Rapid COJEC versus standard induction therapies for high-risk neuroblastoma

  • Review
  • Intervention

Authors


Abstract

Background

Neuroblastoma is a rare malignant disease and mainly affects infants and very young children. The tumors mainly develop in the adrenal medullary tissue and an abdominal mass is the most common presentation. The high-risk group is characterized by metastasis and other characteristics that increase the risk for an adverse outcome. In the rapid COJEC induction schedule, higher single doses of selected drugs than standard induction schedules are administered over a substantially shorter treatment period, with shorter intervals between cycles. Shorter intervals and higher doses increase the dose intensity of chemotherapy and might improve survival.

Objectives

The aim of this study was to evaluate the efficacy and adverse events of the rapid COJEC induction schedule as compared to standard induction schedules in patients with high-risk neuroblastoma (as defined by the International Neuroblastoma Risk Group (INRG) classification system). Outcomes of interest were complete response, early toxicity and treatment-related mortality as primary endpoints and overall survival, progression- and event-free survival, late non-hematological toxicity, and health-related quality of life as secondary endpoints.

Search methods

We searched the electronic databases CENTRAL (2014, Issue 11), MEDLINE (PubMed), and EMBASE (Ovid) for articles from inception to 11 November 2014. Further searches included trial registries, conference proceedings, and reference lists of recent reviews and relevant articles. We did not apply limits on publication year or languages.

Selection criteria

Randomized controlled trials evaluating the rapid COJEC induction schedule for high-risk neuroblastoma patients compared to standard induction schedules.

Data collection and analysis

Two review authors performed study selection, abstracted data on study and patient characteristics, and assessed risk of bias independently. We resolved differences by discussion or by appeal to a third review author. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We used the five GRADE considerations, study limitations, consistency of effect, imprecision, indirectness, and publication bias, to judge the quality of the evidence. We downgraded for risk of bias and imprecision

Main results

We identified one randomized controlled trial (CCLG-ENSG-5) that included 262 patients with high-risk neuroblastoma who were randomized to receive either rapid COJEC (N = 130) or standard OPEC/COJEC (N = 132) induction chemotherapy. We graded the evidence as low quality; we downgraded for risk of bias and imprecision.

There was no clear evidence of a difference between the treatment groups in complete response (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.71 to 1.38), treatment-related mortality (RR 1.21, 95% CI 0.33 to 4.39), overall survival (hazard ratio (HR) 0.83, 95% CI 0.63 to 1.10), and event-free survival (HR 0.86, 95% CI 0.65 to 1.13). We calculated the HRs using the complete follow-up period of the trial.

Febrile neutropenia (two or more episodes), proven fungal infections, septicemia (one or more episodes), gastrointestinal toxicity (grade 3 or 4), renal toxicity (glomerular filtration rate < 80 ml/min per body surface area of 1.73 m2), neurological toxicity (grade 3 or 4), and ototoxicity (Brock grade 2 to 4) were addressed as early toxicities (during pre-operative chemotherapy). For febrile neutropenia, septicemia, and renal toxicity, a statistically significant difference in favor of the standard treatment arm was identified; for all other early toxicities no clear evidence of a difference between treatment groups was identified. With regard to late non-hematological toxicities (median follow-up 12.7 years; range 6.9 to 16.5 years), the study provided data on any complication, renal toxicity (glomerular filtration rate < 80 ml/min per body surface area of 1.73m2), ototoxicity (Brock grade 1 to 4), endocrine complications, neurocognitive complications (i.e. behavioral, speech, or learning difficulties), and second malignancies. For endocrine complications and neurocognitive complications, a statistically significant difference in favor of the rapid COJEC arm was found; for all other late non-hematological toxicities no clear evidence of a difference between treatment groups was identified.

Data on progression-free survival and health-related quality of life were not reported.

Authors' conclusions

We identified one randomized controlled trial that evaluated rapid COJEC versus standard induction therapy in patients with high-risk neuroblastoma. No clear evidence of a difference in complete response, treatment-related mortality, overall survival, and event-free survival between the treatment alternatives was found. This could be the result of low power or too short a follow-up period. Results of both early and late toxicities were ambiguous. Information on progression-free survival and health-related quality of life were not available. This trial was performed in the 1990s. Since then, many changes in, for example, treatment and risk classification have occurred. Therefore, based on the currently available evidence, we are uncertain about the effects of rapid COJEC and standard induction therapy in patients with high-risk neuroblastoma. More research is needed for a definitive conclusion.

Resumen

Inducción rápida con COJEC versus tratamiento de inducción estándar para el neuroblastoma de alto riesgo

Antecedentes

El neuroblastoma es una enfermedad maligna rara que afecta principalmente a neonatos y a niños muy pequeños. Los tumores aparecen principalmente en el tejido medular suprarrenal y una masa abdominal es la presentación más común. El grupo de alto riesgo se caracteriza por metástasis y otras características que aumentan el riesgo de un resultado adverso. En el régimen de inducción rápida con COJEC, se administran dosis únicas mayores de los fármacos seleccionados en comparación con los regímenes de inducción estándar durante un período de tratamiento significativamente más corto, con intervalos más cortos entre los ciclos. Los intervalos más cortos y las dosis mayores aumentan la intensidad de la dosis de quimioterapia y podrían mejorar la supervivencia.

Objetivos

El objetivo de este estudio fue evaluar la eficacia y los eventos adversos del régimen de inducción rápida con COJEC en comparación con los regímenes de inducción estándar en los pacientes con neuroblastoma de alto riesgo (según lo definido por el sistema de clasificación International Neuroblastoma Risk Group [INRG]). Los resultados de interés fueron la respuesta completa, la toxicidad temprana y la mortalidad relacionada con el tratamiento como variables de evaluación primarias y la supervivencia general, la supervivencia libre de progresión y la supervivencia sin eventos, la toxicidad tardía no hematológica y la calidad de vida relacionada con la salud como variables de evaluación secundarias.

Métodos de búsqueda

Se buscaron artículos en las bases da datos electrónicas CENTRAL (2014, número 11), MEDLINE (PubMed) y en EMBASE (Ovid) desde su inicio hasta el 11 noviembre 2014. Otras búsquedas incluyeron registros de ensayos, actas de congresos y listas de referencias de revisiones recientes y artículos relevantes. No se aplicaron límites en el año de publicación o idioma.

Criterios de selección

Ensayos controlados aleatorios que evaluaran el régimen de inducción rápida con COJEC para los pacientes con neuroblastoma de alto riesgo en comparación con los regímenes de inducción estándar.

Obtención y análisis de los datos

Dos revisores de forma independiente seleccionaron los estudios, extrajeron los datos sobre las características de los estudios y los pacientes y evaluaron el riesgo de sesgo. Las diferencias se resolvieron mediante discusión o por la apelación a un tercer autor de la revisión. Los análisis se realizaron según las guías del Manual Cochrane para Revisiones Sistemáticas de Intervenciones (Cochrane Handbook for Systematic Reviews of Interventions). Para evaluar la calidad de las pruebas se utilizaron las cinco consideraciones GRADE limitaciones del estudio, consistencia del efecto, falta de precisión, falta de direccionalidad y sesgo de publicación. Se disminuyó la calidad debido al riesgo de sesgo y la falta de precisión

Resultados principales

Se identificó un ensayo controlado aleatorio (CCLG-ENSG-5) que incluyó a 262 pacientes con neuroblastoma de alto riesgo y que se asignaron al azar a recibir quimioterapia de inducción rápida con COJEC (n = 130) o estándar con OPEP/COJEC (n = 132). Las pruebas se clasificaron como de baja calidad; la calidad se disminuyó debido al riesgo de sesgo y la falta de precisión.

No hubo pruebas claras de una diferencia entre los grupos de tratamiento en la respuesta completa (cociente de riesgos [CR] 0,99; intervalo de confianza [IC] del 95%: 0,71 a 1,38), la mortalidad relacionada con el tratamiento (CR 1,21; IC del 95%: 0,33 a 4,39), la supervivencia general (cociente de riesgos instantáneos [CRI] 0,83; IC del 95%: 0,63 a 1,10) y la supervivencia sin eventos (CRI 0,86; IC del 95%: 0,65 a 1,13). Los CRI se calcularon mediante el uso del período completo de seguimiento del ensayo.

La neutropenia febril (dos episodios o más), las micosis comprobadas, la sepsis (un episodio o más), la toxicidad gastrointestinal (grado 3 ó 4), la toxicidad renal (tasa de filtración glomerular < 80 ml/min por área de superficie corporal de 1,73 m2), la toxicidad neurológica (grado 3 ó 4) y la ototoxicidad (grado Brock 2 a 4) se consideraron como toxicidades tempranas (durante la quimioterapia preoperatoria). Para la neutropenia febril, la sepsis y la toxicidad renal, se identificó una diferencia estadísticamente significativa a favor del brazo de tratamiento estándar; para todas las otras toxicidades tempranas no se identificaron pruebas claras de una diferencia entre los grupos de tratamiento. Con respecto a las toxicidades tardías no hematológicas (mediana del seguimiento 12,7 años; rango: 6,9 a 16,5 años), el estudio proporcionó datos sobre cualquier complicación, toxicidad renal (tasa de filtración glomerular < 80 ml/min por área de superficie corporal de 1,73 m2), ototoxicidad (grado Brock 1 a 4), complicaciones endocrinas, complicaciones neurocognitivas (es decir dificultades conductuales, del habla o dificultades del aprendizaje) y neoplasias malignas secundarias. Para las complicaciones endocrinas y las complicaciones neurocognitivas se encontró una diferencia estadísticamente significativa a favor del brazo de inducción rápida con COJEC; para todas las otras toxicidades tardías no hematológicas no se identificaron pruebas claras de una diferencia entre los grupos de tratamiento.

No se informaron datos sobre la supervivencia libre de progresión y la calidad de vida relacionada con la salud.

Conclusiones de los autores

Se identificó un ensayo controlado aleatorio que evaluó inducción rápida con COJEC versus tratamiento de inducción estándar en pacientes con neuroblastoma de alto riesgo. No se encontraron pruebas claras de una diferencia en la respuesta completa, la mortalidad relacionada con el tratamiento, la supervivencia general y la supervivencia sin eventos entre las opciones de tratamiento. Lo anterior podría ser el resultado del poco poder estadístico o del período de seguimiento demasiado corto. Los resultados de las toxicidades tempranas y tardías fueron ambiguos. No hubo información disponible sobre la supervivencia libre de progresión y la calidad de vida relacionada con la salud. Este ensayo se realizó en la década de 1990. Desde entonces han ocurrido muchos cambios, por ejemplo, en el tratamiento y la clasificación de los riesgos. Por lo tanto, sobre la base de las pruebas disponibles actualmente, no existe seguridad acerca de los efectos de la inducción rápida con COJEC y el tratamiento de inducción estándar en los pacientes con neuroblastoma de alto riesgo. Se necesita más investigación para una conclusión definitiva.

Plain language summary

Rapid COJEC versus standard induction therapies for high-risk neuroblastoma

High-risk neuroblastoma is a rare malignant disease and mainly affects infants and very young children. The tumors mainly develop in the core part (medulla) of the adrenal gland. The adrenal gland is located on top of the kidneys. A tumor increasing in size would primarily expected to appear in the belly. High-risk means patients having one or several clinical symptoms or signs, such as metastasis or specific genetic features, which are known to increase the risk for an adverse outcome. The assignment to a high-risk group is defined by the International Neuroblastoma Risk Group (INRG) classification system. In the rapid COJEC induction schedule, higher single doses of selected drugs than standard induction schedules are administered over a substantially shorter treatment period, with shorter intervals between cycles. Shorter intervals and higher doses increase the dose intensity of chemotherapy and might improve survival.

We identified one randomized controlled trial with 262 patients. We excluded other study designs as they give less reliable results. However, randomized studies are difficult to perform in children with neuroblastoma and other evidence might be available. In the identified randomized study, patients with high-risk neuroblastoma were randomized to receive either rapid COJEC or standard OPEC/OJEC induction chemotherapy. Complete response, treatment-related mortality, overall survival, and event-free survival were not different between the two treatment alternatives. Results of both early and late toxicities were not clear cut, for example, some early toxicities were in favor of the standard arm and some late non-hematological toxicities were in favor of the rapid COJEC arm. For other toxicities there was no evidence of a difference between the treatment arms. Data on progression-free survival and health-related quality of life were not reported. Not all biases could be ruled out in this study. Before definitive conclusions can be made more research is needed.

Laički sažetak

Usporedba brzog COJEC protokola i standardnog indukcijskog liječenja visokorizičnog neuroblastoma

Visokorizični neuroblastom je rijetka zloćudna bolest od koje najčešće obolijevaju dojenčad i mala djeca. Zloćudna tvorevina je najčešće smještena u srži nadbubrežne žlijezde, a koja se nalazi na gornjem dijelu bubrega. Rastuća novotvorevina se prvenstveno pojavljuje u trbušnoj šupljini. Visoka rizičnost obilježava svojstvo jednog ili više simptoma (znakova) bolesti, primjerice metastaziranje ili genetska obilježja, a koja povećavaju rizik lošeg ishoda. Visokorizična skupina je definirana klasifikacijom Međunarodne skupine rizika neuroblastoma (engl. International Neuroblastoma Risk Group, INRG). Indukcijski brzi COJEC protokol sadrži visoke pojedinačne doze određenih lijekova i primjenjuje se u kraćem razdoblju i u kraćim razmacima između ciklusa liječenja. Kraći razmaci između ciklusa liječenja i visoke doze kemoterapije bi mogli poboljšati preživljenje.

Nađena je jedna randomizirana kontrolirana klinička studija koja je uključila 262 bolesnika. Isključene su studije provedene na druge načine zbog nepouzdanosti rezultata. Randomizirane studije je teško provesti u djece s neuroblastomom i vjerojatno postoje drugi dokazi. U toj studiji su bolesnici s visokorizičnim neuroblastomom bili randomizirani za liječenje brzim COJEC protokolom ili standardni m OPEC/OJEC oblikom kemoterapije. Potpuni odgovor, smrtnost povezana s liječenjem, sveukupno preživljenje i preživljenje bez događaja se nisu razlikovali između dva oblika liječenja. Rezultati rane i kasne toksičnosti nisu bili jednoznačni, primjerice neki oblici rane toksičnosti su davali prednost standardnom liječenju, a neke kasne toksičnosti brzom COJEC protokolu. Za druge toksičnosti nije bilo dokaza postojanja razlika između dva oblika liječenja. Nije bilo podataka o preživljenju bez pogoršanja bolesti i kvaliteti života povezanoj sa zdravljem. Pristranost nije bila u potpunosti isključena. Konačan zaključak nije moguće donijeti bez dodatnih istraživanja.

Bilješke prijevoda

Hrvatski Cochrane
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Resumen en términos sencillos

Inducción rápida con COJEC versus tratamiento de inducción estándar para el neuroblastoma de alto riesgo

El neuroblastoma de alto riesgo es una enfermedad maligna poco frecuente que afecta principalmente a los neonatos y a los niños muy pequeños. Los tumores se presentan principalmente en la parte central (médula) de la glándula suprarrenal. La glándula suprarrenal está ubicada encima de los riñones. Se esperaría la aparición de un tumor que aumenta de tamaño principalmente en el abdomen. "De alto riesgo" significa que los pacientes tienen uno o varios síntomas o signos clínicos, como metástasis o características genéticas específicas que se sabe que aumentan el riesgo de un resultado adverso. La asignación a un grupo de alto riesgo es definida por el sistema de clasificación del International Neuroblastoma Risk Group (INRG). En el régimen de inducción rápida con COJEC, se administran dosis únicas mayores de los fármacos seleccionados en comparación con los regímenes de inducción estándar durante un período de tratamiento significativamente más corto, con intervalos más cortos entre los ciclos. Los intervalos más cortos y las dosis mayores aumentan la intensidad de la dosis de quimioterapia y podrían mejorar la supervivencia.

Se identificó un ensayo controlado aleatorio con 262 pacientes. Se excluyeron otros diseños de estudio porque proporcionaban resultados menos fiables. Sin embargo, los estudios aleatorios son difíciles de realizar en niños con neuroblastoma y podría haber otras pruebas disponibles. En el estudio aleatorio identificado, los pacientes con neuroblastoma de alto riesgo se asignaron al azar a recibir quimioterapia de inducción rápida con COJEC o quimioterapia de inducción estándar con OPEP/OJEC. La respuesta completa, la mortalidad relacionada con el tratamiento, la supervivencia general y la supervivencia sin eventos no fueron diferentes entre las dos opciones de tratamiento. Los resultados de las toxicidades tempranas y tardías no fueron específicos, por ejemplo, algunas toxicidades tempranas estuvieron a favor del brazo estándar y algunas toxicidades tardías no hematológicas estuvieron a favor del brazo de inducción rápida con COJEC. Para otras toxicidades no hubo pruebas de una diferencia entre los brazos de tratamiento. No se informaron datos sobre la supervivencia libre de progresión y la calidad de vida relacionada con la salud. No fue posible descartar todos los sesgos en este estudio. Para poder extraer conclusiones definitivas, se necesita más investigación.

Notas de traducción

La traducción y edición de las revisiones Cochrane han sido realizadas bajo la responsabilidad del Centro Cochrane Iberoamericano, gracias a la suscripción efectuada por el Ministerio de Sanidad, Servicios Sociales e Igualdad del Gobierno español. Si detecta algún problema con la traducción, por favor, contacte con Infoglobal Suport, cochrane@infoglobal-suport.com.

Summary of findings(Explanation)

Summary of findings for the main comparison. Rapid COJEC compared to standard induction therapies for high-risk neuroblastoma
  1. 1The assumed risk is based on the prevalence in the control group of the included study.
    2The presence of selection bias, performance bias, detection bias, and other bias was unclear; there was a high risk of attrition bias.
    3The total number of events was fewer than 300 (the threshold rule-of-thumb value stated in the GRADEpro software).
    4The assumed risk is based on the number of events in the control group at the final time point of the survival curve presented in the included study.
    5The presence of selection bias, performance bias, and other bias was unclear; there was a high risk of attrition bias.
    6As yet no threshold rule-of-thumb value for the minimal number of events for time-to-event data is included in the GRADEpro software; however, since this is a small study and the 95% confidence interval include values both favoring the intervention and the control treatment, we downgraded for imprecision.

Rapid COJEC compared to standard induction therapies for high-risk neuroblastoma
Patient or population: patients with high-risk neuroblastoma
Settings: pediatric oncology departments
Intervention: rapid COJEC
Comparison: standard induction therapy
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Standard induction therapy Rapid COJEC
Complete response 456 per 1000 1 451 per 1000
(323 to 629)
RR 0.99
(0.71 to 1.38)
170
(1 study)
⊕⊕⊝⊝
low 2,3

Length of follow-up was not reported regarding the 262 randomized patients; median follow-up of 62 alive patients was 12.5 years (range 0 to 16.5 years)

This was an available data analysis

Early toxicities (during preoperative chemotherapy): febrile neutropenia (2 or more episodes), proven fungal infections, septicemia (1 or more episodes), gastrointestinal toxicity (grade 3 or 4), renal toxicity (glomerular filtration rate < 80 ml/min per body surface area of 1.73 m2), neurological toxicity (grade 3 or 4), ototoxicity (Brock grade 2 to 4)---248
(1 study)
⊕⊕⊝⊝
low 2,3

Length of follow-up was not reported regarding the 262 randomized patients; median follow-up of 62 alive patients was 12.5 years (range 0 to 16.5 years)

Febrile neutropenia: there was a significant difference in favor of the standard induction therapy arm (RR 1.23, 95% CI 1.10 to 1.36)

Proven fungal infections: no significant difference between treatment groups (RR 2.50, 95% CI 0.23 to 27.18)

Septicemia: there was a significant difference in favor of the standard induction therapy arm (RR 1.61, 95% CI 1.14 to 2.27)

Gastrointestinal toxicity: no significant difference between treatment groups (RR 1.41, 95% CI 0.96 to 2.08)

Renal toxicity: there was a significant difference in favor of the standard induction therapy arm (RR 2.19, 95% CI 1.39 to 3.44)

Neurological toxicity: no significant difference between treatment groups (RR 3.07, 95% CI 0.63 to 14.93)

Ototoxicity: no significant difference between treatment groups (RR 1.04, 95% CI 0.27 to 4.01)

These were all available data analyses

Treatment-related mortality 35 per 1000 1 42 per 1000
(11 to 153)
RR 1.21
(0.33 to 4.39)
234
(1 study)
⊕⊕⊝⊝
low 2,3

Length of follow-up was not reported regarding the 262 randomized patients; median follow-up of 62 alive patients was 12.5 years (range 0 to 16.5 years)

This was an available data analysis

Overall survival 811 per 1000 4 749 per 1000
(649 to 840)
HR 0.83
(0.63 to 1.1)
262
(1 study)
⊕⊕⊝⊝
low 5,6
Length of follow-up was not reported regarding the 262 randomized patients; median follow-up of 62 alive patients was 12.5 years (range 0 to 16.5 years)
Progression-free survival - not reportedSee commentSee commentNot estimable-See commentNo information on this outcome was provided
Event-free survival 818 per 1000 4 769 per 1000
(670 to 854)
HR 0.86
(0.65 to 1.13)
262
(1 study)
⊕⊕⊝⊝
low 2,6
Length of follow-up was not reported regarding the 262 randomized patients; median follow-up of 62 alive patients was 12.5 years (range 0 to 16.5 years)
Late non-hematological toxicities: any complication, renal toxicity (Glomerular Filtration Rate < 80 ml/min per body surface area of 1.73 m2), ototoxicity (Brock grade 1 to 4), endocrine complications (see table of included studies for included disorders), neurocognitive complications (i.e. behavioral, speech, or learning difficulties), and second malignancies---57
(1 study)
⊕⊕⊝⊝
low 2,3

Length of follow-up was not reported regarding the 69 patients eligible for late toxicities (i.e. at least 5-year survivors); median follow-up for the 57 analyzed long-term survivors was 12.7 years (6.9 to 16.5 years)

Any complication: no significant difference between treatment groups (RR 0.95, 95% CI 0.71 to 1.26)

Renal toxicity: no significant difference between treatment groups (RR 0.32, 95% CI 0.09 to 1.22)

Ototoxicity: no significant difference between treatment groups (RR 1.35, 95% CI 0.73 to 2.50)

Endocrine complications: there was a significant difference in favor of the rapid COJEC arm (RR 0.42, 95% CI 0.18 to 0.96)

Neurocognitive complications: there was a significant difference in favor of the rapid COJEC arm (RR 0.27, 95% CI 0.09 to 0.79)

Second malignancies: no significant difference between treatment groups (Fischer's exact P value = 0.55)

These were all available data analyses

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; HR: hazard ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Neuroblastoma is a rare malignant disease that affects mainly infants and very young children (GARD 2013). Tumors develop in the sympathetic nervous system (e.g. in the adrenal medullary tissue or paraspinal ganglia) and may be localized or metastatic at diagnosis (Cole 2012). The median age at diagnosis is 17 months and the incidence rate of neuroblastoma is age-dependent, with an incidence rate of 64 per million children in the first year of life, falling to 29 per million children in the second year of life (Goodman 2012). The incidence rate in adults is less than one per million per year, but adults have a considerably worse prognosis (Esiashvili 2007). The International Neuroblastoma Risk Group (INRG) classification system, proposed by Cohn 2009, is shown in Table 1. The authors of Cohn 2009 estimated the event-free survival for each of the four risk groups and tested the clinical importance of 13 potential prognostic factors. The Children's Oncology Group assignment to low, intermediate, and high-risk group, published by the National Cancer Institute (NCI) at the National Institutes of Health (NIH) (NCI PDQ 2013), is shown in Table 2.

Table 1. The International Neuroblastoma Risk Group (INRG) consensus pretreatment classification schema
  1. Reference: Cohn 2009

    The International Neuroblastoma Risk Group (INRG) consensus classification schema includes the criteria for INRG stage, age, histologic category, grade of tumor differentiation, MYC-N status, presence/absence of 11q aberrations, and tumor cell ploidy. Sixteen statistically and/or clinically different pretreatment groups of patients (lettered A through R) have been identified using these criteria. The categories are designated as very low (A, B, C), low (D, E, F), intermediate (G, H, I, J), or high (K, N, O, P, Q, R) pretreatment risk subsets.

    Abbreviations: INRG: International Neuroblastoma Risk Group; MYC-N: the official gene symbol approved by the Human Genome Organisation (HUGO) Gene Nomenclature Committee (HGNC), which is a short abbreviated form of the gene name 'v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog';

INRG stageAge (months)Histologic categoryGrade of tumor differentiationMYC-N11q aberrationPloidyPretreatment risk group
CodeInterpretation
L1/L2-Ganglioneuroma maturing; ganglioneuroblastoma intermixed----AVery low
L1-Any, except ganglioneuroma or ganglioneuroblastoma-Not amplified--BVery low
Amplified--KHigh
L2< 18Any, except ganglioneuroma or ganglioneuroblastoma-Not amplifiedNo-DLow
Yes-GIntermediate
≥ 18Ganglioneuroblastoma nodular; neuroblastomaDifferentiatingNot amplifiedNo-ELow
Yes-HIntermediate
Poorly differentiated or undifferentiatedNot amplified--HIntermediate
-Amplified--NHigh
M< 18--Not amplified-HyperdiploidFLow
< 12--Not amplified-DiploidIIntermediate
12 to < 18--Not amplified-DiploidJIntermediate
< 18--Amplified--OHigh
≥ 18-----PHigh
MS< 18--Not amplifiedNo-CVery low
Yes-QHigh
Amplified--RHigh
Table 2. Children's Oncology Group (COG) assignment to low, intermediate, and high-risk group
  1. Reference: NCI PDQ 2013

    DNA index: favorable > 1 (hyperdiploid) or < 1 (hypodiploid); unfavorable = 1 (diploid)

    Abbreviations: COG: Children's Oncology Group; d: days; DNA: deoxyribonucleic acid; INPC: International Neuroblastoma Pathology Committee (also called Shimada system); INSS: The International Neuroblastoma Staging System; MYC-N: the official gene symbol approved by the Human Genome Organisation (HUGO) Gene Nomenclature Committee (HGNC), which is a short abbreviated form of the gene name 'v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog'; y: years

INSS stage Age MYC-N INPC classification DNA index Risk group
10 to 21 yAnyAnyAnyLow
2A/2B< 365 dAnyAnyAnyLow
≥ 365 d to 21 yNon-amplifiedAny-Low
≥ 365 d to 21 yAmplifiedFavorable-Low
≥ 365 d to 21 yAmplifiedUnfavorable-High
3< 365 dNon-amplifiedAnyAnyIntermediate
< 365 dAmplifiedAnyAnyHigh
≥ 365 d to 21 yNon-amplifiedFavorable-Intermediate
≥ 365 d to 21 yNon-amplifiedUnfavorable-High
≥ 365 d to 21 yAmplifiedAny-High
4< 548 dNon-amplifiedAnyAnyIntermediate
< 365 dAmplifiedAnyAnyHigh
≥ 548 d to 21 yAnyAny-High
4S< 365 dNon-amplifiedFavorable> 1Low
< 365 dNon-amplifiedAny= 1Intermediate
< 365 dNon-amplifiedUnfavorableAnyIntermediate
< 365 dAmplifiedAnyAnyHigh

An abdominal mass is the most common presentation of neuroblastoma. In general, neuroblastoma occurs at a single location, usually the medulla of the adrenal gland or along the paravertebral sympathetic chain. As approximately 70% of patients with neuroblastoma have metastatic disease at diagnosis, organ-specific symptoms may be caused by the local presence of metastases, such as eye problems associated with retrobulbar tumors, pancytopenia associated with bone marrow infiltration, abdominal distension and respiratory problems associated with liver enlargement, and paralysis and Horner syndrome associated with ganglion involvement (NCI PDQ 2013). Furthermore, neuroblastoma is associated with general signs and symptoms, such as tiredness, weakness, or pain. Some neuroblastomas regress spontaneously without therapy, whereas others progress and have a fatal outcome despite therapy. One study in infants aged younger than 12 months showed that nearly half of the study population within three years of diagnosis had a spontaneous regression at follow-up (Hero 2008). A tumor mass may be confirmed on ultrasound, X-ray, computed tomography, or magnetic resonance imaging. Guidelines for using imaging methods have been developed in response to the increased importance of image-defined factors in staging and risk assessment (Brisse 2011). The International Neuroblastoma Staging System (INSS) for neuroblastoma is shown in Table 3; INSS definitions of treatment response are shown in Table 4 (Brodeur 1993).

Table 3. The International Neuroblastoma Staging System (INSS)
  1. Reference: Brodeur 1993

    Note: Multifocal primary tumors (e.g. bilateral adrenal primary tumors) should be staged according to the greatest extent of disease, as defined above, and followed by a subscript letter M (e.g. 3M).
    1The midline is defined as the vertebral column. Tumors originating on one side and crossing the midline must infiltrate to or beyond the opposite side of the vertebral column.
    2Marrow involvement in stage 4S should be minimal (i.e. < 10% of total nucleated cells identified as malignant on bone marrow biopsy or on marrow aspirate). More extensive marrow involvement would be considered to be stage 4. An MIBG (meta-iodobenzylguanidine) scan (if performed) should be negative in the marrow.

    Abbreviations: INSS: The International Neuroblastoma Staging System;

Stage Definition
1Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumor microscopically (nodes attached to and removed with the primary tumor may be positive)
2ALocalized tumor with incomplete gross excision; representative ipsilateral non-adherent lymph nodes negative for tumor microscopically
2BLocalized tumor with or without complete gross excision, with ipsilateral non-adherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically
3Unresectable unilateral tumor infiltrating across the midline,1 with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement
4Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs (except as defined for stage 4S)
4SLocalized primary tumor (as defined for stages 1, 2A, or 2B), with dissemination limited to skin, liver, and/or bone marrow2 (limited to infants < 1 year of age)
Table 4. Response to treatment
  1. Reference: Brodeur 1993

Response Primary tumor Metastatic sites
Complete responseNo tumorNo tumor; catecholamines normal
Very good partial responseDecreased by 90% to 99%No tumor; catecholamines normal; residual 99Tc bone changes allowed
Partial responseDecreased by more than 50%All measurable sites decreased by greater than 50%. Bones and bone marrow: number of positive bone sites decreased by greater than 50%; no more than one positive bone marrow site allowed
Minimal responseNo new lesions; more than 50% reduction in any measurable lesion (primary or metastases) with less than 50% reduction in any other; less than 25% increase in any existing lesion
No responseNo new lesions; less than 50% reduction but less than 25% increase in any existing lesion
Progressive diseaseAny new lesion; greater than 25% increase in any measurable lesion; previous negative marrow positive for tumor

Description of the intervention

Intervention

The rapid COJEC schedule comprises the chemotherapeutic agents cisplatin (represented by the first C of the acronym, otherwise abbreviated P), vincristine (O), carboplatin (J), etoposide (E), and cyclophosphamide (C). The schedule is administered in eight cycles separated by intervals of 10 days and is completed within 70 days from the first to the last drug administered. One example of a rapid COJEC chemotherapeutic regimen has been reported by Pearson 2008.

In patients with high-risk neuroblastoma, the aim of the rapid COJEC schedule is to administer higher single doses of selected drugs than standard schedules over a substantially shorter treatment period, with shorter intervals between cycles. Shorter intervals and higher doses increase the dose intensity of chemotherapy, making possible earlier myeloablative autologous hematopoietic stem cell transplantation and, possibly, improving survival. However, increased toxicity such as neutropenia may compromise any favorable effect.

Comparators

Various standard cumulative chemotherapy schedules are available for induction therapy in patients with high-risk neuroblastoma prior to myeloablative autologous hematopoietic stem cell transplantation. Standard induction chemotherapy schedules are characterized by several successive administrations of drugs, and the time intervals between the drug applications are planned to allow the bone marrow to recover and to prevent high-grade toxicities. One frequently reported chemotherapy regimen for children with high-risk neuroblastoma was developed by the Memorial Sloan-Kettering Cancer Center in New York. Kushner 1994 introduced the N6 protocol including seven courses of high-dose induction chemotherapy, Cheung 2001 introduced the N7 multimodality protocol continuing the same induction chemotherapy, and Kushner 2004 reported the use of five instead of seven courses. Severe adverse events associated with such schedules are mainly hematological and include neutropenia (Ladenstein 2010). Examples of standard induction chemotherapy schedules available for use in patients with high-risk neuroblastoma include the following.

  1. The OPEC/OJEC schedule, comprising cisplatin (P), vincristine (O), carboplatin (J), etoposide (E), and cyclophosphamide (C), is administered in seven cycles separated by intervals of 21 days and is completed within 126 days from the first to the last drug administered. One example of a chemotherapeutic OPEC/OJEC regimen has been reported by Pearson 2008.

  2. Different schedules of the Children's Oncology Group (COG): One example of a chemotherapeutic COG regimen has been reported by Matthay 1999 and again recently by Matthay 2009, which comprised three cycles of cisplatin, etoposide, doxorubicin, and ifosfamide. Notice: Matthay 1999 was included in the Cochrane Review Yalcin 2013. The objective of this review was to compare the efficacy of high-dose chemotherapy and autologous bone marrow or stem cell rescue with conventional therapy in children with high-risk neuroblastoma. Other examples of different COG induction chemotherapy schedules were reported by Park 2011 and Kreissman 2013.

  3. The Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) - in English: Association for Pediatric Oncology and Hematology - schedule, comprising the alternating of so-called N5 and N6 cycles. One example of a chemotherapeutic GPOH regimen has been reported by Berthold 2005 and was used in the NB2004 trial (GPOH 2004). Notice: Berthold 2005 was also included in the Cochrane Review Yalcin 2013.

How the intervention might work

The administration of drugs in short intervals and at high tolerated doses could interfere with the recovery of cancer cells from toxic chemotherapeutic doses and could result in more cancer cell death. The substantially reduced total time of drug administration might lower the risk of drug resistance. These possible advantages, taken together, could lead to more effective treatment and improved patient survival.

Why it is important to do this review

Rapid COJEC could improve patient survival compared with standard induction therapy, but could also give rise to more frequent and more severe adverse events than standard induction therapy. The efficacy of and the adverse events associated with this therapy should be confirmed in randomized controlled trials. As the rapid COJEC schedule could be investigated in future studies, this review is important in order to evaluate the evidence base for the efficacy and possible adverse events associated with this treatment.

Objectives

The aim of this study was to evaluate the efficacy and adverse events of the rapid COJEC induction schedule as compared to standard induction schedules in patients with high-risk neuroblastoma (as defined by the International Neuroblastoma Risk Group (INRG) classification system). Outcomes of interest were complete response, early toxicity and treatment-related mortality as primary endpoints and overall survival, progression- and event-free survival, late non-hematological toxicity, and health-related quality of life as secondary endpoints.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials.

Types of participants

Patients with high-risk neuroblastoma according to the International Neuroblastoma Risk (NRG) Group (Table 1) or the Children's Oncology Group (COG) (Table 2) classification systems.

Types of interventions

Intervention

Rapid COJEC as induction chemotherapy.

Comparators

Different standard induction chemotherapy options, including:

  1. the OPEC/OJEC schedule;

  2. the COG schedule; and

  3. the GPOH schedule.

Rapid COJEC induction chemotherapy is associated with a substantially shorter treatment period, shorter intervals between cycles, and higher single doses of selected drugs than standard schedules. We planned to assess the role of the intervention in the induction period and in the initial treatment response. Consequently, the treatment initiated after the induction period will need to be identical for both the intervention and comparator schedules.

Types of outcome measures

Outcomes listed here are not used as criteria for including studies, but are the outcomes of interest within studies identified for inclusion.

Primary outcomes
  • Complete response versus other responses such as partial or no response.

  • Early toxicity: adverse events within 90 days of the therapy; incidence of all reported adverse events and severe (grade 3 and 4) events; and incidence of toxicity-related discontinuations from treatment. Results may be pooled if similar definitions are used in studies. Examples of potentially used classification systems: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 2010) and World Health Organization (WHO) toxicity grading scale for determining the severity of adverse events (ICSSC 2003).

  • Treatment-related mortality: incidence of deaths during the induction period that are classified as treatment-related or attributed to treatment complications.

Secondary outcomes
  • Overall survival (OS): death from any cause from the start of rapid COJEC or standard induction therapy.

  • Progression-free survival (PFS): time free of disease progression (death from all causes or any disease progression) from the start of rapid COJEC or standard induction therapy; patients may still have the disease but their disease is stable or showed a partial response to treatment.

  • Event-free survival (EFS): time free of any of a group of defined events (death from all causes, any sign of the disease in participants who had a complete response to treatment, any relapse or progression of the disease, or events defined by the individual study protocol) from the start of rapid COJEC or standard induction therapy; patients may still have the disease.

  • Late non-hematological toxicity such as organ toxicity and secondary malignancy.

  • Health-related quality of life measured by validated questionnaires and compared between the intervention and control groups.

Search methods for identification of studies

We used the search methods suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011) and by the Cochrane Childhood Cancer Review Group (Kremer 2008). We did not apply language restrictions.

Electronic searches

We conduced an electronic literature database search in the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 11) (Appendix 1). We searched in MEDLINE (PubMed) for articles published from 1946 to 11 November 2014 by using the search strategy shown in Appendix 2. We searched in EMBASE (Ovid) for articles published from 1980 to 11 November 2014 (Appendix 3). We tailored the terms and the syntax used for the search in MEDLINE to the requirements of the other two databases. The Cochrane Childhood Cancer Group ran the searches in the three mentioned electronic databases. The review authors ran all other searches.

We searched for ongoing trials by scanning two online registries, ClinicalTrials.gov (ClinicalTrials.gov 2014) and the World Health Organization International Clinical Trials Registry Platform (ICTRP 2014), on 3 April 2014 using the term 'neuroblastoma' in the search field 'condition' and the term 'rapid cojec' in the search field 'intervention'.

We searched for abstracts presented at the annual meetings of the American Society of Clinical Oncology (ASCO), the International Society of Paediatric Oncology (SIOP), and the Advances in Neuroblastoma Research (ANR) (all 2009 to 2013), which were available for online searching. We requested an online search of the ASCO abstracts using the term 'neuroblastoma' AND 'rapid' AND 'cojec' in the search fields 'title' and 'abstract'. We handsearched the SIOP and ANR abstracts.

Searching other resources

We searched for information about trials not registered in electronic databases in reference lists of relevant articles and review articles.

Data collection and analysis

Selection of studies

While preparing this systematic review, we endorsed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, adhered to its principles, and conformed to its checklist (Moher 2009). We downloaded all titles and abstracts retrieved by electronic searching to the reference management database EndNote 2014, removed duplicates, and two review authors independently examined the remaining references. We included a study selection flow chart in the review. We obtained the full texts of potentially relevant references. Two authors independently assessed the eligibility of retrieved papers. Disagreements were resolved by discussion between the two review authors and consultation with a third author if necessary. We documented reasons for exclusion. If we identified multiple reports of one study we used the latest results. We checked the multiple reports for possible duplicate data, addressed the issue, and did not include duplicate data in the analysis.

Data extraction and management

For each included study, two authors independently abstracted data on study design, patient characteristics (such as inclusion criteria, age, stage, co-morbidity, previous treatment, number enrolled in each arm), interventions (such as type of rapid COJEC and standard induction therapy, dose applied, duration of therapy), risk of bias, duration of follow-up, and outcomes. We resolved differences between review authors by discussion or by appeal to a third author.

For time-to-event data, such as survival, we extracted the hazard ratio (HR) and its standard error or confidence interval from trial reports; if these were not reported, we estimated the logHR and its standard error using the methods of Parmar 1998 and using the tool provided by Tierney 2007. For dichotomous outcomes (e.g. response, toxicity, and treatment-related mortality), we extracted the number of patients in each treatment arm who experienced the outcome of interest and the number of patients assessed at endpoint, in order to estimate a risk ratio. For continuous outcomes (e.g. quality of life measures), we planned to extract the final value or change from baseline and corresponding standard deviation of the outcome of interest and the number of patients assessed at endpoint in each treatment arm at the end of follow-up to estimate the mean difference or standardized mean difference between treatment arms. However, since no data on health-related quality of life were available this was not applicable. Where possible, all data extracted are those relevant to an intention-to-treat analysis, in which all participants are analyzed in the groups to which they were assigned. If this was not possible we stated this. We noted the time points at which outcomes were collected and reported.

Assessment of risk of bias in included studies

Two authors independently appraised the risk of bias in the included studies. We resolved differences between review authors by discussion or by appeal to a third author. We used the items listed in the Cochrane Childhood Cancer Group manual (Kremer 2008), which is based on The Cochrane Collaboration's tool for assessing risk of bias (Higgins 2011), but the Cochrane Childhood Cancer Group has made some adjustments:

  1. Random sequence generation (selection bias).

  2. Allocation concealment (selection bias).

  3. Blinding of participants (performance bias).

  4. Blinding of personnel (performance bias).

  5. Blinding of outcome assessment (detection bias) was assessed for each outcome separately.

  6. Incomplete outcome data, such as missing data, was assessed for each outcome separately (attrition bias).

  7. Selective reporting, such as not reporting pre-specified outcomes (reporting bias).

  8. Other sources of bias, such as bias related to the specific study design (other bias).

We applied The Cochrane Collaboration's tool for assessing risk of bias (Higgins 2011). In general, a 'low risk' of bias is judged if plausible bias is unlikely to seriously alter the results, for example, participants and investigators enrolling participants could not foresee assignment. A 'high risk' of bias is judged if plausible bias seriously weakens confidence in the results, for example, participants or investigators enrolling participants could possibly foresee assignments. 'Unclear' risk of bias is judged if plausible bias raises some doubt about the results, for example, the method of concealment is not described or not described in sufficient detail to allow a definite judgement. In addition to the 'Risk of bias' tables, we included 'methodological quality' summaries. We took into account the results of the 'Risk of bias' assessment when interpreting the results of the review.

Measures of treatment effect

For analyses of time-to-event data, the primary effect measure was the hazard ratio. If the hazard ratio was not directly given in the publication, we estimated hazard ratios according to the methods proposed by Parmar 1998 and Tierney 2007. We calculated the hazard ratio using the inverse variance method in a random-effects model.

For dichotomous outcomes, the primary effect measure was the risk ratio. We calculated the risk ratio using the Mantel-Haenszel method in a random-effects model. We did not observe rare events and thus did not apply the Peto odds ratio method. For outcomes where only one study was available, we were unable to calculate a risk ratio if one of the treatment groups experienced no events, and we used the Fisher's exact test instead.

We planned to analyze and present continuous data using the mean difference, if all results were measured on the same scale. If this was not the case, we planned to use the standardized mean difference. However, we did not identify continuous data.

Unit of analysis issues

We did not encounter any unit of analysis issues.

Dealing with missing data

We conformed to The Cochrane Collaboration's principal options for dealing with missing data (Higgins 2011). We contacted the authors of the included study, CCLG-ENSG-5, to clarify the methods used to analyze the time-to-event data. We contacted the authors of the included study, CCLG-ENSG-5, to clarify contrasting numbers of patients with respect to overall response in figure 1 and table 5 of the article Pearson et al 2008. We contacted the authors of the ongoing study HR-NBL1/SIOPEN to clarify the expected completion of recruiting participants and the expected publication of the analyzed data. There was no need to contact authors with respect to study selection.

We completed all analyses on an available case analysis basis, with the exception of two outcomes, the overall survival analysis and event-free survival analysis. We conducted both of these analyses on an intention-to-treat basis, using the methods of Parmar 1998 to obtain the necessary data for the analysis.

Assessment of heterogeneity

We planned to assess heterogeneity between studies by visual inspection of forest plots, by estimation of the percentage of heterogeneity between trials that cannot be ascribed to sampling variation (I2 statistic) (Higgins 2003) and, if possible, by subgroup analyses. If there was evidence of substantial heterogeneity, we planned to investigate and report the possible reasons for this. We considered an I2 value greater than 50% to indicate substantial heterogeneity. However, since only one study was included in this review, this was not applicable.

Assessment of reporting biases

In addition to the evaluation of reporting bias as described in the Assessment of risk of bias in included studies section, we planned to assess reporting bias (such as publication bias, time lag bias, multiple publication bias, location bias, citation bias, language bias) by constructing a funnel plot when there were a sufficient number of included studies (that is at least 10 studies included in a meta-analysis) because otherwise the power of the tests is too low to distinguish chance from real asymmetry (Higgins 2011). Since only one study could be included in the review, this was not applicable.

Data synthesis

We analyzed the data using Review Manager 2013. This was done by one author and checked by another. If sufficient clinically similar studies were available, we planned to pool their results, but since only one study was included this was not applicable. We did not identify trials with multiple groups that 'shared' a comparison group, so it was not necessary to divide the 'shared' comparison group into the number of treatment groups and comparisons between each treatment group and treat the split comparison group as independent comparisons. We used random-effects models with inverse variance weighting for all analyses (DerSimonian 1986). We calculated all risk ratio (RR), hazard ratio (HR), 95% confidence interval (CI), and P values mentioned in the results in Review Manager 2013, with the exception of the Fisher's exact P value (calculated in statcalc.exe).

We used GRADEpro 2008 to create the 'Summary of findings' table as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We presented complete response, early toxicity, treatment-related mortality, overall survival, progression-free survival, event-free survival, and late non-hematological toxicity provided that data were presented for both treatment arms.

Subgroup analysis and investigation of heterogeneity

We planned a subgroup analysis based on age (younger than 12 months versus 12 months and older). Patients younger than 12 months have a better prognosis than older children. A considerable proportion of patients younger than 12 months have tumor features that are associated with spontaneous regression. As a consequence, the INSS limits stage 4S to infants younger than 12 months of age (Brodeur 1993) and the COG assignment uses the age of 365 days as a cut-off for stage and risk group assignments (NCI PDQ 2013). However, the included study did not provide enough data to be able to do this.

Sensitivity analysis

We planned to conduct sensitivity analyses of studies with low risk of bias versus studies with high or uncertain risk of bias. We identified a single study with an uncertain risk of bias. A sensitivity analysis was not applicable.

Results

Description of studies

Results of the search

Running the searches in the electronic databases CENTRAL, MEDLINE, and EMBASE yielded a total of 250 references (Figure 1). We identified one additional reference through searching the ongoing trials registries. We identified two abstracts associated with the publication by Moreno et al 2013 in the proceedings of the Advances in Neuroblastoma Research (ANR) 2010 conference. We added the abstracts to the references of the CCLG-ENSG-5 study. Scanning the conference proceedings of the American Society of Clinical Oncology (ASCO) and the International Society of Paediatric Oncology (SIOP), as well as the reference lists of relevant studies, did not identify any additional references. Following initial screening of the titles, abstracts, or both, we excluded 225 references, which clearly did not meet all criteria required for considering studies for this review. We assessed the 28 remaining references in full, of which four fulfilled all the criteria for considering studies for this review and were thus eligible for inclusion. These four publications described the same study, so the total number of included studies was one (CCLG-ENSG-5). The publication by Pearson et al 2008 reported the main information and results of the included RCT. The publication by Moreno et al 2013 updated the data on late toxicity. As mentioned above, two further conference abstracts were linked to Moreno et al 2013. We identified one ongoing study (see Characteristics of ongoing studies table). We excluded the other 23 references. See Figure 1 providing an overview of reference and study selection.

Figure 1.

Study flow diagram.

Included studies

The characteristics of the one included study CCLG-ENSG-5 are also described in the Characteristics of included studies table. The name of the study is composed of two abbreviations. CCLG stands for Children's Cancer and Leukaemia Group, the trial lead organization. ENSG-5 stands for European Neuroblastoma Group Fifth Study.

Design

We included one study that we judged to be a randomized, prospective, parallel, controlled clinical trial. The study CCLG-ENSG-5 enrolled patients from 1990 to 1999.

Sample sizes

The study CCLG-ENSG-5 randomized 262 patients with high-risk neuroblastoma to induction chemotherapy, either rapid COJEC (N = 130) or standard OPEC/COJEC (N = 132).

Setting

The study CCLG-ENSG-5 was conducted as a multi-center study in 29 centres in Europe including Belgium, Denmark, Ireland, Norway, Sweden, and the UK. The study center was the Children's Cancer and Leukaemia Group located at the University of Leicester in the UK.

Participants

The study CCLG-ENSG-5 included patients aged 12 months and older and adults who fulfilled the International Neuroblastoma Staging System (INSS) criteria for stage 4 neuroblastoma and who had not received previous chemotherapy for their disease were eligible. Patients with stage 4S neuroblastoma were not eligible. The characteristics of the participants were fairly comparable between the rapid COJEC arm and the standard arm. The median age was 2.86 in the rapid COJEC arm and 2.98 in the standard arm. The proportions in the rapid COJEC arm versus the standard arm were: male gender 58% versus 57%, bone marrow involvement 82% versus 83%, lymph node metastases 62% versus 63%, multiple bone metastases 61% versus 58%. MYC-N amplified was found more often in the rapid COJEC arm (43%) compared to the standard arm (33%). Follow-up time was not reported regarding the 262 randomized patients. The median follow-up of 62 alive patients in the Pearson et al 2008 publication was 12.5 years (range 0 to 16.5). Follow-up time was not reported regarding the 69 patients eligible for long-term follow-up who survived five years. The median follow-up of 57 analyzed long-term survivors in the Moreno et al 2013 publication was 12.7 years (6.9 to 16.5).

Interventions

The study CCLG-ENSG-5 randomized 130 patients to the rapid COJEC arm. The rapid COJEC arm treatment consisted of eight alternating courses given over 10 weeks (see Characteristics of included studies table for more treatment details).

The study CCLG-ENSG-5 randomized 132 patients to the standard arm. The standard arm treatment consisted of seven alternating courses given over 18 weeks (see Characteristics of included studies table for more treatment details).

The study CCLG-ENSG-5 assigned all 262 patients to receive the same five different chemotherapeutic agents with almost the same total doses. However, the daily doses and the time schedules were quite different at least for some treatment components.

Primary outcome

The study CCLG-ENSG-5 reported the following primary outcomes defined by the present review:

  • Complete response

  • Early toxicity

  • Treatment-related mortality

Secondary outcomes

The study CCLG-ENSG-5 reported the following secondary outcomes defined by the present review:

  • Overall survival

  • Event-free survival

  • Late non-hematological toxicity (updated by the publication by Moreno et al 2013)

Progression-free survival and health-related quality of life were not reported.

Excluded studies

We excluded 23 publications (Figure 1). We determined the reasons for exclusions as follows:

  • not population of interest: high-risk neuroblastoma (N = 0);

  • not intervention of interest: not rapid COJEC as a induction chemotherapy (N = 15);

  • not comparator of interest: standard induction chemotherapy such as OPEC/OJEC, COG, or GPOH schedules (N = 3);

  • not outcome of interest (N = 0);

  • not publication type or study type of interest such as systematic or nonsystematic review, editorial, letter, duplicate data, or not a randomized controlled trial (N = 5).

We described the excluded studies in the Characteristics of excluded studies table.

Risk of bias in included studies

The 'Risk of bias' table Characteristics of included studies provides details of each item of the 'Risk of bias' tool for randomized controlled trials. Figure 2 and Figure 3 provide an overview.

Figure 2.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Allocation

In the study CCLG-ENSG-5, allocation concealment was achieved by telephone contact to a study center (N = 251) and by sealed envelopes during out-of-hours (N = 11). We judged a low risk for the 251 patients and an unclear risk for the 11 patients since it was not reported if the envelopes were opaque. However, since it was unclear if the sequence generation was random we judged the risk of selection bias to be unclear.

Blinding

The study CCLG-ENSG-5 did not report on blinding of participants and personnel, so we judged an unclear risk of performance bias. Blinding of outcome assessors was also not reported, so we judged the risk of detection bias to be unclear, with the exception of the risk of detection bias for overall survival. Since blinding of the outcome assessor is not relevant for this outcome here we judged the risk of detection bias to be low. 

Incomplete outcome data

For all reported outcomes, i.e. complete response, early toxicity, treatment-related death, overall survival, event-free survival, and late non-hematological toxicities, we judged the risk of attrition bias to be high.

Selective reporting

In CCLG-ENSG-5, we did not identify any sign of selective reporting comparing the outcomes and methods of the publication with those of published protocol items at ClinicalTrials.gov (http://www.clinicaltrials.gov/ct2/show/NCT00365755) and at the National Cancer Institute (http://www.cancer.gov/clinicaltrials/search/view?cdrid=454576&version=HealthProfessional), so we judged this to be a low risk of reporting bias.

Other potential sources of bias

We judged the risk for other potential sources of bias to be unclear. A full explanation can be found in the risk of bias part of the table of included studies. 

Effects of interventions

See: Summary of findings for the main comparison Rapid COJEC compared to standard induction therapies for high-risk neuroblastoma

Primary outcomes

Complete response

The original article of Pearson et al 2008 reported different numbers regarding response in table 5 and figure 1. After asking the authors for clarification, it became clear that none of the options mentioned in the original article were correct. The authors provided us with the correct numbers, which we used in our analysis.

In the study (CCLG-ENSG-5), 62% of patients (80 of 130) in the rapid COJEC arm and 68% of patients (90 of 132) in the standard arm were assessed for overall response. A complete response was achieved by 45% (36 of 80) of patients in the rapid COJEC arm and 46% (41 of 90) of patients in the standard arm, as confirmed by the authors of the article by Pearson et al 2008. In the available data analysis, we chose complete response as the favorable outcome that was compared to all other responses including very good partial response, partial response, mixed response, no response, and progressive disease. The risk ratio of 0.99 (95% confidence interval (CI) 0.71 to 1.38, P value = 0.94) was not statistically significant (Analysis 1.1; Figure 4). Please note that due to the nature of this measurement (that is, the number of patients with a complete remission) a high event rate is favorable. Therefore, in the figure of this analysis 'favors standard' is on the left and 'favors rapid COJEC' is on the right, as opposed to the figures for the other analyses.

Figure 4.

Forest plot of comparison: 1 Rapid COJEC versus standard induction, outcome: 1.1 Complete response.

Early toxicity

In the study CCLG-ENSG-5, the authors reported toxic effects during preoperative chemotherapy. For each subgroup, we presented the data from the rapid COJEC arm versus the data from the standard arm.

Febrile neutropenia (two or more episodes): 94% (116 of 123) versus 77% (96 versus 125). The relative risk between the two event rates was statistically significant: risk ratio 1.23 (95% CI 1.10 to 1.36, P value = 0.0001) (Analysis 1.2; Figure 5). Please note that this was an available data analysis.

Figure 5.

Forest plot of comparison: 1 Rapid COJEC versus standard induction, outcome: 1.2 Early toxicities.

Proven fungal infections: 2% (2 of 100) versus 0.8% (1 of 125). The relative risk between the two event rates was not statistically significant: risk ratio 2.50 (95% CI 0.23 to 27.18, P value = 0.45) (Analysis 1.2; Figure 5). Please note that this was an available data analysis.

Number of patients with septicemia (one or more episodes): 45% (55 of 122) versus 28% (35 of 125). The relative risk between the two event rates was statistically significant: risk ratio 1.61 (95% CI 1.14 to 2.27, P value = 0.006) (Analysis 1.2; Figure 5). Please note that this was an available data analysis.

Grade 3 or 4 gastrointestinal toxic effects: 35% (43 of 122) versus 25% (31 of 124). The relative risk between the two event rates was not statistically significant: risk ratio 1.41 (95% CI 0.96 to 2.08, P value = 0.08) (Analysis 1.2; Figure 5). Please note that this was an available data analysis.

Renal toxic effects, where glomerular filtration rate (GFR) < 80 ml/min per body surface area of 1.73m2: (37% (46 of 124) versus 17% (21 of 124). The relative risk between the two event rates was statistically significant: risk ratio 2.19 (95% CI 1.39 to 3.44, P value = 0.0007) (Analysis 1.2; Figure 5). Please note that this was an available data analysis.

Grade 3 or 4 neurological toxic effects: 4.9% (6 of 122) versus 1.6% (2 of 125). The relative risk between the two event rates was not statistically significant: risk ratio 3.07 (95% CI 0.63 to 14.93, P value = 0.16) (Analysis 1.2; Figure 5). Please note that this was an available data analysis.

Ototoxicity (Brock 2 to 4): 5.8% (4 of 69) versus 5.6% (4 of 72). The relative risk between the two event rates was not statistically significant: risk ratio 1.04 (95% CI 0.27 to 4.01, P value = 0.95) (Analysis 1.2; Figure 5). Please note that this was an available data analysis.

Treatment-related mortality

The authors of the study CCLG-ENSG-5 reported that treatment-related deaths occurred in 4% of patients (5 of 119) in the rapid COJEC arm and in 3% of patients (4 of 115) in the standard arm. In the available data analysis, the risk ratio of 1.21 (95% CI 0.33 to 4.39, P value = 0.77) was not statistically significant (Analysis 1.3; Figure 6).

Figure 6.

Forest plot of comparison: 1 Rapid COJEC versus standard induction, outcome: 1.3 Treatment-related mortality.

Secondary outcomes

Overall survival

The overall survival analysis was done on an intention-to-treat basis. In the study CCLG-ENSG-5, the hazard ratio of overall survival of 0.83 (95% CI 0.63 to 1.10, P value = 0.19) was not statistically significant (Analysis 1.4). We used Parmar's method to obtain the necessary data for the analysis.

Progression-free survival

We did not find data on progression-free survival in the study CCLG-ENSG-5.

Event-free survival

We conducted the event-free survival analysis on an intention-to-treat basis. In the study CCLG-ENSG-5, the hazard ratio of event-free survival of 0.86 (95% CI 0.65 to 1.13, P value = 0.28) was not statistically significant (Analysis 1.5). We used Parmar's method to obtain the necessary data for the analysis.

Late non-hematological toxicity

In the study CCLG-ENSG-5, the authors reported data on late non-hematological toxicity in the publication by Moreno et al 2013. The authors considered data from patients who survived at least five years after diagnosis. They identified 69 of 262 patients as eligible, excluded data from 12 patients, and finally analyzed data from 57 patients. After a median follow-up of 12.7 years (6.9 to 16.5), the following number of adverse events/total number of patients in the particular organ subgroup were observed in the rapid COJEC arm versus the standard arm. The number of events present the number of patients with at least one complication. Neurocognitive issues comprise behavioral, speech, or learning difficulties.

Complications independent of the type of organ system affected: 75.7% (28 of 37) versus 80.0% (16 of 20). The relative risk between the two event rates was not statistically significant: risk ratio 0.95 (95% CI 0.71 to 1.26, P value = 0.70) (Analysis 1.6).

Renal toxicity, glomerular filtration rate less than 80 ml/(min * 1.73 m2): 8.1% (3 of 37) versus 25% (5 of 20). The relative risk between the two event rates was not statistically significant: risk ratio 0.32 (95% CI 0.09 to 1.22, P value = 0.10) (Analysis 1.6).

Hearing loss: 54.1% (20 of 37) versus 40.0% (8 of 20). The relative risk between the two event rates was not statistically significant: risk ratio 1.35 (95% CI 0.73 to 2.50, P value = 0.34) (Analysis 1.6).

Endocrine complication: 18.9% (7 of 37) versus 45.0% (9 of 20). The event rate in the rapid COJEC arm was statistically significantly lower than in the standard arm: risk ratio 0.42 (95% CI 0.18 to 0.96, P value = 0.04) (Analysis 1.6).

Neurocognitive complication: 10.8% (4 of 37) versus 40.0% (8 of 20). The event rate in the rapid COJEC arm was statistically significantly lower than in the standard arm: risk ratio 0.27 (95% CI 0.09 to 0.79, P value = 0.02) (Analysis 1.6).

Second malignancies: 8.1% (3 of 37) in the rapid COJEC arm versus 0% (0 of 20) in the standard arm had second malignancies. Since in one of the treatment groups there were no events we were unable to calculate a relative risk, so we used Fisher's exact test instead: Fisher's exact P value = 0.55. The three second malignancies were osteosarcoma, carcinoma of the parotid gland, and anaplastic ependymoma. They developed 10.1 to 11.4 years after the neuroblastoma diagnosis. It should be noted that one patient in the standard arm developed a rhabdomyosarcoma 2.3 years after the neuroblastoma diagnosis. This patient was not included in this analysis as she died before becoming a long-term survivor (i.e. five years from neuroblastoma diagnosis).

Health-related quality of life

We did not find data on health-related quality of life in the study CCLG-ENSG-5.

Discussion

Summary of main results

This systematic review evaluated the current state of evidence on the efficacy of rapid COJEC versus standard induction therapy in patients diagnosed with high-risk neuroblastoma.

We identified one randomized controlled trial (RCT) (CCLG-ENSG-5), which included 262 patients with high-risk neuroblastoma who received induction chemotherapy by a randomized allocation to rapid COJEC (n = 130) or standard induction therapy (n = 132). The primary objectives of study CCLG-ENSG-5 were to "to compare survival, treatment response and dose-limiting treatment-related severe adverse events in patients with high-risk neuroblastoma receiving induction therapy with either rapid COJEC or a standard schedule".

There was no statistically significant difference between the treatment groups in complete response (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.71 to 1.38, P value = 0.94, low quality of evidence), treatment-related mortality (RR 1.21, 95% CI 0.33 to 4.39, P value = 0.77, low quality evidence), overall survival (hazard ratio (HR) 0.83, 95% CI 0.63 to 1.10, P value = 0.19, low quality of evidence), and event-free survival (HR 0.86, 95% CI 0.65 to 1.13, P value = 0.28, low quality of evidence). We calculated the HRs using the complete follow-up period of the trial.

Both treatment arms received the same treatment including the same drugs and the same total dose. Therefore, adverse events caused by the type or dose of a chemotherapeutic substance are not to be expected different between the two arms. Nevertheless, the increased time intensity in the rapid COJEC arm or the longer drug application period in the standard arm may cause differences in the frequency of adverse events between the two arms.

With regard to early toxicities (during pre-operative chemotherapy) the study provided data on febrile neutropenia (two or more episodes), proven fungal infections, septicemia (one or more episodes), gastrointestinal toxicity (grade 3 or 4), renal toxicity (glomerular filtration rate < 80 ml/min per body surface area of 1.73 m2), neurological toxicity (grade 3 or 4), and ototoxicity (Brock grade 2 to 4). For febrile neutropenia, septicemia, and renal toxicity, we identified a statistically significant difference in favor of the standard treatment arm (low quality evidence); for all other early toxicities, we identified no statistically significant difference between treatment groups (low quality evidence).

With regard to late non-hematological toxicities (median follow-up 12.7 years; range 6.9 to 16.5 years), the study provided data on any complication, renal toxicity (glomerular filtration rate < 80 ml/min per body surface area of 1.73 m2), ototoxicity (Brock grade 1 to 4), endocrine complications (see Characteristics of included studies table for included disorders), neurocognitive complications (i.e. behavioral, speech, or learning difficulties), and second malignancies. For endocrine complications and neurocognitive complications we found a statistically significant difference in favor of the rapid COJEC arm (low quality evidence); for all other late non-hematological toxicities, we identified no statistically significant difference between treatment groups (low quality evidence).

No data were available for the other outcomes of interest (i.e. progression-free survival and health-related quality of life) (see Summary of findings for the main comparison).

Overall completeness and applicability of evidence

The inclusion of only one study in the present review limits the inferences we can make from the extracted data. 'No evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. The reason that no statistically significant difference between study groups was identified could be the fact that the number of patients included was too small to detect a difference between the treatment groups (i.e. low power). Although the exact length of follow-up for the patients of interest was not mentioned, it could have been too short to detect a significant difference between the treatment groups.

Furthermore, patients were treated in the time period from 1990 to 1999 (CCLG-ENSG-5). The applicability of these data to current clinical practice is considerably restricted as medical knowledge and terms of health care have progressed and changed significantly since then. Thus, the results may not be applicable to patients who are treated today. Since only one eligible study was identified we could not assess this issue.

Another point is that the included RCT used an age of one year as the cut-off point for pre-treatment risk stratification. Recently, the age cut-off for high-risk disease was changed from one year to 18 months (Cohn 2009). As a result, it is possible that patients with what is now classified as intermediate-risk disease were included in the high-risk groups. Consequently the relevance of the results of these studies to current practice can be questioned. Survival rates may be overestimated due to the inclusion of patients with intermediate-risk disease.

Finally, the included study did not provide data on progression-free survival and health-related quality of life in these patients. As a result we cannot make any conclusions regarding those outcomes, but they are of course important for clinical practice.

As reported by Moreno et al in their 2013 publication (CCLG-ENSG-5), 77.2% of long-term survivors (44 of 57) treated with either treatment option had some sort of complication and as 19.3% (11 of 57) had severe complications, tight monitoring of late toxicity is recommended for all patients having received rapid COJEC or standard induction therapy.

We only included RCTs since it is widely recognized that a RCT is the only study design that can be used to obtain unbiased evidence on the use of different treatment options, provided that the design and execution of the RCTs are adequate. However, even though RCTs are the highest level of evidence, it should be recognized that data from non-randomized studies are available.

Quality of the evidence

The risk of bias in the included study was difficult to assess, in part due to a lack of reporting. As a result, the presence of selection bias, performance bias, detection bias (for outcomes other than overall survival), and other bias could not be ruled out. There was a high risk of attrition bias for all included outcomes. However, at the moment this is the best available evidence from RCTs comparing the efficacy of rapid COJEC versus standard induction therapy in high-risk neuroblastoma patients.

Based on the GRADE assessments, for which we have looked at the five GRADE considerations study limitations, consistency of effect, imprecision, indirectness, and publication bias, we judged the quality of the evidence for the outcomes for which data were available as being low; we downgraded for risk of bias and imprecision (see Summary of findings for the main comparison).

Potential biases in the review process

One of the strengths of this systematic review is the broadness of the search strategy such that study retrieval bias is very unlikely. Nevertheless, there remains a slight possibility that an unknown number of studies were not registered and not published. Duplicate publication bias is very unlikely because we searched for follow-up papers of a single study, to ensure that we included the updated version, and we excluded secondary analyses of registers or databases, which may use data that have been published previously by individual contributing study centers. Overall, the possible presence of reporting bias seems to be low.

Authors' conclusions

Implications for practice

We identified one randomized controlled trial (RCT) that evaluated rapid COJEC as an induction therapy versus standard induction therapy in patients with high-risk neuroblastoma. The difference in complete response and treatment-related toxicity, as well as overall survival and event-free survival, between the treatment alternatives was not statistically significantly different. This could be the result of low power or too short a follow-up period. Results of both early and late toxicities were ambiguous. Information on progression-free survival and health-related quality of life were not available. Also, this trial was performed between 1990 and 1999; since then many changes in, for example, treatment and risk classification have occurred. Therefore, based on the currently available evidence, we are uncertain about the effects of rapid COJEC and standard induction therapy in patients with high-risk neuroblastoma. More research is needed for a definitive conclusion.

Implications for research

Future trials on the use of rapid COJEC as an induction therapy for children with high-risk neuroblastoma should be RCTs focusing on survival, early and late adverse events, and quality of life. RCTs should be performed in homogeneous study populations (for example, stage of disease) and have a long-term follow-up. The number of included patients should be sufficient to obtain the power needed for the results to be reliable. Different risk groups, using the most recent definitions, should be taken into account. For example, potential subgroups of patients may benefit from rapid COJEC.

Acknowledgements

The editorial base of the Cochrane Childhood Cancer Group is funded by Stichting Kinderen Kankervrij (KiKa). We would like to thank Edith Leclercq, the Trials Search Co-ordinator of the Childhood Cancer Group, for running the search strategy in the different databases and providing us with the titles and abstracts of the searches. We thank Ruth Ladenstein for providing information about the ongoing study HR-NBL1/SIOPEN. We thank the editors and peer reviewers for their helpful comments.

Data and analyses

Download statistical data

Comparison 1. Rapid COJEC versus standard induction
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Complete response1170Risk Ratio (M-H, Random, 95% CI)0.99 [0.71, 1.38]
2 Early toxicities1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Febrile neutropenia (two or more episodes)1248Risk Ratio (M-H, Random, 95% CI)1.23 [1.10, 1.36]
2.2 Proven fungal infections1225Risk Ratio (M-H, Random, 95% CI)2.5 [0.23, 27.18]
2.3 Number of patients with septicemia (one or more episodes)1247Risk Ratio (M-H, Random, 95% CI)1.61 [1.14, 2.27]
2.4 Grade 3 or 4 gastrointestinal toxic effects1246Risk Ratio (M-H, Random, 95% CI)1.41 [0.96, 2.08]
2.5 Renal toxicity, GFR < 80 ml/(min*1.73m*m)1248Risk Ratio (M-H, Random, 95% CI)2.19 [1.39, 3.44]
2.6 Grade 3 or 4 neurological toxic effects1247Risk Ratio (M-H, Random, 95% CI)3.07 [0.63, 14.93]
2.7 Ototoxicity (Brock 2 to 4)1141Risk Ratio (M-H, Random, 95% CI)1.04 [0.27, 4.01]
3 Treatment-related mortality1234Risk Ratio (M-H, Random, 95% CI)1.21 [0.33, 4.39]
4 Overall survival1262Hazard Ratio (Random, 95% CI)0.83 [0.63, 1.10]
5 Event-free survival1262Hazard Ratio (Random, 95% CI)0.86 [0.65, 1.13]
6 Late non-hematological toxicities1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
6.1 Complications157Risk Ratio (M-H, Random, 95% CI)0.95 [0.71, 1.26]
6.2 Renal toxicity, GFR < 80 ml/(min*1.73m*m)157Risk Ratio (M-H, Random, 95% CI)0.32 [0.09, 1.22]
6.3 Hearing loss157Risk Ratio (M-H, Random, 95% CI)1.35 [0.73, 2.50]
6.4 Endocrine complication157Risk Ratio (M-H, Random, 95% CI)0.42 [0.18, 0.96]
6.5 Neurocognitive complication157Risk Ratio (M-H, Random, 95% CI)0.27 [0.09, 0.79]
Analysis 1.1.

Comparison 1 Rapid COJEC versus standard induction, Outcome 1 Complete response.

Analysis 1.2.

Comparison 1 Rapid COJEC versus standard induction, Outcome 2 Early toxicities.

Analysis 1.3.

Comparison 1 Rapid COJEC versus standard induction, Outcome 3 Treatment-related mortality.

Analysis 1.4.

Comparison 1 Rapid COJEC versus standard induction, Outcome 4 Overall survival.

Analysis 1.5.

Comparison 1 Rapid COJEC versus standard induction, Outcome 5 Event-free survival.

Analysis 1.6.

Comparison 1 Rapid COJEC versus standard induction, Outcome 6 Late non-hematological toxicities.

Appendices

Appendix 1. Search strategy for Cochrane Central Register of Controlled Trials (CENTRAL)

1. For COJEC the following text words were used:

induction therapy OR consolidation therapy OR OPEC OR OJEC OR COJEC OR rapid COJEC OR (carboplatin AND cisplatin AND cyclophosphamide AND etoposide AND vincristine)

For carboplatin, cisplatin, cyclophosphamide, etoposide and vincristine the following search strategies were applied:

Carboplatin

Carboplatin OR cis-Diammine(cyclobutanedicarboxylato)platinum II OR CBDCA OR Carbosin OR Pharmachemie Brand of Carboplatin OR Carbotec OR Columbia Brand of Carboplatin OR Ercar OR Almirall Brand of Carboplatin OR JM-8 OR JM 8 OR JM8 OR Neocarbo OR Neocorp Brand of Carboplatin OR NSC-241240 OR NSC 241240 OR NSC241240 OR Paraplatin OR Carboplat OR Paraplatine OR Bristol-Myers Squibb Brand of Carboplatin OR Platinwas OR Chiesi Brand of Carboplatin OR Ribocarbo OR ribosepharm Brand of Carboplatin OR Blastocarb OR Lemery Brand of Carboplatin OR Nealorin OR Prasfarma Brand of Carboplatin OR carboplatin*

Cisplatinum

Cisplatin OR cis-Diamminedichloroplatinum(II) OR Platinum Diamminodichloride OR Diamminodichloride, Platinum OR cis-Platinum OR cis Platinum OR Dichlorodiammineplatinum OR cis-Diamminedichloroplatinum OR cis Diamminedichloroplatinum OR cisDichlorodiammineplatinum(II) OR Platinol OR Platidiam OR Platino OR NSC-119875 OR Biocisplatinum OR CDDP OR CACP OR cisplatin* OR abiplatin OR neoplatin OR cis-DDP

Cyclophosphamide

cyclophosphamide OR cyclophosphane OR cytophosphan OR B-518 OR cyclophosphamide monohydrate OR monohydrate, cyclophosphamide OR endoxan OR cytoxan OR neosar OR procytox OR sendoxan OR NSC-26271 OR NSC 26271 OR NSC26271 OR cyclophosphamide, (R)-isomer OR cyclophosphamide, (S)-isomer OR endox* OR cyclophospha*

Etoposide

etoposide OR etoposid* OR Eposide OR Eposin OR 33419-42-0

Vincristine

vincristine OR vincristin* OR 57-22-7

2. For Neuroblastoma the following text words were used:

neuroblastoma OR neuroblastomas OR neuroblast* OR ganglioneuroblastoma OR ganglioneuroblastomas OR ganglioneuroblast* OR neuroepithelioma OR neuroepitheliomas OR neuroepitheliom* OR esthesioneuroblastoma OR esthesioneuroblastomas OR esthesioneuroblastom* OR schwannian

Final search 1 and 2
The search was performed in title, abstract or keywords

[* = zero or more characters]

Appendix 2. Search strategy for PubMed

1. For COJEC the following MeSH headings and text words were used:

induction therapy[tiab] OR consolidation therapy[tiab] OR OPEC OR OJEC OR COJEC OR rapid COJEC OR (carboplatin AND cisplatin AND cyclophosphamide AND etoposide AND vincristine).

For carboplatin, cisplatin, cyclophosphamide, etoposide and vincristine the following search strategies were applied:

Carboplatin

Carboplatin OR cis-Diammine(cyclobutanedicarboxylato)platinum II OR CBDCA OR Carbosin OR Pharmachemie Brand of Carboplatin OR Carbotec OR Columbia Brand of Carboplatin OR Ercar OR Almirall Brand of Carboplatin OR JM-8 OR JM 8 OR JM8 OR Neocarbo OR Neocorp Brand of Carboplatin OR NSC-241240 OR NSC 241240 OR NSC241240 OR Paraplatin OR Carboplat OR Paraplatine OR Bristol-Myers Squibb Brand of Carboplatin OR Platinwas OR Chiesi Brand of Carboplatin OR Ribocarbo OR ribosepharm Brand of Carboplatin OR Blastocarb OR Lemery Brand of Carboplatin OR Nealorin OR Prasfarma Brand of Carboplatin OR carboplatin*

Cisplatinum

Cisplatin OR cis-Diamminedichloroplatinum(II) OR Platinum Diamminodichloride OR Diamminodichloride, Platinum OR cis-Platinum OR cis Platinum OR Dichlorodiammineplatinum OR cis-Diamminedichloroplatinum OR cis Diamminedichloroplatinum OR cisDichlorodiammineplatinum(II) OR Platinol OR Platidiam OR Platino OR NSC-119875 OR Biocisplatinum OR CDDP OR CACP OR cisplatin* OR abiplatin OR neoplatin OR cis-DDP

Cyclophosphamide

cyclophosphamide OR cyclophosphane OR cytophosphan OR B-518 OR cyclophosphamide monohydrate OR monohydrate, cyclophosphamide OR endoxan OR cytoxan OR neosar OR procytox OR sendoxan OR NSC-26271 OR NSC 26271 OR NSC26271 OR cyclophosphamide, (R)-isomer OR cyclophosphamide, (S)-isomer OR cyclophosphamide, (+)-isomer OR endox* OR cyclophospha*

Etoposide

etoposide OR etoposid* OR Eposide OR Eposin OR 33419-42-0

Vincristine

vincristine OR vincristin* OR 57-22-7

2. For Neuroblastoma the following MeSH headings and text words were used:

neuroblastoma OR neuroblastomas OR neuroblast* OR ganglioneuroblastoma OR ganglioneuroblastomas OR ganglioneuroblast* OR neuroepithelioma OR neuroepitheliomas OR neuroepitheliom* OR esthesioneuroblastoma OR esthesioneuroblastomas OR esthesioneuroblastom* OR schwannian

3. For RCTs and CCTs the following MeSH headings and text words were used:

((randomized controlled trial[pt]) OR (controlled clinical trial[pt]) OR (randomized[tiab]) OR (placebo[tiab]) OR (drug therapy[sh]) OR (randomly[tiab]) OR (trial[tiab]) OR (groups[tiab])) AND (humans[mh])

Final search 1 and 2 and 3

[pt = publication type; tiab = title, abstract; sh = subject heading; mh = MeSH term; *=zero or more characters; RCT = randomized controlled trial; CCT = controlled clinical trial]

Appendix 3. Search strategy for EMBASE (OVID)

1. For COJEC the following Emtree terms and text words were used:

1. (induction therapy or consolidation therapy).mp.

2. (OPEC or OJEC or COJEC or rapid COJEC).mp.

3. (Carboplatin or CBDCA or Carbosin or Pharmachemie Brand of Carboplatin or Carbotec or Columbia Brand of Carboplatin or Ercar or Almirall Brand of Carboplatin or JM-8 or JM 8 or JM8 or Neocarbo or Neocorp Brand of Carboplatin or NSC-241240 or NSC 241240 or NSC241240 or Paraplatin or Carboplat or Paraplatine or Bristol-Myers Squibb Brand of Carboplatin or Platinwas or Chiesi Brand of Carboplatin or Ribocarbo or ribosepharm Brand of Carboplatin or Blastocarb or Lemery Brand of Carboplatin or Nealorin or Prasfarma Brand of Carboplatin or carboplatin$).mp.

4. (Cisplatin or cis-Diamminedichloroplatinum or Platinum Diamminodichloride or Diamminodichloride, Platinum or cis-Platinum or cis Platinum or Dichlorodiammineplatinum or cis-Diamminedichloroplatinum or cis Diamminedichloroplatinum or cisDichlorodiammineplatinum or Platinol or Platidiam or Platino or NSC-119875 or Biocisplatinum or CDDP or CACP or cisplatin$ or abiplatin or neoplatin or cis-DDP).mp.

5. (cyclophosphamide or cyclophosphane or cytophosphan or B-518 or cyclophosphamide monohydrate or endoxan or cytoxan or neosar or procytox or sendoxan or NSC-26271 or NSC 26271 or NSC26271 or cyclophosphamide derivative or endox$ or cyclophospha$ or cyclofosfa$ or 50-18-0).mp.

6. (etoposide or etoposid$ or Eposide or Eposin or 33419-42-0).mp.

7. (vincristine or vincristin$ or 57-22-7).mp.

8. (1 OR 2 OR (3 AND 4 AND 5 AND 6 AND 7))

2. For Neuroblastoma the following Emtree terms and text words were used:

1. exp neuroblastoma/
2. (neuroblastoma or neuroblastomas or neuroblast$).mp.
3. (ganglioneuroblastoma or ganglioneuroblastomas or ganglioneuroblast$).mp.
4. (neuroepithelioma or neuroepitheliomas or neuroepitheliom$).mp.
5. exp esthesioneuroblastoma/
6. (esthesioneuroblastoma or esthesioneuroblastomas or esthesioneuroblastoma$).mp.
7. schwannian.mp.
8. or/1-7

3. For RCTs and CCTs the following Emtree terms and text words were used:

1. Randomized Controlled Trial/
2. Controlled Clinical Trial/
3. randomized.ti,ab.
4. placebo.ti,ab.
5. randomly.ti,ab.
6. trial.ti,ab.
7. groups.ti,ab.
8. drug therapy.sh.
9. or/1-8
10. Human/
11. 9 and 10

Final search 1 and 2 and 3

[mp = title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name; ti,ab = title, abstract, / = Emtree term; sh = subject heading; $ = zero or more characters; RCT = randomized controlled trial; CCT = controlled clinical trial]

What's new

DateEventDescription
14 April 2016AmendedContact details updated.

Contributions of authors

All authors approved the final version of the review.

FP: concept, selecting, and appraising studies, extracting and analyzing data, interpretation of results, and primary manuscript preparation.

DAT: selecting and appraising studies, extracting and analyzing data, and manuscript review.

ECVD: appraising studies, extracting and analyzing data, interpretation of results, and manuscript review.

FB: selecting and appraising studies, providing a clinical perspective, interpretation of results, and manuscript review.

Declarations of interest

FP declares no conflicts of interest.

DAT declares no conflicts of interest.

ECVD declares no conflicts of interest.

FP declares no conflicts of interest.

Sources of support

Internal sources

  • University of Cologne, Germany.

    Provision of the full texts of articles

  • Stichting Kinderen Kankervrij (KiKa), Netherlands.

    The salary of ECVD is paid by KiKa; KiKa was not involved in the design and execution of this review.

External sources

  • No sources of support supplied

Differences between protocol and review

As opposed to what was mentioned in the protocol we did not ask authors to provide any missing information regarding eligible studies not identified with the other searches. 

With regard to the 'Summary of findings' table: as opposed to what was mentioned in the protocol we did not include health-related quality of life, but complete response. We have chosen the outcomes for this table according to the order of outcomes reported in the methods section. We left out health-related quality of life as it was chosen as the last outcome item and the presentation in the table is limited to seven outcomes.

We have clarified that all analyses were completed on an available case analysis basis, with the exception of the two outcomes overall survival and event-free survival.

If one of the treatment groups experienced no events, and we were unable to calculate a risk ratio, then we used Fisher's exact test instead.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

CCLG-ENSG-5

Methods

Setting

  • Multi-center study with patients that were enrolled from 29 centres

  • Belgium, Denmark, Ireland, Norway, Sweden, and UK

Duration of enrollment

  • From 1990 to 1999

Randomization

  • Randomization was done by telephone at the Children's Cancer and Leukaemia Group (CCLG) Data Centre (Leicester, UK), N = 251. During national holidays, out-of-hours randomization by use of sealed envelopes was done by the principal investigators, N = 11

  • Randomization was stratified by centre with equal numbers in each treatment group in successive blocks of 16 comprising sub-blocks of 4, 6, and 6

Follow-up time

  • Follow-up was not reported regarding the 262 randomized patients

  • Median follow-up of 62 alive patients in the Pearson et al 2008 publication was 12.5 years (range 0 to 16.5)

  • Follow-up was not reported regarding the 69 patients eligible for long-term follow-up who survived 5 years

  • Median follow-up of 57 analyzed long-term survivors in the Moreno et al 2013 publication was 12.7 years (6.9 to 16.5)

Participants

Eligibility criteria

  • Patients aged 12 months and older and adults who fulfilled the International Neuroblastoma Staging System (INSS) criteria for stage 4 neuroblastoma and who had not received previous chemotherapy for their disease were eligible

  • Patients with stage 4S neuroblastoma were not eligible

Number of patients: 262 high-risk patients were enrolled and randomized

  • Rapid COJEC arm: N = 130

  • Standard arm: N = 132

Number of high-risk neuroblastoma survivors with long-term follow-up: 57 were analyzed

  • Rapid COJEC arm: N = 37

  • Standard arm: N = 20

Histology: rapid COJEC arm versus standard arm

  • Neuroblastoma 76% versus 82%

  • Ganglioneuroblastoma 4% to 5%

  • Unclassified 20% to 14%

Age and gender: rapid COJEC arm versus standard arm

  • Age in years, median (range): 2.86 (1 to 15) versus 2.98 (1 to 20)

  • Gender, male: 58% versus 57%

Comorbidity: rapid COJEC arm versus standard arm

  • Bone marrow involvement: 82% versus 83%

  • Lymph node metastases: 62% versus 63%

  • Bone metastases, multiple: 61% versus 58%

  • MYC-N amplified: 43% versus 33%

Previous treatment: rapid COJEC arm versus standard arm

  • Emergency radiotherapy: 0 versus 3 patients

  • Surgery: 8 versus 9 patients

Interventions

Treatment

  • Number of arms: 2

  • Type of intervention: test arm: rapid COJEC; control arm: standard OPEC/OJEC

Rapid COJEC arm

  • Rapid treatment consisted of 8 alternating courses of the following chemotherapeutic agents given at intervals of 10 days over 10 weeks. Of 130 patients randomly assigned to the rapid COJEC arm, 109 completed chemotherapy and 96 had post-chemotherapy surgery. Of 96 patients who had surgery, 84 had consolidation high-dose melphalan (200 mg/m2) followed by autologous stem cell transplantation (source 69: bone marrow, 15 peripheral stem cells). Stem cell harvest was only undertaken if a complete response had been achieved in the bone marrow

  • O = vincristine: 8 × 1.5 mg/m2 = 12.0 mg/m2 total dose

  • P = cisplatin: 4 × 80 mg/m2 = 320 mg/m2 total dose

  • J = carboplatin: 2 × 750 mg/m2 = 1500 mg/m2 total dose

  • E = etoposide: 4 × 350 mg/m2 = 1400 mg/m2 total dose

  • C = cyclophosphamide: 2 × 2100 mg/m2 = 4200 mg/m2 total dose

Standard arm

  • Standard treatment consisted of 7 alternating courses of the following chemotherapeutic agents given at intervals of 21 days over 18 weeks. Of 132 patients randomly assigned to the standard arm, 111 completed chemotherapy and 89 had post-chemotherapy surgery. Of 89 patients who had surgery, 78 had consolidation high-dose melphalan (200 mg/m2) followed by autologous stem cell transplantation (source 61: bone marrow, 17 peripheral stem cells). Stem cell harvest was only undertaken if a complete response had been achieved in the bone marrow

  • O = vincristine: 7 × 1.5 mg/m2 = 10.5 mg/m2 total dose

  • P = cisplatin: 4 × 80 mg/m2 = 320 mg/m2 total dose

  • J = carboplatin: 3 × 500 mg/m2 = 1500 mg/m2 total dose

  • E = etoposide: 7 × 200 mg/m2 = 1400 mg/m2 total dose

  • C = cyclophosphamide: 7 × 600 mg/m2 = 4200 mg/m2 total dose

Attempt of surgical removal of the primary tumor after induction therapy

  • Rapid COJEC arm 78% (101 of 130) versus standard arm 71% (94 of 132)

Reasons for not attempting surgical removal adds up to rapid COJEC arm 29 versus standard arm 38 patients

  • No detectable primary tumor rapid COJEC arm 1 patient versus standard arm 2 patients

  • Surgical resection at diagnosis: rapid COJEC arm 5 versus standard arm 6 patients

  • Early death: rapid COJEC arm 11 versus standard arm 4 patients

  • Disease progression: rapid COJEC arm 2 versus standard arm 10 patients

  • Poor or no response: rapid COJEC arm 4 versus standard arm 12 patients

  • Complete response: rapid COJEC arm 3 versus standard arm 0 patients

  • Inoperable primary tumor: rapid COJEC arm 3 versus standard arm 4 patients

Complete surgical removal of the primary tumor

  • Rapid COJEC arm 58% (56 of 96) versus standard arm 66% (59 of 89)

High-dose chemotherapy

  • Rapid COJEC arm 65% (84 of 130) versus standard arm 60% (78 of 132)

Outcomes

Primary outcomes

  • Complete response: response to chemotherapy was assessed according to the conventional International Neuroblastoma Response Criteria (INRC) including 'complete response'

  • Early toxicity:

    • Febrile neutropenia: number of patients with 2 or more episodes (no definition provided)

    • Proven fungal infections (no definition provided)

    • Septicemia: number of patients with 1 or more episodes (no definition provided)

    • Grade 3 or 4 gastrointestinal toxic effects (no definition provided)

    • Renal toxicity, GFR < 80 ml/(min*1.73m*m)

    • Grade 3 or 4 neurological toxic effects (no definition provided)

    • Ototoxicity (Brock 2 to 4)

  • Treatment-related mortality: no criteria specified.

Secondary outcomes

  • Overall survival: Overall survival was calculated from the date of randomization to date of death from any cause or to date of the last follow-up for those who were alive

  • Event-free survival: Event-free survival was calculated from the date of randomization to date of relapse or progression or death from any cause. Surviving event-free patients were censored at the date of the last follow-up

  • Late non-hematological toxicity was updated by Moreno et al 2013 and assessed in those patients who survived at least 5 years after diagnosis. Complications were graded according to CTCAE v3.0 criteria (NCI CTCAE 2010). Ototoxicity was graded according to the Brock criteria (Brock 1991)

    • Complications: number of patients with any of the following organ or system specified toxicities

    • Renal toxicity: number of patients with decreased glomerular filtration rate (< 80 ml/min/1.73 m2)

    • Ototoxicity: number of patients with hearing loss in audiometry Brock grade 1 to 4

    • Endocrine complications: number of patients with any of the following issues: hypogonadism, small testes, growth retardation, delayed puberty, gynecomastia, diabetes insulin dependent, recurrent hypoglycemia, adrenal insufficiency, hypothyroidism, obesity, mild osteopenia (asymptomatic, i.e. osteopenia observed by radiography in a patient without symptoms)

    • Neurocognitive issues comprise behavioral, speech, or learning difficulties

    • Second malignancies

Notes

No competing interest reported; funding, grants, and awards received from non-for profit organizations. The funding source (Cancer Research UK, London, UK) had no role in the design, data collection, data analysis, interpretation of the findings, or writing of the report

In Table 2 of the publication by Moreno et al 2013, we identified unclear reporting with respect to "Other late effects", i.e. chronic bone pain, spondylolisthesis/back pain, scoliosis (NF1), and chronic diarrhea/bowel dysmotility post-surgery issues. The number of patients with any other late effect remains unclear. We were not able to receive additional information from the authors and we were thus not able to include this outcome in the review

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization was done by a study center. The sequence generation was not described in detail
Allocation concealment (selection bias)Low riskAllocation concealment was achieved by telephone contact to a study center (N = 251) and by sealed envelopes during out-of-hours (N = 11). We judged a low risk for the 251 patients and an unclear risk for the 11 patients since it was not reported if the envelopes were opaque. Overall, we judged this study as having a low risk
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of patients and physicians and nurses was not reported. We judged an unclear risk
Blinding of outcome assessment (detection bias)
Overall survival
Low riskBlinding of outcome assessors was not reported, but that is not relevant for this outcome. Thus, we judged a low risk
Blinding of outcome assessment (detection bias)
All outcomes except overall survival
Unclear riskBlinding of outcome assessors was not reported and we judged an unclear risk
Incomplete outcome data (attrition bias)
Complete response
High riskAccording to additional data received from the authors of Pearson et al 2008, 62% (80 of 130) patients in the rapid COJEC arm and 68% (90 of 132) patients in the standard arm were assessed for overall response. Consequently, 38% (50 of 130) patients in the rapid COJEC arm and 32% (42 of 132) patients in the standard arm were not formally assessed or were not evaluable. We judge this to be a high risk of bias because the proportion of patients not assessed is considerably high
Incomplete outcome data (attrition bias)
Early toxicities
High riskAccording to table 4 of Pearson et al 2008, ototoxicity (Brock 2 to 4) was evaluated in 69 patients in the rapid COJEC arm and in 72 in the standard arm. Thus, 61 patients in the rapid COJEC arm and 60 patients in the standard arm were not evaluated. The other evaluated early toxicities were assessed in 100 to 124 patients in the rapid COJEC arm and in 124 to 125 patients in the standard arm. Thus, 8 to 30 patients were not evaluated in the rapid COJEC arm and 7 to 8 patients were not evaluated in the standard arm. Overall, we judged this to be a high risk of bias
Incomplete outcome data (attrition bias)
Treatment-related mortality
High riskTreatment-related deaths were evaluated in 119 out of 130 patients in the rapid COJEC arm and in 115 out of 132 patients in the standard arm. Data from 11 patients in the rapid COJEC arm and data from 17 patients of the standard arm were missing. We judge this to be a high risk of bias.
Incomplete outcome data (attrition bias)
Overall survival
High riskAccording to figure 4, the numbers at risk for the rapid COJEC arm versus the standard arm were as follows: at 0 years 130 versus 132, at 3 years 47 versus 44, at 5 years 42 versus 29, at 10 years 30 versus 17, and at 15 years 6 versus 5. The courses of overall survival estimates from the 5-year time point to the 15-year time point did not change considerably and were about 30% in the rapid COJEC arm and about 20% in the standard arm. The results may be interpreted as that the reduction of numbers of patients from the 5-year point to the 15-year point was primarily caused by censoring and not by mortality. Subsequently, the total attrition is probably considerably higher than 11 patients in the rapid COJEC arm and 10 patients in the standard arm as reported in the manuscript. We judge this to be a high risk of bias
Incomplete outcome data (attrition bias)
Event-free survival
High riskAccording to figure 3, the numbers at risk for the rapid COJEC arm versus the standard arm were as follows: at 0 years 130 versus 132, at 3 years 41 versus 33, at 5 years 40 versus 25, at 10 years 28 versus 15, and at 15 years 5 versus 4. The courses of event-free survival estimates from the 5-year time point to the 15-year time point did not change considerably and were about 30% in the rapid COJEC arm and about 20% in the standard arm. The results may be interpreted as that the reduction of numbers of patients from the 5-year point to the 15-year point was primarily caused by censoring and not by mortality. Subsequently, the total attrition is probably considerably higher than 11 patients in the rapid COJEC arm and 10 patients in the standard arm as reported in the manuscript. We judge this to be a high risk of bias
Incomplete outcome data (attrition bias)
Late non-hematological toxicities
High riskAccording to figure 1 of Moreno et al 2013, 69 of 262 randomized children survived more than 5 years and were eligible for the assessment. Late non-hematological toxicities were reported for 57 patients. More then 17% (12 of 69) patients were excluded because 4 were not in stage 4 on central review, there were insufficient data regarding 5 patients, and 3 patients died shortly after 5 years due to relapse. We judge this to be a high risk of bias
Selective reporting (reporting bias)Low riskWe did not identify any sign of selective reporting when comparing the outcomes and methods of the publication with those of published protocol items at ClinicalTrials.gov (http://www.clinicaltrials.gov/ct2/show/NCT00365755) and the National Cancer Institute (http://www.cancer.gov/clinicaltrials/search/view?cdrid=454576&version=HealthProfessional)
Other biasUnclear risk
  • 73% of patients (96 of 130) in the rapid COJEC arm and 67% of patients (89 of 132) in the standard arm had surgical resection. Surgery was required to receive myeloablation. Furthermore, a complete response in the bone marrow was also required for a stem cell harvest. The number of patients with bone marrow involvement were reported. We could not identify the number of patients with a complete response in the bone marrow. 64% of patients (84 of 130) in the rapid COJEC arm and 59% of patients (78 of 132) in the standard arm had myeloablation

  • Reasons for not attempting surgery were described; total: rapid 29 versus 38

  • Assumed disadvantages; subtotal: rapid COJEC arm 17 versus standard arm 26

    • Early death: rapid COJEC arm 11 versus standard arm 4 patients

    • Disease progression: rapid COJEC arm 2 versus standard arm 10 patients

    • Poor or no response: rapid COJEC arm 4 versus standard arm 12 patients

    • Inoperable primary tumor: rapid COJEC arm 3 versus standard arm 4 patients

  • Assumed advantages; subtotal: rapid COJEC arm 9 versus standard arm 8

    • No detectable primary tumor: rapid COJEC arm 1 versus standard arm 2 patients

    • Surgical resection at diagnosis: rapid COJEC arm 5 versus standard arm 6 patients

    • Complete response: rapid COJEC arm 3 versus standard arm 0 patients

  • Patients with myeloablation needed to have the following 2 advantages: an operable tumor and complete response in the bone marrow. There was a difference between the treatment arms with respect to assumed disadvantages and advantages in the patients who did not receive surgery and hence no myeloablation. In the standard arm, an excess of +9 patients had disadvantages and an excess of -1 had advantages

  • In the conclusion the authors suggested "that a rapid induction regimen enables myeloablation to be given much earlier, which might contribute to a better outcome." 10 patients in the standard arm could have potentially contributed to prolong the median time from randomization to myeloablation due to their assumed disadvantages but were disproportionally not included

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Bomken 2011Not study type of interest: not a randomized allocation
Castel 2004Not intervention of interest: standard COJEC but not rapid COJEC
De Bernardi 2003Not intervention of interest
Habib 2012Not intervention of interest
Hero 1997Not intervention of interest
Kogner 2004Not study type of interest: not a randomized controlled trial
Ladenstein 2004Not intervention of interest: rapid COJEC prior to randomization in both arms
Ladenstein 2010Not intervention of interest: rapid COJEC prior to randomization in both arms
Ladenstein 2011Not comparator of interest: rapid COJEC but no comparison
Ladenstein 2011aNot intervention of interest: rapid COJEC prior to randomization in both arms
Ladenstein 2011bNot intervention of interest: rapid COJEC prior to randomization in both arms
Ladenstein 2012Not intervention of interest: rapid COJEC prior to randomization in both arms
Ladenstein 2012aNot comparator of interest: rapid COJEC but no comparison
Lewington 2011Not comparator of interest: rapid COJEC but no comparison
Mastrangelo 2011Not intervention of interest
Nitschke 1980Not intervention of interest
Pinkerton 2000Not study design of interest: nonsystematic review
Sawaguchi 1990Not intervention of interest
Schrey 2013Not study design of interest: retrospective analysis
Shafford 1984Not intervention of interest
Tweddle 2001Not intervention of interest
Valteau-Couanet 2014Not intervention of interest
Viprey 2014Not study design of interest: prognosis study

Characteristics of ongoing studies [ordered by study ID]

HR-NBL1/SIOPEN

Trial name or title

High Risk Neuroblastoma Study 1 (1.5) of SIOP-Europe (SIOPEN)

SIOPEN: International Society of Paediatric Oncology, Europe, Neuroblastoma/Société Internationale d'Oncologie Pédiatrique, Europe, Neuroblastome

The expression '1.5' in the original title of the study refers to the 5th amendment

MethodsThis is a randomized study of the European SIOP Neuroblastoma Group (SIOPEN) in high-risk neuroblastoma that includes 115 participating centers currently recruiting. The study is composed of 4 different randomizations, R0, R1, R2, and R3. R3 randomization after induction is the part of interest for the present review as R3 randomization compares 2 different induction therapy regimens, Rapid COJEC and modified N7 induction regimen
Participants

Study

  • Estimated enrollment: 2000

  • Stages 2, 3, 4 and 4s MYC-N-amplified neuroblastoma, stage 4 MYC-N non amplified > 12 months at diagnosis

R3 randomization before induction

  • Estimated enrollment: not reported

  • All patients with stage 4 neuroblastoma and those with stage 4s MYC-N-amplified neuroblastoma > 12 months at diagnosis

Interventions

R3 randomization before induction:

  • Rapid COJEC arm: rapid COJEC

  • Standard arm: modified N7 induction regimen

Outcomes

R3 randomization before induction:

  • Complete metastatic response

  • Event-free survival

Starting date

Study

  • Start date: February 2002

R3 randomization before induction

  • Start date: June 2011

Contact information

ClinicalTrials.gov identifier: NCT01704716

Sponsor: St. Anna Kinderkrebsforschung

Principal Investigator: Ruth L Ladenstein

NotesThe principal investigator stated that patients are still being recruited as of today and that closure of the study will not be expected before 2017

Ancillary