considered (Supplemental Appendix III), as this combination was successful in obtaining response in 30% of resistant or relapsed patients [bib_ref] Phase II randomized comparison of topotecan plus cyclophosphamide versus topotecan alone in..., London [/bib_ref]. An alternative therapy option would be to continue induction therapy (POG 9341) for another 4 cycles. It is reasonable to continue such chemotherapy with curative intent, as there were still >20% EFS for patients treated with intensive consolidation chemotherapy on the randomized CCG protocol [bib_ref] Long-term results for children with high-risk neuroblastoma treated on a randomized trial..., Matthay [/bib_ref]. We recommend administration of 21.6 Gy radiation to the primary tumor bed and to residual bone metastases (fewer than six sites) at the end of consolidation phase of therapy [bib_ref] Intensified external-beam radiation therapy improves the outcome of stage 4 neuroblastoma in..., Simon [/bib_ref] [bib_ref] Local control with multimodality therapy for stage 4 neuroblastoma International, Wolden [/bib_ref].

## Minimal residual disease therapy
Although myeloablative therapy has improved the outcome, up to 40% of patients will relapse after this therapy. The CCG reported the benefit of treating children after myeloablative therapy with a differentiating agent, isotretinoin, with significant improvement in EFS for all children post consolidation [bib_ref] Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation,..., Matthay [/bib_ref]. Isotretinoin for 6 months is recommended in all settings as post-consolidation therapy for patients who have achieved a complete remission [fig_ref] TABLE V: Consolidation and MRD Therapy for High Risk Neuroblastoma Cyclophosphamide 25 mg/m2/day PO... [/fig_ref]. It is not effective, and not recommended, for patients with gross residual disease. We would urge particular caution before prescribing isotretinoin for women of child-bearing age to review risks and reinforce pregnancy prevention measures, as there is a serious risk of birth defects in exposed pregnancies. Currently, the

## Recurrent/progressive disease and alternative regimens
Despite intensive upfront multimodal therapy, over 50% of highrisk neuroblastoma patients continue to relapse. After relapse these patient have poor outcomes with 5-year OS < 10% [bib_ref] Clinical and biologic features predictive of survival after relapse of neuroblastoma: A..., London [/bib_ref]. Regimens such as cyclophosphamide combined with topotecan or irinotecan combined with temozolamide have demonstrated response rates for refractory/relapse disease of 32% and 15%, respectively [bib_ref] Phase II randomized comparison of topotecan plus cyclophosphamide versus topotecan alone in..., London [/bib_ref] [bib_ref] Phase II study of irinotecan and temozolomide in children with relapsed or..., Bagatell [/bib_ref]. 131 I-mIBG therapy is also effective in relapsed disease, with a 30% response rate, but is available in few LMIC [bib_ref] Phase II study on the effect of disease sites, age, and prior..., Matthay [/bib_ref]. External beam radiation therapy will often effectively control symptomatic sites of disease [bib_ref] Palliative radiotherapy in children with neuroblastoma, Paulino [/bib_ref]. Oral metronomic therapies may be options for palliation for settings without access to camptothecins or temozolomide [bib_ref] A phase II trial of a multi-agent oral antiangiogenic (metronomic) regimen in..., Robison [/bib_ref] [bib_ref] Oral etoposide for refractory and relapsed neuroblastoma, Kushner [/bib_ref]. Localized recurrence, particularly in low and intermediate risk disease, may be salvageable with additional surgery, radiation, and chemotherapy [bib_ref] Outcome after reduced chemotherapy for intermediate-risk neuroblastoma, Baker [/bib_ref] [bib_ref] Biologic variables in the outcome of stages I and II neuroblastoma treated..., Perez [/bib_ref] [bib_ref] Outcomes of children with intermediate-risk neuroblastoma after treatment stratified by MYCN status..., Bagatell [/bib_ref]. The determination of therapy is guided by timing of recurrence, previous therapies received, individual patient factors and preferences of the family and providers, in addition to the resources available within those centers.

## Supportive care
Ability to care for children with fever and neutropenia is critical in terms of life threatening complications. Therefore aggressive multi-agent therapy should only be given at center capable of ensuring that patients have rapid access to medical care and broad spectrum antibiotic therapy either by providing affordable housing in close proximity to the medical center or at a facility close to patients' home. It is equally important to educate on fever management with handouts provided to patients and families at each visit [bib_ref] Recommendations for supportive care of children with cancer in a low-income setting, Israels [/bib_ref]. For Setting 3, a central venous catheter should deliver intensive therapy and blood products. It is also recommended in Setting 3 that a pediatric intensive care unit is located within the treating center. Ongoing education should be provided for nursing and medical assistants regarding the care of a child with cancer. Red blood cell products and antibiotics should also be readily available in all settings.

## Advancing treatment intensity
The optimal intensity of therapy at each institution should be determined based on the center's own toxicity data, including grade 3 or 4 infection, sepsis, renal impairment, and death. Review of relapses may also guide the decision to adjust therapy, since reduction of intensity may produce a modest decrease in toxic death but a larger increase in relapse. HIC currently report toxic death rates below 5% for both induction and consolidation therapies [bib_ref] Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A..., Kreissman [/bib_ref]. A toxic death rate >5% for induction or 10% for consolidation should trigger careful assessment and use of lower treatment intensity if supportive care cannot be improved. Reviewing institutional data on abandonment rates may help guide practices to promote patient adherence.

# Conclusion
Risk classification using an adapted approach that takes into consideration limitations in diagnostic imaging and tumor biology allows risk assignment for children with neuroblastoma, regardless of their setting, and selection of feasible and appropriate treatment. This approach does not preclude active efforts to implement the full range of capabilities in every pediatric cancer unit, but can improve outcomes for those patients who must be treated with the current resources.
[table] TABLE I: Resource Settings for Neuroblastoma Diagnosis, Staging, and Risk Stratification Pediatr Blood Cancer DOI 10.1002/pbc [/table]