Dilemmas in the Management of an Infant with Neuroblastoma Metastasized to the Muscles

The risk stratification of infants with metastatic neuroblastoma (NB) has evolved over time from stage 4/M or IVs/4S/MS/Ms according to various staging systems. Despite these developments for some genetic aberrations, the prognostic value and the impact of soft tissue metastases in infants are not fully understood, nor well described in the different classification systems, hampering the definitions to uniformly treat patients and predict prognosis. A literature review on staging of infants with M/MS disease was performed at the occasion of the diagnosis of NB in an 8-month-old boy who presented with atypical metastatic sites in soft tissue and an aberrant tumor biology. The definitions of stage 4/4S/4s/M/MS/Ms were evaluated and compared to enable tumor risk stratification and inform management. International NB groups use different criteria for defining stage of infants with metastasized NB, resulting in differences in management. Limited literature is available on soft tissue metastases, especially muscular metastases, and is poorly incorporated into management guidelines mainly due to the lack of data. The uncertain prognosis of rare genetic aberrancies may add to the difficulties in treatment decisions. In some rare cases of NB in infants, the international treatment classification is not sufficient for staging and treatment decisions. Based on tumor progression, biology of unknown significance and a lack of evidence to classify a child under 12 months with NB and multiple muscular metastases, the patient was treated as stage 4/M and intermediate-risk protocols with a favorable outcome

Reporting incidences of neuroblastoma in various resource settings

PURPOSE : The incidences of neuroblastoma (NB) differ significantly between various resource settings because of varying quality of cancer registries and underdiagnoses. This study aimed to evaluate current regional variations as reported by international cancer registries and the theoretical and reported differences in international NB incidences and to evaluate South Africa (SA) as a case for variable reporting. METHODS : A comprehensive literature review on registries reporting on NB was performed to construct incidence tables. The SEER Program incidence of 10.5/million children was used to calculate the expected number of NB cases for each country. Registry data of NB cases between 2000 and 2016 were requested from The South African National Cancer registry (SA-NCR) and the South African Children’s Tumour Registry (SACTR) for comparison and to perform a probabilistic linkage study. RESULTS : Internationally, incidences varied between –97.1% and +80% compared with the SEER program. SA under-reported NB cases by an estimated 74.2%. Between 2000 and 2016, the SA-NCR reported between 23 and 51 cases/year, whereas the SACTR reported between 18 and 57 cases/year for the same period. The incidence reported by the SA-NCR varied between 1.5 and 2.8/million children under 15-year per year, whereas the SACTR reported 1.74-2.6 cases/million children. Both registries reported incidences less than high-income country. A probabilistic record linkage of the two registries resulted in a combined incidence of 2.9 cases/million children. CONCLUSION : As with most low- and middle-income countries, SA has either a lower incidence or underdiagnoses of NB cases. The reasons for under-reporting are not clear, but can be due to undiagnosed NB cases with spontaneous regression, missed possible cases because of lack of autopsies, and diagnosed cases not recorded in registries.http://ascopubs.org/journal/goam2022Paediatrics and Child Healt

Age at diagnosis as a prognostic factor in South African children with neuroblastoma

PURPOSE : Low- and middle-income countries (LMICs) reported a higher median age at diagnosis of neuroblastoma (NB) compared to high-income countries. The aim was to determine if the optimal age at diagnosis, which maximizes the difference in overall survival between younger versus older patients in the South African population was similar to the internationally validated 18 months age cut-point. METHODS : Four hundred sixty NB patients diagnosed between 2000 and 2016 were included. Receiver operating characteristic (ROC) curves were used to predict potential age cut-point values for overall survival in all risk group classifications. Risk ratios, sensitivity, specificity, and positive and negative predictive values at the specific cut-points were estimated with 95% confidence intervals, and time to mortality by age at the specific cut-points was shown with Kaplan-Meier curves and compared using log-rank tests. RESULTS : The median age at diagnosis for the total cohort was 31.9 months (range 0.2-204.7). For high-risk (HR), intermediate-risk, low-risk, and very low-risk patients, the median age at diagnosis was, respectively, 36 months (range 0.4-204.7), 16.8 months (range 0.7-145.1), 14.2 months (range 2.0-143.5), and 8.7 months (range 0.2-75.6). The ROC curves for the total NB cohort (area under the curve [AUC] 0.696; P < .001) and HR (AUC 0.682; P < .001) were analyzed further. The optimal cut-point value for the total cohort was at 19.1 months (sensitivity 59%; specificity 78%). The HR cohort had potential cut-point values identified at 18.4 months age at diagnosis (sensitivity 45%; specificity 87%) and 31.1 months (sensitivity 67%; specificity 62%). The 19.1 months cut-point value in the total cohort and the 18.4 months cut-point value in HR were as useful in predicting overall survival as 18 months age at diagnosis. CONCLUSION : The 18 months cut-point value appears to be the appropriate age for prognostic determination, despite the higher median age at diagnosis in South Africa.https://wileyonlinelibrary.com/journal/pbchj2022Paediatrics and Child Healt

The management and outcomes of neuroblastoma in South Africa

Thesis (PhD)--Stellenbosch University, 2021.ENGLISH ABSTRACT: Neuroblastoma (NB) is the second most diagnosed childhood solid tumour in high-income countries (HIC), but the incidence has not accurately been described in low- and middle-income countries (LMICs). The diagnostic difficulty, with limited treatment modalities, contributes to poor outcomes in LMICs. This PhD dissertation investigates the management of NB in South Africa with the aim to develop the first prospective national neuroblastoma treatment protocol/clinical trial to improve overall survival (OS).Using the South African Cancer Study Group’s Tumour Registry data, between 2000 and 2016 the incidence of NB in South Africa was found to be between 1.74 to 2.6 cases/million children, which waslower than the 10.5 cases per million children reported in HICs. South Africa had a higher number of patients with high-risk (HR) tumours (75.6%), mainly due to advanced disease (70%). The 2-year OS was excellent for very low risk (VLR) (94.1%) and low risk (LR) disease (81.6%), while acceptable for intermediate risk (IR) disease (66.7%) but poor for HR disease (27.6%) (p<0.001, 95% CI). Limitations in risk stratification included the low number of tumours tested for MYCN (38.4%), with more than half being MYCN-amplified (54%), and no other NB related genetic characteristics. Several treatment protocols were used in the different paediatric oncology units in South Africa during the study period (2000-2014) and the OPEC/OJEC (carboplatin, cisplatin, etoposide, cyclophosphamide and vincristine) induction chemotherapy regimen proved to be the least toxic with better metastatic remission rates for HR-NB. Ferritin had predictive value for complete metastatic remission rate, while LDH had predictive value for two-year OS and were found to be suitable tumour markers to use as surrogates for sophisticated genetic testing and mIBG-scans in the context of limited resources. Age at diagnosis, specifically the 18-month cut-point value, remained a significant prognostic factor, similar to HICs.Due to limited access to autologous stem cell transplants, the role of surgery and radiotherapy in the management of HR disease were investigated and found to significantly improve five-year OS with surgery and marginally with radiotherapy (p<0.001, 95% CI). Furthermore, the disparities in neuroblastoma health care provision in the different provinces in South Africa was found to exist and should be addressed to ensure equitable health care provision for all children as per the South African Constitution. The implementation of the newly developed national NB single arm clinical trial in South Africa, adjusted to available national resources, was a complex process with major navigational bureaucratic challenges. Yet the process might serve as a guideline for similar processes in LMICs. The recruitment of patients into the national NB clinical trial proved to be difficult due to both the COVID-19 pandemic and reluctance to recruit advanced stage patients into clinical trials. However, with careful investigation and in collaborative spirit, rare diseases such as neuroblastoma in South Africa could be managed in national management protocols, aimed at improving overall survival and cure.AFRIKAANSE OPSOMMING: Neuroblastoom (NB) is die tweede mees gediagnoseerde soliede tumor by kinders in hoëinkomstelande (HIL’e). Tog word die voorkoms daarvan in lae- en middelinkomstelande (LMIL’e) nie akkuraat beskryf nie. Die diagnostiese uitdaging, sowel as beperkte behandelingsmetodes, lei dus tot swak uitkomste in LMIL’e. Hierdie PhD dissertasie ondersoek die behandeling van NB in Siud Afrika ten einde die algehele oorlewingsyfer (AO) te verbeter. Deur van data tussen 2000 en 2016 van die Suid Afrikaanse Kinderkanker Studie Groep se Tumor Register gebruik te maak, was die voorkomssyfer van NB in Suid-Afrika as 1,74 tot 2,6 gevalle per miljoen kinders bereken, wat veel laer was as die aangemelde 10,4 gevalle per miljoen kinders in HIL’e. Suid-Afrika het ’n hoër getal pasiënte met hoërisiko- (HR-)tumore (75,6%), hoofsaaklik vanweë gevorderde siekte (70%). Die AO oor twee jaar het was uitstekend vir uiters laerisiko- (ULR-) (94,1%) en laerisiko- (LR-)siekte (81,6%), aanvaarbaar vir matigerisiko- (MR-) (66,7%), maar sleg vir HR-siekte (27,6%) (p<0,001, 95% CI). Beperkings in risikostratifikasie het ingesluit die klein aantal tumore wat vir MYCN getoets is (38,4%), met meer as die helfde met MYCN-amplifikasie (54%), en die onvermoë om NB-verwante genetiese kenmerke te bepaal. Verskeie behandelingsprotokolle was gebruik deur die verskillende kinderkanker eenheide in Suid Afrika gedurende hierdie periode (200-2014) en dit was getoon dat die OPEC/OJEC-regimen (karboplatien, sisplatien, etoposied, siklofosfamied en vinkristien) die grootste voordeel vir HR-NB inhou wat toksisiteit en metastatiese remissiesyfers betref. Ferritien het waarde om die metastatiese algehele-remissiesyfer te voorspel, terwyl LDH by die voorspelling van die AO oor twee jaar waardevol was en kan albei tumormerkers gebruik word as surogate van gesofistikeerde genetiese toetse en mIBG-skandering in omstandighede met beperkte hulpbronne. Soos wat in HIL’e bevind is, bly ouderdom ten tyde van diagnose, maar spesifiek die 18 maande afsnypunt, ’n beduidende prognostiese faktor. Met beperkte toegang tot outoloë stamseloorplantings, was die rol van sowel chirurgie as radioterapieondersoek en dit was bewys dat chirurgie die AO oor vyf jaar noemenswaardig verbeter terwyl tumorbestraling ’n effens beter AO oor vyf jaar getoon het (p<0.001, 95% CI). Verder het ons aangetoon dat daar noemenswaardige hulpbron verskille tussen provinsies bestaan wat aangespreek moet word om regverdige gesondheidsorg aan alle kinders te besorg volgens die Soud Afrikaanse Grondwet. Met die implementering van ’n nasionale NB-protokol enkel arm kliniese studie in Suid-Afrika, met die doel om die benutting van nasionale hulpbronne te optimaliseer, was ‘n kompleks onderneming waartydens vele burokratiese uitdagings genavigeer moes word, maar kan as ‘n riglyn vir ander LMIL’e dien. Die proses om patiente vir die nasionale NB kliniese studie in te win was was uitdagend as gevolg van beide COVID-19 pandemie en die onwilligheid om patiente met gevorderde siekte by die studie in te sluit. Egter, met respekvolle ondersoek en ‘n gees van samewerking, kan seldsame siektes soos neuroblastoom in Suid Afrika volgens ‘n nasionale behandelingsprotokol behandel word met die doel om die algemene oorlewing te verbeter en patiente te genees.Dutch SAMENVATTING: Neuroblastoom (NB) is de tweede, meest gediagnosticeerde solide tumor bij kinderen in ‘high-income countries’ (HIC), maar de incidentie is niet nauwkeurig beschreven in ‘low- and middle-income countries’ (LMIC's). De diagnostische problemen met de beperkte behandelingsmodaliteiten dragen bij aan een slechte prognose in LMIC’s. Dit proefschrift onderzoekt de behandelingsresultaten van NB in Zuid-Afrika met als doel de prognose te verbeteren. De data van het Tumor Register van de Zuid Afrikaanse Kinkerkanker Studie tussen 2000 en 2006 laten een incidentie van NB in Zuid-Afrika zien van 1,74-2,6 gevallen per miljoen kinderen, hetgeen lager is dan de 10,4 gevallen per miljoen kinderen die gerapporteerd worden in HIC. Zuid-Afrika heeft een groter aantal patiënten met hoog risico (HR) tumoren (75,6%), voornamelijk vanwege de gevorderde ziekte bij presentatie (70%). De 2-jaars ‘overal survival’ (OS) waren uitstekend bij zeer laag risico (VLR) (94,1%) en laag risico (LR) (81,6%), aanvaardbaar bij gemiddeld risico (IR) (66,7%), maar slecht bij HR-ziekte (27,6%) (p <0,001, 95% CI). Beperkingen in risicostratificatie waren onder meer, het lage aantal tumoren dat op MYCN werd getest (38,4%), met meer dan het helft (54%) MYCN geamplificeerd, en het onvermogen om NB-gerelateerde genetische kenmerken te bepalen.Tijdens de studie periode (2000-2014) werden meerdere behandelingsprotocollen door verschillende pediatrische oncologie-eenheden gebruikt en bleek het OPEC/OJEC-regime (carboplatine, cisplatine, etoposide, cyclofosfamide en vincristine) de meeste voordelen te bieden met betrekking tot de toxiciteit en tumorremissie bij HR-NB. Ferritine blijkt belangrijk te zijn bij het voorspellen van het percentage van complete remissie, terwijl LDH van waarde is bij het voorspellen van tweejarige OS. Beiden zijn geschikte tumormarkers om te gebruiken als surrogaten voor geavanceerde genetische tests en mIBG-scans in de context van beperkte middelen. Leeftijd bij diagnose, met name de 18-maanden ‘cut-off’, is een belangrijke prognostische factor zoals in HIC's.Gezien de beperkte toegang tot autologe stamceltransplantaties, werden de rollen van zowel chirurgie als radiotherapie bij HR ziekte bestudeerd, en blijkt de vijfjarige OS significant te verbeteren met chirurgie en marginaal met radiotherapie (p<0.001, 95% CI). Bovendien blijken er verschillen in de gezondheidszorg voor neuroblastoom in de verschillende provincies in Zuid-Afrika te bestaan en deze zouden moeten worden aangepakt om te zorgen voor een rechtvaardige gezondheidszorg voor alle kinderen volgens de Zuid-Afrikaanse grondwet. De implementatie van de nieuw ontwikkelde nationale NB klinisch studie in Zuid-Afrika, aangepast aan de beschikbare nationale middelen, was een complex proces met grote bureaucratische uitdagingen die moesten worden overwonnen. Toch zou het proces als richtlijn kunnen dienen voor soortgelijke processen in LMIC's. De rekrutering van patiënten voor de nationale NB klinische studie bleek moeilijk te zijn vanwege zowel de COVID-19 pandemie als de onwil om patiënten in een gevorderd stadium voor klinische studies te werven. Met zorgvuldig onderzoek en in een samenwerkingsgeest zouden zeldzame ziekten zoals neuroblastoom in Zuid-Afrika echter kunnen worden behandeld met behulp van nationale managementprotocollen, gericht op het verminderen van de morbiditeit en mortaliteit.Doctora

Management of neuroblastoma in limited-resource settings

CITATION: Van Heerden, J. & Kruger, M. 2020. Management of neuroblastoma in limited-resource settings. World Journal of Clinical Oncology, 11(8):629-643, doi:10.5306/wjco.v11.i8.0000.The original publication is available at https://www.wjgnet.com/2218-4333BACKGROUND: Neuroblastoma (NB) is a heterogeneous disease with variable outcomes among countries. Little is known about NB in low- and middle-income countries (LMICs). AIM: The aim of this review was to evaluate regional management protocols and challenges in treating NB in paediatric oncology units in LMICs compared to high-income countries (HICs). METHODS: PubMed, Global Health, Embase, SciELO, African Index Medicus and Google Scholar were searched for publications with keywords pertaining to NB, LMICs and outcomes. Only English language manuscripts and abstracts were included. A descriptive review was done, and tables illustrating the findings were constructed. RESULTS: Limited information beyond single-institution experiences regarding NB outcomes in LMICs was available. The disease characteristics varied among countries for the following variables: sex, age at presentation, MYCN amplification, stage and outcome. LMICs were found to be burdened with a higher percentage of stage 4 and high-risk NB compared to HICs. Implementation of evidence-based treatment protocols was still a barrier to care. Many socioeconomic variables also influenced the diagnosis, management and follow-up of patients with NB. CONCLUSION Patients presented at a later age with more advanced disease in LMICs. Management was limited by the lack of resources and genetic studies for improved NB classification. Further research is needed to develop modified diagnostic and treatment protocols for LMICs in the face of limited resources.https://www.wjgnet.com/2218-4333/full/v11/i8/629.htmPublisher's versio

The scope of childhood cancer in South Africa : a response to 'Childhood cancers in a section of the South African private health sector - Analysis of medicines claims data'

Childhood cancer is an under resourced medical field that is emerging as a great healthcare concern in low- and middle-income countries such as South Africa. Therefore, reporting data in this field that may inform policymakers should be representative of the subject matter. This article aims to discuss why medicines claims as an indicator for incidence, as per an article published in 2020, is not representative of childhood malignancies in the South African setting. Literature to support the commentary were sourced using Pubmed, Google scholar, and data presented by members of the South African Children’s Cancer Study Group (SACCSG). Private medical aid coverage in South Africa between 2002 and 2018 varied between 15.5% and 18.2%. Of these, 9.5% were children under 18 years and 3.5% were under the age of six. Only 13.5% of children were treated in private paediatric oncology units during 2015. The limitations in the study were the variable medical aid coverage, the disproportionate age representation, and lack of reliable indicators for measurement and calculation of incidence. Utilising one medicines claims data base to evaluate the incidence of childhood cancer in South Africa is not representative and cannot inform policy. CONTRIBUTION: This article highlights the importance of accurate registration of childhood cancer diagnoses, especially when data and conclusions based on these results inform policy. The study highlights the limitations of extrapolating general conclusions based on data representing only a small sector of the childhood cancer landscape in South Africa

Management of neuroblastoma in limited-resource settings

CITATION: Van Heerden, J. & Kruger, M. 2020. Management of neuroblastoma in limited-resource settings. World Journal of Clinical Oncology, 11(8):629-643, doi:10.5306/wjco.v11.i8.0000.The original publication is available at https://www.wjgnet.com/2218-4333BACKGROUND: Neuroblastoma (NB) is a heterogeneous disease with variable outcomes among countries. Little is known about NB in low- and middle-income countries (LMICs). AIM: The aim of this review was to evaluate regional management protocols and challenges in treating NB in paediatric oncology units in LMICs compared to high-income countries (HICs). METHODS: PubMed, Global Health, Embase, SciELO, African Index Medicus and Google Scholar were searched for publications with keywords pertaining to NB, LMICs and outcomes. Only English language manuscripts and abstracts were included. A descriptive review was done, and tables illustrating the findings were constructed. RESULTS: Limited information beyond single-institution experiences regarding NB outcomes in LMICs was available. The disease characteristics varied among countries for the following variables: sex, age at presentation, MYCN amplification, stage and outcome. LMICs were found to be burdened with a higher percentage of stage 4 and high-risk NB compared to HICs. Implementation of evidence-based treatment protocols was still a barrier to care. Many socioeconomic variables also influenced the diagnosis, management and follow-up of patients with NB. CONCLUSION Patients presented at a later age with more advanced disease in LMICs. Management was limited by the lack of resources and genetic studies for improved NB classification. Further research is needed to develop modified diagnostic and treatment protocols for LMICs in the face of limited resources.https://www.wjgnet.com/2218-4333/full/v11/i8/629.htmPublisher's versio

Children's ability to consent to medical management in South Africa

BACKGROUND : The South African Children's Act No. 38 of 2005 requires paediatric medical consent from 12 years of age. OBJECTIVE : To determine children's ability to provide informed consent for medical treatment. METHODS : Assessment used hypothetical treatment storyboards and structured interviews for assessment of 100 children (aged 10 - 17 years), and 25 adult controls, using a standardised scoring tool to test understanding, ability to deliberate treatment choices, and provide rational reasons. Statistical analysis involved multivariate analyses of variance (MANOVAs) and analysis of variance (ANOVA). RESULTS : The female:male ratios for children and adults were 1:0.92 and 1:0.98, respectively. Children⩾12 years were competent with regard to treatment choices (p<0.001), while 10-year-olds could deliberate reasonable outcomes, similar to adults (p<0.001). However, only children 12 years and older could provide rational reasons, where abstract concepts were not involved, whereas children who were⩾14 years old were able to provide rational reasons involving abstract concepts. The actual understanding of choices, compared with adults, was only observed in children older than 14 years (p<0.001). Gender was not a statistically significant denominator. CONCLUSION : Children of 12 years and older are competent to make medical decisions, but the understanding of medical treatment choices under the age of 14 years is not clear.http://www.sajch.org.za/index.php/SAJCHhj2020Family Medicin