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Tratamiento posconsolidación con ácido retinoico para pacientes con neuroblastoma de alto riesgo tratados con trasplante autólogo de células madre hematopoyéticas

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Resumen

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 la presentación más frecuente es una masa abdominal. Cerca de un 50% de los pacientes presentan metástasis en el momento del diagnóstico. El grupo de alto riesgo se caracteriza por metástasis y otras características que aumentan el riesgo de un resultado adverso. Los pacientes de alto riesgo presentan una supervivencia a cinco años sin eventos de menos del 50%. Se ha demostrado que el ácido retinoico inhibe el crecimiento de las células del neuroblastoma en seres humanos y se ha considerado un candidato potencial para mejorar el resultado de los pacientes con neuroblastoma de alto riesgo. Esta revisión es una actualización de una revisión Cochrane publicada anteriormente.

Objetivos

Evaluar la eficacia y la seguridad del ácido retinoico adicional como parte de un tratamiento posconsolidación después de la con quimioterapia de dosis alta (QDA) seguida de un trasplante autólogo de células madre hematopoyéticas (TCMH) en comparación con ácido retinoico placebo o ningún tratamiento adicional con ácido retinoico en pacientes con neuroblastoma de alto riesgo (según lo definido por el sistema de clasificación del International Neuroblastoma Risk Group [INRG]).

Métodos de búsqueda

Se hicieron búsquedas en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL; the Cochrane Library 2016, número 11), MEDLINE PubMed (1946 hasta el 24 de noviembre de 2016) y Embase en Ovid (1947 hasta el 24 de noviembre de 2016). Otras búsquedas incluyeron registros de ensayos (el 22 de diciembre 2016), actas de congresos (23 de marzo de 2017) y listas de referencias de revisiones recientes y estudios relevantes. No se aplicaron límites por año de publicación o idioma.

Criterios de selección

Ensayos controlados aleatorizados (ECA) que evalúan el ácido retinoico adicional después de QDA seguido de un TCMH para personas con neuroblastoma de alto riesgo en comparación con el ácido retinoico placebo o con ningún ácido retinoico adicional. Los resultados primarios fueron la supervivencia general y la mortalidad relacionada con el tratamiento. Los resultados secundarios fueron la supervivencia sin evolución, la supervivencia sin eventos, la toxicidad temprana y tardía y la calidad de vida relacionada con la salud.

Obtención y análisis de los datos

Se utilizaron los procedimientos metodológicos estándar previstos por Cochrane.

Resultados principales

No se identificaron estudios adicionales en la búsqueda actualizada. Se identificó un ECA que incluyó a pacientes con neuroblastoma de alto riesgo que recibieron QDA seguida de un TCMH autólogo (N = 98) después de una primera asignación aleatoria y que recibieron ácido retinoico (ácido 13‐cis‐retinoico; n = 50) o ninguna terapia adicional (n = 48) tras una segunda asignación aleatoria. Estos 98 pacientes no presentaron evolución de la enfermedad después de la QDA seguida de un TCMH autólogo. No hubo evidencia clara de una diferencia entre los grupos de tratamiento en la supervivencia general (cociente de riesgos instantáneos [CRI] 0,87; intervalo de confianza [IC] del 95%: 0,46 a 1,63; un ensayo; P = 0,66) ni en la supervivencia sin eventos (CRI 0,86, IC del 95%: 0,50 a 1,49; un ensayo; P = 0,59). Los valores del CRI se calcularon mediante el uso del período completo de seguimiento del ensayo. El estudio también informó las estimaciones de supervivencia general en un punto temporal fijo. En el punto temporal de cinco años, la estimación de supervivencia informada fue de 59% para el grupo de ácido retinoico y del 41% para el grupo de ningún tratamiento adicional (valor de p no informado). No se identificaron resultados para la mortalidad relacionada con el tratamiento, la supervivencia libre de progresión, la toxicidad temprana o tardía, o la calidad de vida relacionada con la salud. No fue posible descartar la presencia posible de sesgo de selección, sesgo de realización, sesgo de deserción y otros sesgos. La evidencia en esta revisión se consideró que fueron de baja calidad para la supervivencia general y la supervivencia sin eventos, reducida debido a las limitaciones y la imprecisión de los estudios.

Conclusiones de los autores

Se identificó un ECA que evaluó el ácido retinoico adicional como parte de un tratamiento posconsolidación tras una QDA seguida de un TCMH autólogo versus ningún tratamiento adicional en pacientes con neuroblastoma de alto riesgo. No hubo evidencia clara de una diferencia en la supervivencia general y la supervivencia sin eventos entre las opciones de tratamiento. Esto podría ser el resultado del bajo poder estadístico. La información sobre otros resultados no estaba disponible. Este ensayo se realizó en los años noventa, desde entonces se han producido muchos cambios en el tratamiento y la clasificación del riesgo. Por lo tanto, basado en la evidencia disponible actualmente, no existe seguridad acerca de los efectos del ácido retinoico en los pacientes con neuroblastoma de alto riesgo. Se necesita más investigación para una conclusión definitiva.

PICO

Population
Intervention
Comparison
Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Resumen en términos sencillos

Ácido retinoico después de la quimioterapia intensiva y el trasplante de médula ósea en pacientes con neuroblastoma de alto riesgo

Pregunta de la revisión

Se examinó la evidencia acerca del efecto de añadir ácido retinoico como parte de un tratamiento posconsolidación tras quimioterapia intensiva (de dosis alta) seguida de un trasplante autólogo (de la misma persona) de médula ósea (trasplante de células madre hematopoyéticas) en personas con neuroblastoma de alto riesgo. El tratamiento de consolidación trata de destruir las posibles células cancerosas remanentes después de que un tratamiento anterior haya logrado la eliminación de un tumor detectable. El tratamiento posconsolidación se aplica después del tratamiento de consolidación. La adición de ácido retinoico se comparó con el mismo pretratamiento pero con ácido retinoico placebo (inactivo) o con ninguna adición de ácido retinoico para dos resultados primarios y cinco secundarios. Los resultados primarios fueron la supervivencia general (participantes que no murieron) y la mortalidad relacionada con el tratamiento (participantes que murieron debido a complicaciones de la intervención). Los resultados secundarios fueron la supervivencia sin evolución (la enfermedad no empeoró), la supervivencia sin eventos (no padecer ningún evento de un grupo concreto), la toxicidad (efectos perjudiciales) temprana y tardía y la calidad de vida relacionada con la salud.

Antecedentes

El neuroblastoma es una enfermedad cancerosa rara que afecta principalmente a neonatos y a niños muy pequeños. El grupo de alto riesgo es propenso a la propagación de la enfermedad y posee otras características que aumentan el riesgo de un evento adverso. El ácido retinoico impide el crecimiento celular descontrolado en cultivos celulares de laboratorio y podría reducir la reaparición del tumor tras la quimioterapia de dosis alta seguida de un trasplante autólogo de células madre hematopoyéticas en personas con neuroblastoma de alto riesgo.

Características de los estudios

La evidencia se actualizó hasta el 24 de noviembre de 2016. Se incluyó un único ensayo aleatorizado con 50 personas asignadas a la adición de ácido retinoico después de una quimioterapia de alta dosis seguida de un trasplante autólogo de células madre hematopoyéticas , y 48 personas asignadas al mismo tratamiento pero sin la adición de ácido retinoico.

Resultados clave

No se identificaron nuevos estudios en la búsqueda actualizada. La supervivencia general y la supervivencia sin eventos no fueron diferentes entre las dos opciones de tratamiento. Otros resultados incluidos los relacionados con los eventos adversos no se informaron de manera adecuada. El ácido retinoico añadido como parte de un tratamiento posconsolidación tras quimioterapia de dosis alta seguida de un trasplante autólogo de células madre hematopoyéticas podría no mejorar la supervivencia en personas con neuroblastoma de alto riesgo y no hay información suficiente sobre su seguridad. Se necesitan más estudios para poder establecer conclusiones sólidas.

Calidad de la evidencia

La evidencia se basa en un único estudio. La calidad de la evidencia del estudio incluido es baja.

Authors' conclusions

Implications for practice

We identified one RCT that evaluated additional 13‐cis‐retinoic acid after HDCT followed by autologous HSCT versus no additional retinoic acid in people with high‐risk neuroblastoma without progressive disease. The difference in overall survival and event‐free survival between both treatment alternatives was not statistically significantly different. This could be the result of low power; the included study was not designed to identify a superior treatment combination. Information on other outcomes, like toxicity, were not available. Also, this trial was performed between 1991 and 1996. 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 additional retinoic acid after HDCT followed by autologous HSCT in people with high‐risk neuroblastoma.

Implications for research

More research is needed for a definitive conclusion. Future trials on the use of retinoic acid (either with or without other treatments like anti‐GD2) after HDCT followed by autologous HSCT for people with high‐risk neuroblastoma should be RCTs focusing on overall survival, adverse effects, and quality of life. RCTs should be performed in homogeneous study populations (like stage of disease) and have a long‐term follow‐up. The number of included participants should be sufficient for the power needed for the results to be reliable. Different risk groups, using the most recent definitions, should be taken into account. For example, particular subgroups of participants may benefit from retinoic acid.

Summary of findings

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Summary of findings for the main comparison. Retinoic acid postconsolidation therapy compared to no further treatment for high‐risk neuroblastoma patients treated with autologous haematopoietic stem cell transplantation

Retinoic acid postconsolidation therapy compared to no further treatment for high‐risk neuroblastoma patients treated with autologous HSCT

Patient or population: high‐risk neuroblastoma patients treated with autologous HSCT
Settings: paediatric oncology departments
Intervention: retinoic acid postconsolidation therapy
Comparison: no further treatment

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

No further treatment

Retinoic acid post‐consolidation therapy

Overall survival (reported as mortality)

583 per 10001

533 per 1000
(331 to 760)

HR 0.87
(0.46 to 1.63)

98
(1 study)

⊕⊕⊝⊝
low2,3

The length of follow‐up was not mentioned for the 98 participants eligible for this review

Treatment‐related mortality ‐ not reported

See comment

See comment

Not estimable

See comment

No adequate information on this outcome was provided

Progression‐free survival ‐ not reported

See comment

See comment

Not estimable

See comment

No information on this outcome was provided

Event‐free survival (reported as relapse, disease progression, death from any cause, or second neoplasm)

604 per 10001

549 per 1000
(371 to 749)

HR 0.86
(0.50 to 1.49)

98
(1 study)

⊕⊕⊝⊝
low2,3

The length of follow‐up was not mentioned for the 98 participants eligible for this review

Early toxicity ‐ not reported

See comment

See comment

Not estimable

See comment

No adequate information on this outcome was provided

Late toxicity including secondary malignancies ‐ not reported

See comment

See comment

Not estimable

See comment

No adequate information on this outcome was provided

Health‐related quality of life ‐ not reported

See comment

See comment

Not estimable

See comment

No information on this outcome was provided

*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% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; HR: Hazard ratio; HSCT: haematopoietic stem cell transplantation

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.

1The 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.
2The presence of selection bias, performance bias, attrition bias and other bias was unclear, so we downgraded one level for study limitations.
3Since this is a small study and the 95% CIs include values favouring both the intervention and the control treatment we downgraded one level for imprecision.

Background

Description of the condition

Neuroblastoma is a rare malignant disease and mainly affects infants and very young children (GARD 2017). Tumours develop in the sympathetic nervous system such as adrenal medullary tissue or paraspinal ganglia, and may be localised 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 reducing to 29 per million children in the second year of life (Goodman 2012). The incidence rate in adults is less than one per million a year, but adults have a considerably worse prognosis (Esiashvili 2007). Cohn 2009 proposed the International Neuroblastoma Risk Group (INRG) classification system (see Table 1). Of 8800 people with neuroblastoma, 36.1% had high‐risk neuroblastoma. Berthold 2005 estimated that 50% of people with neuroblastoma have metastatic disease at diagnosis. Patients in the high‐risk group had a five‐year event‐free survival rate (defined as the time from diagnosis until the time of first occurrence of relapse, progression, secondary malignancy, or death, or until the time of last contact if none of these occurred) of less than 50%. Matthay 2012 addressed new approaches with targeted therapy that may improve the outcome in people with high‐risk neuroblastoma.

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Table 1. The INRG consensus pretreatment classification scheme

INRG stage

Age (months)

Histologic category

Grade of tumour differentiation

MYCN

11q aberration

Ploidy

Pretreatment risk group

Code

Interpretation

L1/L2

Ganglioneuroma maturing; ganglioneuroblastoma intermixed

A

Very low

L1

Any, except ganglioneuroma or ganglioneuroblastoma

Not amplified

B

Very low

Amplified

K

High

L2

< 18

Any, except ganglioneuroma or ganglioneuroblastoma

Not amplified

No

D

Low

Yes

G

Intermediate

≥ 18

Ganglioneuroblastoma nodular; neuroblastoma

Differentiating

Not amplified

No

E

Low

Yes

H

Intermediate

Poorly differentiated or undifferentiated

Not amplified

H

Intermediate

Amplified

N

High

M

< 18

Not amplified

Hyperdiploid

F

Low

< 12

Not amplified

Diploid

I

Intermediate

12 to < 18

Not amplified

Diploid

J

Intermediate

< 18

Amplified

O

High

≥ 18

P

High

MS

< 18

Not amplified

No

C

Very low

Yes

Q

High

Amplified

R

High

Reference: Cohn 2009.

The INRG consensus classification schema includes the criteria INRG stage, age, histologic category, grade of tumour differentiation, MYCN status, presence/absence of 11q aberrations, and tumour cell ploidy. Sixteen statistically or clinically different pretreatment groups of patients (lettered A through R), or both, were identified using these criteria. The categories were 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.

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. Organ‐specific symptoms may be caused by the local presence of metastases, such as eye problems associated with retrobulbar tumours, pancytopenia associated with bone marrow infiltration, abdominal distension and respiratory problems associated with liver enlargement, paralysis, and Horner syndrome associated with ganglion involvement (Berthold 2005; NCI PDQ 2017). Furthermore, there are general signs and symptoms like tiredness, weakness or pain. Some neuroblastomas regress spontaneously without therapy, while others progress with a fatal outcome despite therapy. One study of infants younger than 12 months showed that nearly half of the study population within three years of follow‐up had a spontaneous regression at diagnosis (Hero 2008). A tumour mass may be confirmed by ultrasound, X‐rays, 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 provides the current definitions for diagnosis, the stages 1, 2A, 2B, 3, 4, and 4S shown in Table 2, and treatment response shown in Table 3 (Brodeur 1993). The INRG classification system provides the current definitions for the very low, low, intermediate, and high‐risk groups shown in Table 1 (Cohn 2009).

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Table 2. The International Neuroblastoma Staging System

Stage

Definition

1

Localised tumour with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumour microscopically (nodes attached to and removed with the primary tumour may be positive)

2A

Localised tumour with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumour microscopically

2B

Localised tumour with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumour. Enlarged contralateral lymph nodes must be negative microscopically

3

Unresectable unilateral tumour infiltrating across the midlinea, with or without regional lymph node involvement; or localised unilateral tumour with contralateral regional lymph node involvement; or midline tumour with bilateral extension by infiltration (unresectable) or by lymph node involvement

4

Any primary tumour with dissemination to distant lymph nodes, bone, bone marrow, liver, skin and/or other organs (except as defined for stage 4S)

4S

Localised primary tumour (as defined for stage 1, 2A or 2B), with dissemination limited to skin, liver, and/or bone marrowb (limited to infants < 1 year of age)

Reference: Brodeur 1993.

Note: Multifocal primary tumours leg, bilateral adrenal primary tumours should be staged according to the greatest extent of disease, as defined above, and followed by a subscript letter M e.g. 3M.
aThe midline is defined as the vertebral column. Tumours originating on one side and crossing the midline must infiltrate to or beyond the opposite side of the vertebral column.
bMarrow 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. The (Meta‐iodobenzylguanidine) MIBG scan (if performed) should be negative in the marrow.

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Table 3. Response to treatment

Response

Primary tumour

Metastatic sites

Complete response

No tumour

No tumour; catecholamines normal

Very good partial response

Decreased by 90% to 99%

No tumour; catecholamines normal; residual 99Tc bone changes allowed

Partial response

Decreased by more than 50%

All measurable sites decreased by > 50%. Bones and bone marrow: number of positive bone sites decreased by > 50%; no more than 1 positive bone marrow site allowed

Minimal response

No new lesions; > 50% reduction of any measurable lesion (primary or metastases) with < 50% reduction in any other; < 25% increase in any existing lesion

No response

No new lesions; < 50% reduction but < 25% increase in any existing lesion

Progressive disease

Any new lesion; increase of any measurable lesion by > 25%; previous negative marrow positive for tumour

Reference: Brodeur 1993.

Description of the intervention

Retinoic acid is a derivative of vitamin A (retinol) that includes 13‐cis retinoic acid, also known as isotretinoin, among others. Retinoic acid regulates the growth and development of epithelial cells, and inhibits growth of human neuroblastoma cells (Sidell 1982). It reduces morphological signs characteristic of several malignant human neuroblastoma cell lines (Sidell 1983). In a phase I clinical trial, 13‐cis retinoic acid was used in children with neuroblastoma after autologous haematopoietic stem cell transplantation (HSCT) without signs of myelosuppression (Villablanca 1995). In a phase III clinical trial, 13‐cis retinoic acid was added in people with high‐risk neuroblastoma after receiving high‐dose chemotherapy (HDCT) followed by autologous HSCT as well as after receiving standard‐dose chemotherapy (SDCT) (Matthay 1999). The test intervention of this review is the addition of retinoic acid as part of a therapy that comes after the consolidation therapy, which constitutes HDCT followed by autologous HSCT. Yalçin 2015 included three randomised controlled trials (RCTs) in a Cochrane Review including the study Matthay 1999. The objective of the review was to compare the efficacy of HDCT followed by autologous HSCT with standard‐dose chemotherapy in children with high‐risk neuroblastoma.

How the intervention might work

Retinoic acid induces the differentiation of human neuroblastoma cell lines and stops uncontrolled cell growth in vitro (Reynolds 2003). Thus, retinoic acid might reduce the relapse rate, which occurs frequently after intensive chemotherapy with or without autologous HSCT in people with high‐risk neuroblastoma.

Why it is important to do this review

People with high‐risk neuroblastoma might have improved survival if retinoic acid as part of a postconsolidation therapy were added after HDCT followed by autologous HSCT. However, it is possible that a considerable number of patients may not respond to the addition of retinoic acid. It is therefore important to evaluate the current evidence base for the efficacy and the possible adverse events associated with this treatment. This review is an update of an earlier published Cochrane Review (Peinemann 2015).

Objectives

To evaluate the efficacy and adverse events of additional retinoic acid as part of a postconsolidation therapy after high‐dose chemotherapy (HDCT) followed by autologous haematopoietc stem cell transplantation (HSCT), compared to the same pretreatment with placebo retinoic acid or to no additional retinoic acid in people with high‐risk neuroblastoma (as defined by the International Neuroblastoma Risk Group (INRG) classification system).

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs).

Types of participants

People with high‐risk neuroblastoma according to the INRG or the Children's Oncology Group classification of risk groups shown in Table 1 and Table 4.

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Table 4. Children's Oncology Group assignment to low, intermediate, and high‐risk group

INSS stage

Age

MYCN

INPC classification

DNA index

Risk group

1

0 to 21 y

Any

Any

Any

Low

2A/2B

< 365 d

Any

Any

Any

Low

≥ 365 d to 21 y

Nonamplified

Any

Low

≥ 365 d to 21 y

Amplified

Favorable

Low

≥ 365 d to 21 y

Amplified

Unfavorable

High

3

< 365 d

Nonamplified

Any

Any

Intermediate

< 365 d

Amplified

Any

Any

High

≥ 365 d to 21 y

Nonamplified

Favorable

Intermediate

≥ 365 d to 21 y

Nonamplified

Unfavorable

High

≥ 365 d to 21 y

Amplified

Any

High

4

< 548 d

Nonamplified

Any

Any

Intermediate

< 365 d

Amplified

Any

Any

High

≥ 548 d to 21 y

Any

Any

High

4S

< 365 d

Nonamplified

Favorable

> 1

Low

< 365 d

Nonamplified

Any

= 1

Intermediate

< 365 d

Nonamplified

Unfavorable

Any

Intermediate

< 365 d

Amplified

Any

Any

High

Reference: NCI PDQ 2017
DNA index: favorable > 1 (hyperdiploid) or < 1 (hypodiploid); unfavorable = 1 (diploid).
Abbreviations. d: days of age; y: years of age.

Types of interventions

  • Intervention

    • Addition of retinoic acid as part of a postconsolidation therapy after HDCT followed by autologous HSCT

  • Comparator

    • Placebo retinoic acid or no addition of retinoic acid to postconsolidation therapy as described above

Types of outcome measures

We did not use the outcomes listed here as criteria for including studies, but these are the outcomes of interest within studies we identified for inclusion.

Primary outcomes

  • Overall survival: the event is death by any cause from the start of retinoic acid treatment

  • Treatment‐related mortality: incidence of deaths that were classified as treatment‐related, or the participants died of treatment complications

Secondary outcomes

  • Progression‐free survival: time staying free of disease progression from start of retinoic acid treatment; participants may still have the disease but their disease is stable or showing a partial response to treatment; the events are death from all causes or any progression of the disease

  • Event‐free survival: time staying free of any of a particular group of defined events from the start of retinoic acid treatment; participants may still have the disease; the events are 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 that were defined by the individual study protocol

  • Early toxicity: adverse events within 90 days of the therapy; incidence of all reported adverse events, severe events (grades 3 and 4 of toxicity), and incidence of toxicity‐related discontinuation of treatment. Examples of possibly‐reported classifications: the Cancer Therapy Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events (CTEP 2010); WHO Toxicity Grading Scale for Determining the Severity of Adverse Events (ICSSC 2003)

  • Late toxicity: adverse events including secondary malignancy occurring 90 days or more beyond therapy

  • Health‐related quality of life measured by validated questionnaires

Search methods for identification of studies

We used search methods as suggested in the Cochrane Handbook for Systematic Reviews of Interventions and by Cochrane Childhood Cancer (Higgins 2011; Kremer 2008). We applied no language restrictions.

Electronic searches

We searched in the following medical literature databases. We tailored the terms and syntax used for the search in MEDLINE to the requirements of the other two databases. Cochrane Childhood Cancer ran the searches in the three mentioned electronic databases; the review authors ran all other searches.

  • Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (2016, Issue 11) using the search strategy shown in Appendix 1.

  • MEDLINE in PubMed (1946 to 24 November 2016) using the search strategy shown in Appendix 2.

  • Embase in Ovid (1947 to 24 November 2016) using the search strategy shown in Appendix 3.

We searched for ongoing trials by scanning the following online registries on 22 December 2016:

  • ClinicalTrials.gov (clinicaltrials.gov/). Search: diagnosis 'neuroblastoma'; intervention 'retinoic acid'. Limits: study type 'interventional studies'; phase '2' or '3'.

  • World Health Organization International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/). Search: diagnosis 'neuroblastoma'; intervention 'retinoic acid'. Limits: none.

We searched abstracts of the following annual meeting proceedings on 23 March 2017:

  • Annual Meetings of the American Society of Clinical Oncology (ASCO) (meetinglibrary.asco.org/abstracts): 2012, 2013, 2014, 2015, and 2016 (ASCO Meetings 2012 to 2016). Search online by browsing abstracts by meeting and by category (Pediatric Oncology, Pediatric Solid Tumors): 'retinoic'. Search online all abstracts: 'retinoi'.

  • Annual Meetings of the American Society of Hematology (ASH) (www.bloodjournal.org/page/ash‐annual‐meeting‐abstracts): ASH meetings in 2012, 2013, 2014, 2015, and 2016. Search online all abstracts: 'neuroblastoma'.

  • Congresses of the International Society of Paediatric Oncology (SIOP) (Pediatric Blood & Cancer at onlinelibrary.wiley.com/): 2012, 2013, 2014, 2015, and 2016. Search in the downloaded PDF: 'retinoi'.

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

In preparing this updated Cochrane 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 and removed duplicates. Two review authors independently examined the remaining references. We obtained the full texts of potentially relevant references. Two review authors independently examined the eligibility of retrieved papers, resolving any disagreements by discussion and consultating with a third review author if necessary. We documented reasons for exclusion. If we identified multiple reports of one study we used the most recently published results. We checked the multiple reports for possible duplicate data, addressed the issue, and did not include duplicate data in our analyses. We include a study selection flow chart in the review.

Data extraction and management

For each included study, two review authors independently abstracted study characteristics and outcomes, including information on study design, participant characteristics (such as inclusion criteria, age, stage, co‐morbidity, previous treatment, number enrolled in each arm), interventions (such as type of retinoic acid, dose applied, duration of therapy, control treatment), risk of bias, follow‐up duration, outcome measures, and deviations from protocol, onto a data extraction form specifically designed for this review. We resolved any differences in opinion between the review authors by discussion or by appeal to a third review author.

Where possible, all data extracted were those relevant to an intention‐to‐treat (ITT) analysis, in which all participants were analysed in the groups to which they were assigned. If this was not possible, we reported it. We noted the time points at which outcomes were collected and reported.

Assessment of risk of bias in included studies

Two review authors independently appraised the risks of bias in the included studies, resolving differences between review authors by discussion or by appeal to a third review author. We used the items listed in the Cochrane Childhood Cancer module (Kremer 2008), which is based on the Cochrane tool for assessing risk of bias (Higgins 2011):

  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) for each outcome separately

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

  7. Selective reporting such as not reporting prespecified outcomes (reporting bias)

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

We applied the Cochrane tool for assessing risk of bias (Higgins 2011). In general, a low risk of bias means that 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 means that plausible bias seriously weakens confidence in the results (for example, participants or investigators enrolling participants could possibly foresee assignments). Unclear risk of bias means that 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 the results of the 'Risk of bias' assessment into account when interpreting the review results.

Measures of treatment effect

For analyses of time‐to‐event data, the primary effect measure was the HR. If the HR was not directly given in the publication, we estimated HRs according to methods proposed by Parmar 1998 and Tierney 2007. For all analyses we reported the 95% CIs.

We would have calculated the risk ratio for dichotomous outcomes. In the case of rare events, we planned to use the Peto odds ratio instead. We planned to analyse continuous data and present them using the mean difference (MD) if all results were measured on the same scale (e.g. length of hospital stay). If this was not the case (e.g. pain or quality of life), we planned to use the standardised mean difference (SMD). However, we did not identify either dichotomous or continuous data.

Dealing with missing data

We conformed to the Cochrane guidance for dealing with missing data (Higgins 2011). If data were missing or only imputed data were reported, we planned to contact trial authors to request data on the outcomes among participants who were assessed. When relevant data for study selection, data extraction, and risk of bias assessment were missing, we contacted study authors to retrieve the missing data.

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 which 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 statistic value greater than 50% to indicate substantial heterogeneity. However, as only one trial met our inclusion criteria, 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 enough 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 we only included one trial in the review, this was not applicable.

Data synthesis

One review author analysed the data using Review Manager 2014, and another review author checked them. If sufficient clinically‐similar studies were available, we planned to pool their results, but since we included only one study 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 a random‐effects model with inverse variance weighting for all analyses (DerSimonian 1986).

We used GRADEpro 2015 to create the 'Summary of findings' table as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We presented overall survival, treatment‐related mortality, progression‐free survival, event‐free survival, early toxicity, late toxicity, and health‐related quality of life, provided that data were presented for both treatment arms. For each outcome two review authors independently assessed the quality of the evidence by using the five GRADE considerations, that is, study limitations, inconsistency, indirectness, imprecision and publication bias as described in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2011).

Subgroup analysis and investigation of heterogeneity

We planned a subgroup analysis by age (younger than 18 months versus older than 18 months) since the International Neuroblastoma Risk Group classification has established 18 months as the optimum cut‐off for age. We also planned a subgroup analysis on MYCN gene amplification (with versus without MYCN amplification). However, the included study did not provide enough data to enable us to do this.

Sensitivity analysis

We planned to conduct sensitivity analyses of studies at low risk of bias versus studies at high or uncertain risk of bias, but since we include only one trial this was not applicable.

Results

Description of studies

Results of the search

See Figure 1 for the study flow diagram of the search for the previous and the current version of this Cochrane Review.


1Study flow diagram of current review version.Abbreviations. CT.gov: ClinicalTrials.gov; ICTRP: International Clinical Trials Registry Platform

1Study flow diagram of current review version.

Abbreviations. CT.gov: ClinicalTrials.gov; ICTRP: International Clinical Trials Registry Platform

For the original version of the review we retrieved 591 records after searching the databases CENTRAL, MEDLINE, and Embase (on 1 October 2014) and removing duplicates. We screened the title or abstract, or both, and excluded 492 records. We screened the full texts of 99 publications that reported potentially relevant data and excluded 91 publications. We included eight publications associated with one RCT (Matthay 1999). The study by Matthay et al., published in 1999, reported the main information and results and the publication by Matthay et al. 2009 updated these data. Four further publications were also associated with the study. Two conference proceedings (Reynolds 1998; Reynolds 2002; see Characteristics of studies awaiting classification table) were associated with the study Matthay 1999. However, as it is known that information provided in conference proceedings often differs substantially from information provided in subsequent full‐text publications (Yoon 2012), we did not include these results in our analyses. We retrieved 31 records searching the study registries ClinicalTrials.gov and the International Clinical Trials Registry Platform Search Portal, duplicates removed (27 December 2013), but found no additional relevant studies. We found no additional studies by screening the reference lists of relevant articles and reviews.

For this update we retrieved 67 records after searching the databases CENTRAL, MEDLINE, and Embase (on 24 November 2016) and removing duplicates. We screened the title or abstract, or both, and excluded 62 records. We screened the full texts of five publications that reported potentially relevant data and excluded all five of them. We retrieved nine records by searching the study registries ClinicalTrials.gov and the International Clinical Trials Registry Platform Search Portal, duplicates removed (22 December 2016), but found no additional relevant studies. We found no additional studies by screening the reference lists of relevant articles and reviews or by screening the conference abstracts. We knew about an erratum associated with the Matthay 1999 study (Erratum 2014), which we incorporated in this update. It was not necessary to contact authors to for missing information.

Included studies

We have described the characteristics of the included RCT in the Characteristics of included studies table.

Design

We include a randomised, prospective, parallel, controlled clinical trial. Matthay 1999 enrolled participants from 1991 to 1996.

Sample sizes

Matthay 1999 randomised 379 participants with high‐risk neuroblastoma to either HDCT followed by autologous HSCT (N = 189) or to continuous standard‐dose chemotherapy without transplantation (N = 190) in a first randomisation (Figure 2). After the first randomisation, 98 of the transplanted participants progressed to a second randomisation. Of the 98 transplanted participants, 50 were randomised to additional retinoic acid and 48 to no further therapy (Figure 2).


Flow of patients in the Matthay 1999 study (as prepared by review author FP).
 Abbreviations. BMT: bone marrow transplantation; ContCT: continuation chemotherapy; CT: chemotherapy; HDCT: high‐dose chemotherapy; RA: retinoic acid.

Flow of patients in the Matthay 1999 study (as prepared by review author FP).
Abbreviations. BMT: bone marrow transplantation; ContCT: continuation chemotherapy; CT: chemotherapy; HDCT: high‐dose chemotherapy; RA: retinoic acid.

Setting

Matthay 1999 was a multicentre study conducted in the United States of America.

Participants

Matthay 1999 included participants with high‐risk neuroblastoma stages 1, 2, 3, and 4, although most had stage 4. Patients who had progressive disease before week eight of the protocol were deemed ineligible for the trial. The characteristics of 98 participants with autologous HSCT randomised to retinoic acid or to no further therapy were not separately reported. The duration of their follow‐up was not mentioned.

Interventions

Participants in the retinoic arm received six cycles of retinoic acid. One cycle consisted of 13‐Cis retinoic acid at a dose of 160 mg/mg/m2 a day for 14 consecutive days in a 28‐day cycle (14 days on, 14 days off), resulting in a cumulative dose after 28 days of 2240 mg/m2. The control group received no further treatment. Regarding the consolidation therapy, high‐dose chemotherapeutic substances and doses were specified, such as carboplatin, etoposide, melphalan, and total‐body irradiation.

Primary outcomes

Matthay 1999 reported overall survival. Treatment‐related mortality was not reported separately for the treatment groups of interest.

Secondary outcomes

Matthay 1999 reported event‐free survival. It did not report early and late toxicity separately for the treatment groups of interest. Progression‐free survival and health‐related quality of life were not reported.

Excluded studies

We excluded 96 records of potentially relevant full‐text articles, 91 records in the previous version and five records (Chen 2015; Kushner 2015; Kushner 2016; Mora 2015; Mostoufi‐Moab 2016) in the current version (Figure 1) based on:

  • not the diagnosis of interest: n = 7 (seven in the previous version and none in the current version);

  • not the intervention of interest: n = 21 (20 in the previous version and one in the current version); this includes Kohler 2000 in which 49 of 175 participants (28%) did not receive high‐dose chemotherapy and bone marrow transplantation and no separate data for eligible participants were available;

  • not the comparator of interest: n = 47 (46 in the previous version and one in the current version);

  • not the outcome of interest or not reported separately: n = 5 (five in the previous version and none in the current version);

  • not the publication type of interest: n = 16 (13 in the previous version and three in the current version).

We have described the excluded studies in more detail in the Characteristics of excluded studies table.

Risk of bias in included studies

The 'Risk of bias' tables in the Characteristics of included studies section provide details of each item of the 'Risk of bias' tool for RCTs. Figure 3 and Figure 4 provide an overview.


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

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


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

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

Allocation

Matthay 1999 clearly described the random sequence generation, which we judged to be at low risk of bias. The concealment of the allocation was not specified, which prompted us to judge it as an unclear risk of selection bias.

Blinding

Matthay 1999 did not report blinding of investigators and participants and we judged it to be at unclear risk of performance bias. We judged a low risk of detection bias, as the study committee and investigators were unaware of participants' treatment assignments, and the study was monitored by an independent committee according to a group sequential monitoring plan.

Incomplete outcome data

The study did not report whether in all eligible participants all outcomes (i.e. overall and event‐free survival) were assessed, so there was an unclear risk of attrition bias.

Selective reporting

Matthay 1999 reported the outcomes in accord with their protocol. Concerning multiple (duplicate) publication bias, we found eight publications that reported results from the Matthay 1999 study. It appears probable that data for the same participants were included in several publications. However, we did not include duplicate data in the review. Overall, we judged there to be a low risk of reporting bias.

Other potential sources of bias

Analysis of data in Matthay 1999 was conducted using the data of the randomised participants, which should be consistent with the ITT principle. However, it was unclear if all 98 participants received the treatment to which they were randomised. Also, not all participants treated with transplantation in the first randomisation and without progressive disease afterwards were included in the second randomisation. It is unclear how many eligible participants did not undergo the second randomisation. The consequences of two randomisations in one study for the risk of bias are unclear. We judged there to be an unclear risk of other potential sources of bias.

Effects of interventions

See: Summary of findings for the main comparison Retinoic acid postconsolidation therapy compared to no further treatment for high‐risk neuroblastoma patients treated with autologous haematopoietic stem cell transplantation

Primary outcomes  

Overall survival

We extrapolated the appropriate data on overall survival from the Kaplan Meier survival curve displayed in Figure 4B of the 2009 update article of Matthay 1999. We then calculated a HR of 0.87 (95% CI 0.46 to 1.63; low quality of evidence; Analysis 1.1; Figure 5). The difference between the groups was not statistically significant (P = 0.66). It was not reported if data for all 98 eligible participants were available, so it is unclear if this is an ITT analysis.


Forest plot of comparison: 1 Retinoic acid versus no further therapy, outcome: 1.1 Overall survival.
 Abbreviations. CI: confidence interval; IV: inverse variance; SE: standard error.

Forest plot of comparison: 1 Retinoic acid versus no further therapy, outcome: 1.1 Overall survival.
Abbreviations. CI: confidence interval; IV: inverse variance; SE: standard error.

We calculated the HR using the complete follow‐up period of the trial. The study also reported five‐year overall survival rates: 59% (standard error 8%) for the retinoic acid group and 41% (standard error 8%) for the no‐further‐therapy group (P value not reported). The values comply with the erratum, which corrected the value of the second standard error.

Treatment‐related mortality

We did not identify any results for treatment‐related mortality reported separately for the retinoic acid group and the control group.

Secondary outcomes  

Progression‐free survival

We did not identify any results for progression‐free survival.

Event‐free survival

We extrapolated the appropriate data on event‐free survival from the Kaplan Meier survival curves displayed in Figure 4A of the 2009 update article of Matthay 1999. Then, using the complete follow‐up period of the trial, we calculated a HR of 0.86 (95% CI 0.50 to 1.49; low quality of evidence; Analysis 1.2; Figure 6). The difference between the groups was not statistically significant (P = 0.59). It was not reported if data for all 98 eligible participants were available, so it is unclear if this is an ITT analysis.


Forest plot of comparison: 1 Retinoic acid versus no further therapy, outcome: 1.2 Event‐free survival.
 CI: confidence interval; IV: inverse variance; SE: standard error.

Forest plot of comparison: 1 Retinoic acid versus no further therapy, outcome: 1.2 Event‐free survival.
CI: confidence interval; IV: inverse variance; SE: standard error.

Early toxicity

Matthay 1999 did not separately report severe adverse events for the eligible 98 participants.

Late toxicity including secondary malignancy

We did not identify any results for late toxicity including secondary malignancy reported separately for the retinoic acid group and the control group.

Health‐related quality of life

We did not identify any results for health‐related quality of life.

Discussion

Summary of main results

This Cochrane Review evaluates the current state of evidence on the efficacy of retinoic acid versus control treatment in people diagnosed with high‐risk neuroblastoma, pretreated with HDCT followed by autologous HSCT. This is an update of a previously published Cochrane Review. We did not identify any new studies.

We include one RCT (Matthay 1999) of 98 participants with high‐risk neuroblastoma who received autologous HSCT after a first randomisation and then 13‐cis‐retinoic acid (n = 50) or no further treatment (n = 48) after a second randomisation. This group had no progressive disease after HDCT followed by autologous HSCT. The objectives of study Matthay 1999 were to assess "whether myeloablative therapy in conjunction with transplantation of autologous bone marrow improved event‐free survival compared with chemotherapy alone, and whether subsequent treatment with 13‐cis‐retinoic acid (isotretinoin) further improves event‐free survival". The comparisons were between groups that differed in more than only the intervention of interest. Our review, however, was only interested in the efficacy of retinoic acid versus control treatment in people who were pretreated with transplantation. As a result, only a subset of the participants from the Matthay 1999 were eligible for for inclusion in the review.

There was no statistically significant difference between the treatment groups in either overall survival (HR 0.87, 95% CI 0.46 to 1.63; one trial; P = 0.66, low quality of evidence) or event‐free survival (HR 0.86, 95% CI 0.50 to 1.49; one trial; P = 0.59, low quality of evidence). We calculated the HRs using the complete follow‐up period of the trial. The study also reported survival estimates at a fixed point in time. At the time point of five years, overall survival was estimated to be 59% (SE 8%) for the retinoic acid group and 41% (SE 8%) for the no‐further‐therapy group (P value not reported). No data were available for the other outcomes of interest (i.e. treatment‐related mortality, progression‐free survival, early and late toxicity, and health‐related quality of life) (see summary of findings Table for the main comparison).

Overall completeness and applicability of evidence

The inclusion of only one study in this review limits the inferences we can draw 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 we found no statistically significant difference between study groups could be the fact that the number of participants included was too small to detect a difference between the treatment groups (i.e. low power). Also, the included study was not designed to identify a superior treatment combination.

Furthermore, the study was conducted from 1991 to 1996 (Matthay 1999). The applicability of these data to current clinical practice is limited, as medical knowledge and terms of health care have progressed and changed significantly since then. The results may therefore not be applicable to patients who are treated today. Also, the applicability may depend on the dosing regimen. According to Veal 2013, the medication dose may have a marked influence on retinoic acid plasma concentrations in children with high‐risk neuroblastoma. Matthay 2013 suggested that the medication dose may have the potential to cause different outcomes between studies. Prior treatment and the response to that treatment may also play a role. Since we only found only one eligible study we could not assess these issues.

Another point is that the included RCT used an age of one year as the cut‐off point for pretreatment 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 people 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 participants with intermediate‐risk disease.

Only data on overall and event‐free survival were available for the patient population we were interested in (high‐risk neuroblastoma patients pretreated with HDCT followed by autologous HSCT). The included study did not provide data on, for example, toxicity and quality of life in these participants. As a result we cannot draw any conclusions regarding those outcomes, but they are of course important for clinical practice.

Cheung 2014 addressed the problem of end point selection and questioned the importance of HDCT followed by autologous HSCT: "A rethinking of the consolidation strategy for HR‐NB [explanation: high‐risk neuroblastoma] would be consistent with the general consensus among pediatric oncologists that ASCT [explanation: HDCT followed by autologous HSCT] in all other extracranial pediatric solid tumours is no longer recommended based on unsatisfactory risk‐benefit and cost‐benefit ratios assembled worldwide [the following references was used: Ratko 2012]."

Since information on the toxicity of an intervention is very important we decided to perform a post hoc search in the previous version for studies describing toxicity possibly associated with retinoic acid treatment, to get an impression of the importance of this outcome. We did not update the post hoc search for studies on toxicity data. We screened the 91 studies excluded in the search for the previous version for results on adverse events after retinoic acid application after HDCT followed by autologous HSCT in people with high‐risk neuroblastoma. We included all types of clinical studies and accepted meeting abstracts. We excluded narrative publication types such as nonsystematic reviews, letters and editorials. We did not report on those who received retinoic acid but did not receive transplantation. Thirty‐three out of these 91 potentially relevant publications were relevant (see Table 5); more than 1000 participants with high‐risk neuroblastoma were evaluated. In Kohler 2000, the exact number of relevant participants was not reported. 13‐cis‐retinoic acid (CRA, isotretinoin) was applied in 30 studies. 4‐hydroxyphenylretinamide (fenretinide) was applied in three studies. In 22 of the 33 studies, the authors reported participants with mild to severe organ toxicities associated with retinoic acid treatment. Most participants had mild and transient symptoms such as dry skin, cheilitis, rash, and bone pain. Retinoic acid was applied after a series of highly toxic chemotherapeutic regimens such as induction chemotherapy, myoablative chemotherapy, and autologous HSCT. It is difficult to distinguish adverse events associated with one agent rather than another, and it is difficult to draw causal inferences. Nevertheless, Khan 1996 reported a correlation between peak serum levels of retinoic acid and grade 3 to 4 toxicity such as involvement of skin, liver, as well as hypercalcaemia. We did not extract grade 1 to 2 toxicities. Maurer 2013 reported two participants with probable attribution of an elevation of serum alanine transaminase and aspartate transaminase and reported one participant with definite attribution of diarrhoea. However, six of 32 evaluated participants did not have a prior HDCT followed by autologous HSCT and the assignment of individual participants was not reported. We identified 13 studies that specifically reported an association of distinct adverse events with retinoic acid treatment (Clarke 2003; Cross 2009; Haysom 2005; Inamo 1999; Kohler 2000; Kreissman 2013; Marmor 2008; Mugishima 2008; Nishimura 1997; Rayburg 2009; Turman 1999; Villablanca 1993; Villablanca 1995). It should be noted that this was not a complete search for toxicity data and we did not assess the risks of bias in these studies. As a result, we can draw no definitive conclusions from these data.

Open in table viewer
Table 5. Toxicity possibly associated with retinoic acid after high‐dose chemotherapy followed by autologous haematopoietic stem cell transplantation

Study

Study design

Type of HSCT

Type of RA

Dose1

Pat2

Type of adverse event (N of affected participants)

Clarke 2003

CR

PBSCT

CRA

160

1

Pneumocystis carinii pneumonia (1)

Cross 2009

CR

NR

CRA

160

1

Hypercalcaemia (1), osteoblastic lesions (1)

De Kraker 2008

SA‐IS

BMT or PBSCT

CRA

160

44

NR

Granger 2012

SA‐IS

PBSCT

CRA

160

33

NR

Hamidieh 2012

SA‐IS

PBSCT

CRA

120 to 160

14

NR

Haysom 2005

CR

BMT

CRA

160

2

Bone marrow transplant nephropathy (2)

Inamo 1999

CR

BMT

CRA

33 to 1023

1

Growth failure (1)

Khan 1996

SA‐IS

BMT

CRA

100 to 200

31

Grade 3/4 toxicity of skin, liver and hypercalcaemia correlated with peak serum levels of CRA

Kletzel 2002

SA‐IS

PBSCT

CRA

160

12

Ataxia (1)

Kogner 2004

RCT

BMT

CRA

NR

12

NR

Kohler 2000

RCT

NR

CRA

15 to 224

NR

Dry skin (47), cheilitis (24), bone pain (16), other (13)

Kreissman 2013

RCT

PBSCT

CRA

160

192

Grade 3 toxic effects: hypertension (4), hematuria (2), elevated serum creatinine (2), proteinuria (3); purged and non‐purged transplantation group combined

Kushner 2003a

CS

NR

CRA

160

1

Cheilitis (1)

Laskin 2011

CS

NR

CRA

NR

20

NR

Marabelle 2009

CR

NR

CRA

160

3

Hypercalcaemia (3)

Marmor 2008

CR

NR

Fenretinide

666 to 20515

2

Rod electroretinogram suppression (2)

Mastrangelo 2011

SA‐IS

PBSCT

CRA

160

8

NR

Matthay 2006

SA‐IS

BMT

CRA

160

22

NR

Mugishima 2008

CR

BMT

CRA

130 to 400

2

Hypercalcaemia (2)

Nishimura 1997

CR

BMT

CRA

33 to 1023

1

Generalised metaphyseal modification (1)

Park 2011

SA‐IS

PBSCT

CRA

160

30

NR

Rayburg 2009

CR

NR

Fenretinide

2210

1

Langerhans cell histiocytosis (1)

Saarinen‐Pihkala 2012

SA‐IS

BMT or PBSCT

CRA

NR

36

NR

Simon 2011

SA‐IS

NR

CRA

160

75

NR

Sirachainan 2008

CR

NR

CRA

140

1

NR

Sung 2007

SA‐IS

PBSCT

CRA

125

44

Skin eruption, particularly face

Turman 1999

CR

BMT

CRA

160

2

Bone marrow transplant nephropathy (2)

Veal 2007

SA‐IS

NR

CRA

160

28

Mild skin toxicity (9), cheilitis (1), hypercalcaemia (2)

Veal 2013

SA‐IS

NR

CRA

160

103

Grade 3 ‐ 4 skin toxicity or cheilitis (5)

Villablanca 1993

SA‐IS

BMT

CRA

100 to 200

49

Dose‐limiting toxicity of hypercalcaemia (3), arthralgia and myalgia (1), grade 1 to 3 hypercalcaemia (9)

Villablanca 1995

SA‐IS

BMT

CRA

200

51

Hypercalcaemia (3), rash (2)

Villablanca 2011

SA‐IS

NR

Fenretinide

1800 to 2475

626

Rash (1), diarrhoea (1), nausea (2), vomiting (1), nyktalopia (1), abdominal pain (4)

Yu 2010

RCT

NR

CRA

160

108

"Few toxic effects"

Notice: Studies presented in this table were not eligible for inclusion in this review.

1Dose in mg/m2/day. The unit mg/kg may be transformed to mg/m2. The average body weight, body length, and body surface of a 6‐month‐old child may be 8 kg, 67 cm, and 0.39 m2, thus 8 kg divided by 0.39 m2 is roughly equalto a conversion factor of 20 (CDC 2000a). This factor increases continuously with age. The average body weight, body length, body surface of an 11‐year‐old child may be 36 kg, 143 cm, and 1.20 m2, thus 36 kg divided by 1.20 m2 is roughly equal to a conversion factor of 30 (CDC 2000b). The unit mg per day may be transformed to m2 per day. For example, 300 mg per day may vary on average between 769 mg/m2 (300 mg/0.39 m2) and 250 m2 (300 mg/1.20 m2)

2Participants treated with retinoic acid after HDCT followed by autologous HSCT acid and evaluated for toxicity.

3Inamo 1999; Nishimura 1997: Patients received retinoic acid at a dose of 40 mg per day. The daily dose may vary on average between 102 mg/m2 (40 mg/0.39 m2) and 33 m2 (40 mg/1.20 m2)

4Kohler 2000: Participants received retinoic acid at a dose of 0.75 mg/kg per day. The daily dose may vary on average between 15 mg/m2 (0.75 mg/kg * 20) and 22 mg/m2 (0.75 mg/kg * 30).

5Marmor 2008: Participants received retinoic acid at a dose of 800 mg per day. The daily dose may vary on average between 2051 mg/m2 (800 mg/0.39 m2) and 666 m2 (800 mg/1.20 m2).

6Villablanca 2011: 51 of the 62 participants received HSCT.

BMT: bone marrow transplantation; CR: case report; CS: case series; CRA: 13‐cis‐retinoic acid; HDCT: high‐dose chemotherapy; HSCT: haematopoietic stem cell transplantation; N: number of participants; NR: not reported; PBSCT: peripheral blood stem cell transplantation; RA: retinoic acid; SA‐IS: single‐arm intervention study such as phase‐1 or phase‐2 clinical trial

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

Quality of the evidence

Separate analyses of transplanted patients treated with or without additional retinoic acid were not reported in the included study. Nevertheless, the data were expressed in the survival curves presented in the study report. We extrapolated survival data from these graphs and estimated a HR to compare the two treatment groups. However, these estimates may be somewhat imprecise because the deduction and estimation process may deviate from the original data. Nevertheless, even considerable deviations would not be expected to change the observed difference in survival estimates.

The risk of bias in the included study was difficult to assess, in part due to a lack of reporting. As a result, we could not rule out the possible presence of selection bias, performance bias, attrition bias, and other bias. However, this remains the best available evidence from RCTs comparing the efficacy of additional retinoic acid versus control treatment after HDCT followed by autologous HSCT in high‐risk neuroblastoma patients.

Based on the GRADE assessments, in 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 two outcomes for which data were available as low; we downgraded the quality of the evidence due to risks of bias and imprecision.

Potential biases in the review process

One of the strengths of this review is the breadth 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. Also, we excluded secondary analyses of registers or databases, which may use data that have been published previously by individual contributing study centres. Overall, the possibility of reporting bias seems to be low.

1Study flow diagram of current review version.Abbreviations. CT.gov: ClinicalTrials.gov; ICTRP: International Clinical Trials Registry Platform
Figuras y tablas -
Figure 1

1Study flow diagram of current review version.

Abbreviations. CT.gov: ClinicalTrials.gov; ICTRP: International Clinical Trials Registry Platform

Flow of patients in the Matthay 1999 study (as prepared by review author FP).
 Abbreviations. BMT: bone marrow transplantation; ContCT: continuation chemotherapy; CT: chemotherapy; HDCT: high‐dose chemotherapy; RA: retinoic acid.
Figuras y tablas -
Figure 2

Flow of patients in the Matthay 1999 study (as prepared by review author FP).
Abbreviations. BMT: bone marrow transplantation; ContCT: continuation chemotherapy; CT: chemotherapy; HDCT: high‐dose chemotherapy; RA: retinoic acid.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 3

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

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 4

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

Forest plot of comparison: 1 Retinoic acid versus no further therapy, outcome: 1.1 Overall survival.
 Abbreviations. CI: confidence interval; IV: inverse variance; SE: standard error.
Figuras y tablas -
Figure 5

Forest plot of comparison: 1 Retinoic acid versus no further therapy, outcome: 1.1 Overall survival.
Abbreviations. CI: confidence interval; IV: inverse variance; SE: standard error.

Forest plot of comparison: 1 Retinoic acid versus no further therapy, outcome: 1.2 Event‐free survival.
 CI: confidence interval; IV: inverse variance; SE: standard error.
Figuras y tablas -
Figure 6

Forest plot of comparison: 1 Retinoic acid versus no further therapy, outcome: 1.2 Event‐free survival.
CI: confidence interval; IV: inverse variance; SE: standard error.

Comparison 1 Retinoic acid versus no further therapy, Outcome 1 Overall survival.
Figuras y tablas -
Analysis 1.1

Comparison 1 Retinoic acid versus no further therapy, Outcome 1 Overall survival.

Comparison 1 Retinoic acid versus no further therapy, Outcome 2 Event‐free survival.
Figuras y tablas -
Analysis 1.2

Comparison 1 Retinoic acid versus no further therapy, Outcome 2 Event‐free survival.

Summary of findings for the main comparison. Retinoic acid postconsolidation therapy compared to no further treatment for high‐risk neuroblastoma patients treated with autologous haematopoietic stem cell transplantation

Retinoic acid postconsolidation therapy compared to no further treatment for high‐risk neuroblastoma patients treated with autologous HSCT

Patient or population: high‐risk neuroblastoma patients treated with autologous HSCT
Settings: paediatric oncology departments
Intervention: retinoic acid postconsolidation therapy
Comparison: no further treatment

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

No further treatment

Retinoic acid post‐consolidation therapy

Overall survival (reported as mortality)

583 per 10001

533 per 1000
(331 to 760)

HR 0.87
(0.46 to 1.63)

98
(1 study)

⊕⊕⊝⊝
low2,3

The length of follow‐up was not mentioned for the 98 participants eligible for this review

Treatment‐related mortality ‐ not reported

See comment

See comment

Not estimable

See comment

No adequate information on this outcome was provided

Progression‐free survival ‐ not reported

See comment

See comment

Not estimable

See comment

No information on this outcome was provided

Event‐free survival (reported as relapse, disease progression, death from any cause, or second neoplasm)

604 per 10001

549 per 1000
(371 to 749)

HR 0.86
(0.50 to 1.49)

98
(1 study)

⊕⊕⊝⊝
low2,3

The length of follow‐up was not mentioned for the 98 participants eligible for this review

Early toxicity ‐ not reported

See comment

See comment

Not estimable

See comment

No adequate information on this outcome was provided

Late toxicity including secondary malignancies ‐ not reported

See comment

See comment

Not estimable

See comment

No adequate information on this outcome was provided

Health‐related quality of life ‐ not reported

See comment

See comment

Not estimable

See comment

No information on this outcome was provided

*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% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; HR: Hazard ratio; HSCT: haematopoietic stem cell transplantation

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.

1The 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.
2The presence of selection bias, performance bias, attrition bias and other bias was unclear, so we downgraded one level for study limitations.
3Since this is a small study and the 95% CIs include values favouring both the intervention and the control treatment we downgraded one level for imprecision.

Figuras y tablas -
Summary of findings for the main comparison. Retinoic acid postconsolidation therapy compared to no further treatment for high‐risk neuroblastoma patients treated with autologous haematopoietic stem cell transplantation
Table 1. The INRG consensus pretreatment classification scheme

INRG stage

Age (months)

Histologic category

Grade of tumour differentiation

MYCN

11q aberration

Ploidy

Pretreatment risk group

Code

Interpretation

L1/L2

Ganglioneuroma maturing; ganglioneuroblastoma intermixed

A

Very low

L1

Any, except ganglioneuroma or ganglioneuroblastoma

Not amplified

B

Very low

Amplified

K

High

L2

< 18

Any, except ganglioneuroma or ganglioneuroblastoma

Not amplified

No

D

Low

Yes

G

Intermediate

≥ 18

Ganglioneuroblastoma nodular; neuroblastoma

Differentiating

Not amplified

No

E

Low

Yes

H

Intermediate

Poorly differentiated or undifferentiated

Not amplified

H

Intermediate

Amplified

N

High

M

< 18

Not amplified

Hyperdiploid

F

Low

< 12

Not amplified

Diploid

I

Intermediate

12 to < 18

Not amplified

Diploid

J

Intermediate

< 18

Amplified

O

High

≥ 18

P

High

MS

< 18

Not amplified

No

C

Very low

Yes

Q

High

Amplified

R

High

Reference: Cohn 2009.

The INRG consensus classification schema includes the criteria INRG stage, age, histologic category, grade of tumour differentiation, MYCN status, presence/absence of 11q aberrations, and tumour cell ploidy. Sixteen statistically or clinically different pretreatment groups of patients (lettered A through R), or both, were identified using these criteria. The categories were 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.

Figuras y tablas -
Table 1. The INRG consensus pretreatment classification scheme
Table 2. The International Neuroblastoma Staging System

Stage

Definition

1

Localised tumour with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumour microscopically (nodes attached to and removed with the primary tumour may be positive)

2A

Localised tumour with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumour microscopically

2B

Localised tumour with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumour. Enlarged contralateral lymph nodes must be negative microscopically

3

Unresectable unilateral tumour infiltrating across the midlinea, with or without regional lymph node involvement; or localised unilateral tumour with contralateral regional lymph node involvement; or midline tumour with bilateral extension by infiltration (unresectable) or by lymph node involvement

4

Any primary tumour with dissemination to distant lymph nodes, bone, bone marrow, liver, skin and/or other organs (except as defined for stage 4S)

4S

Localised primary tumour (as defined for stage 1, 2A or 2B), with dissemination limited to skin, liver, and/or bone marrowb (limited to infants < 1 year of age)

Reference: Brodeur 1993.

Note: Multifocal primary tumours leg, bilateral adrenal primary tumours should be staged according to the greatest extent of disease, as defined above, and followed by a subscript letter M e.g. 3M.
aThe midline is defined as the vertebral column. Tumours originating on one side and crossing the midline must infiltrate to or beyond the opposite side of the vertebral column.
bMarrow 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. The (Meta‐iodobenzylguanidine) MIBG scan (if performed) should be negative in the marrow.

Figuras y tablas -
Table 2. The International Neuroblastoma Staging System
Table 3. Response to treatment

Response

Primary tumour

Metastatic sites

Complete response

No tumour

No tumour; catecholamines normal

Very good partial response

Decreased by 90% to 99%

No tumour; catecholamines normal; residual 99Tc bone changes allowed

Partial response

Decreased by more than 50%

All measurable sites decreased by > 50%. Bones and bone marrow: number of positive bone sites decreased by > 50%; no more than 1 positive bone marrow site allowed

Minimal response

No new lesions; > 50% reduction of any measurable lesion (primary or metastases) with < 50% reduction in any other; < 25% increase in any existing lesion

No response

No new lesions; < 50% reduction but < 25% increase in any existing lesion

Progressive disease

Any new lesion; increase of any measurable lesion by > 25%; previous negative marrow positive for tumour

Reference: Brodeur 1993.

Figuras y tablas -
Table 3. Response to treatment
Table 4. Children's Oncology Group assignment to low, intermediate, and high‐risk group

INSS stage

Age

MYCN

INPC classification

DNA index

Risk group

1

0 to 21 y

Any

Any

Any

Low

2A/2B

< 365 d

Any

Any

Any

Low

≥ 365 d to 21 y

Nonamplified

Any

Low

≥ 365 d to 21 y

Amplified

Favorable

Low

≥ 365 d to 21 y

Amplified

Unfavorable

High

3

< 365 d

Nonamplified

Any

Any

Intermediate

< 365 d

Amplified

Any

Any

High

≥ 365 d to 21 y

Nonamplified

Favorable

Intermediate

≥ 365 d to 21 y

Nonamplified

Unfavorable

High

≥ 365 d to 21 y

Amplified

Any

High

4

< 548 d

Nonamplified

Any

Any

Intermediate

< 365 d

Amplified

Any

Any

High

≥ 548 d to 21 y

Any

Any

High

4S

< 365 d

Nonamplified

Favorable

> 1

Low

< 365 d

Nonamplified

Any

= 1

Intermediate

< 365 d

Nonamplified

Unfavorable

Any

Intermediate

< 365 d

Amplified

Any

Any

High

Reference: NCI PDQ 2017
DNA index: favorable > 1 (hyperdiploid) or < 1 (hypodiploid); unfavorable = 1 (diploid).
Abbreviations. d: days of age; y: years of age.

Figuras y tablas -
Table 4. Children's Oncology Group assignment to low, intermediate, and high‐risk group
Table 5. Toxicity possibly associated with retinoic acid after high‐dose chemotherapy followed by autologous haematopoietic stem cell transplantation

Study

Study design

Type of HSCT

Type of RA

Dose1

Pat2

Type of adverse event (N of affected participants)

Clarke 2003

CR

PBSCT

CRA

160

1

Pneumocystis carinii pneumonia (1)

Cross 2009

CR

NR

CRA

160

1

Hypercalcaemia (1), osteoblastic lesions (1)

De Kraker 2008

SA‐IS

BMT or PBSCT

CRA

160

44

NR

Granger 2012

SA‐IS

PBSCT

CRA

160

33

NR

Hamidieh 2012

SA‐IS

PBSCT

CRA

120 to 160

14

NR

Haysom 2005

CR

BMT

CRA

160

2

Bone marrow transplant nephropathy (2)

Inamo 1999

CR

BMT

CRA

33 to 1023

1

Growth failure (1)

Khan 1996

SA‐IS

BMT

CRA

100 to 200

31

Grade 3/4 toxicity of skin, liver and hypercalcaemia correlated with peak serum levels of CRA

Kletzel 2002

SA‐IS

PBSCT

CRA

160

12

Ataxia (1)

Kogner 2004

RCT

BMT

CRA

NR

12

NR

Kohler 2000

RCT

NR

CRA

15 to 224

NR

Dry skin (47), cheilitis (24), bone pain (16), other (13)

Kreissman 2013

RCT

PBSCT

CRA

160

192

Grade 3 toxic effects: hypertension (4), hematuria (2), elevated serum creatinine (2), proteinuria (3); purged and non‐purged transplantation group combined

Kushner 2003a

CS

NR

CRA

160

1

Cheilitis (1)

Laskin 2011

CS

NR

CRA

NR

20

NR

Marabelle 2009

CR

NR

CRA

160

3

Hypercalcaemia (3)

Marmor 2008

CR

NR

Fenretinide

666 to 20515

2

Rod electroretinogram suppression (2)

Mastrangelo 2011

SA‐IS

PBSCT

CRA

160

8

NR

Matthay 2006

SA‐IS

BMT

CRA

160

22

NR

Mugishima 2008

CR

BMT

CRA

130 to 400

2

Hypercalcaemia (2)

Nishimura 1997

CR

BMT

CRA

33 to 1023

1

Generalised metaphyseal modification (1)

Park 2011

SA‐IS

PBSCT

CRA

160

30

NR

Rayburg 2009

CR

NR

Fenretinide

2210

1

Langerhans cell histiocytosis (1)

Saarinen‐Pihkala 2012

SA‐IS

BMT or PBSCT

CRA

NR

36

NR

Simon 2011

SA‐IS

NR

CRA

160

75

NR

Sirachainan 2008

CR

NR

CRA

140

1

NR

Sung 2007

SA‐IS

PBSCT

CRA

125

44

Skin eruption, particularly face

Turman 1999

CR

BMT

CRA

160

2

Bone marrow transplant nephropathy (2)

Veal 2007

SA‐IS

NR

CRA

160

28

Mild skin toxicity (9), cheilitis (1), hypercalcaemia (2)

Veal 2013

SA‐IS

NR

CRA

160

103

Grade 3 ‐ 4 skin toxicity or cheilitis (5)

Villablanca 1993

SA‐IS

BMT

CRA

100 to 200

49

Dose‐limiting toxicity of hypercalcaemia (3), arthralgia and myalgia (1), grade 1 to 3 hypercalcaemia (9)

Villablanca 1995

SA‐IS

BMT

CRA

200

51

Hypercalcaemia (3), rash (2)

Villablanca 2011

SA‐IS

NR

Fenretinide

1800 to 2475

626

Rash (1), diarrhoea (1), nausea (2), vomiting (1), nyktalopia (1), abdominal pain (4)

Yu 2010

RCT

NR

CRA

160

108

"Few toxic effects"

Notice: Studies presented in this table were not eligible for inclusion in this review.

1Dose in mg/m2/day. The unit mg/kg may be transformed to mg/m2. The average body weight, body length, and body surface of a 6‐month‐old child may be 8 kg, 67 cm, and 0.39 m2, thus 8 kg divided by 0.39 m2 is roughly equalto a conversion factor of 20 (CDC 2000a). This factor increases continuously with age. The average body weight, body length, body surface of an 11‐year‐old child may be 36 kg, 143 cm, and 1.20 m2, thus 36 kg divided by 1.20 m2 is roughly equal to a conversion factor of 30 (CDC 2000b). The unit mg per day may be transformed to m2 per day. For example, 300 mg per day may vary on average between 769 mg/m2 (300 mg/0.39 m2) and 250 m2 (300 mg/1.20 m2)

2Participants treated with retinoic acid after HDCT followed by autologous HSCT acid and evaluated for toxicity.

3Inamo 1999; Nishimura 1997: Patients received retinoic acid at a dose of 40 mg per day. The daily dose may vary on average between 102 mg/m2 (40 mg/0.39 m2) and 33 m2 (40 mg/1.20 m2)

4Kohler 2000: Participants received retinoic acid at a dose of 0.75 mg/kg per day. The daily dose may vary on average between 15 mg/m2 (0.75 mg/kg * 20) and 22 mg/m2 (0.75 mg/kg * 30).

5Marmor 2008: Participants received retinoic acid at a dose of 800 mg per day. The daily dose may vary on average between 2051 mg/m2 (800 mg/0.39 m2) and 666 m2 (800 mg/1.20 m2).

6Villablanca 2011: 51 of the 62 participants received HSCT.

BMT: bone marrow transplantation; CR: case report; CS: case series; CRA: 13‐cis‐retinoic acid; HDCT: high‐dose chemotherapy; HSCT: haematopoietic stem cell transplantation; N: number of participants; NR: not reported; PBSCT: peripheral blood stem cell transplantation; RA: retinoic acid; SA‐IS: single‐arm intervention study such as phase‐1 or phase‐2 clinical trial

Figuras y tablas -
Table 5. Toxicity possibly associated with retinoic acid after high‐dose chemotherapy followed by autologous haematopoietic stem cell transplantation
Comparison 1. Retinoic acid versus no further therapy

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

1

Hazard Ratio (Random, 95% CI)

0.87 [0.46, 1.63]

2 Event‐free survival Show forest plot

1

Hazard Ratio (Random, 95% CI)

0.86 [0.50, 1.49]

Figuras y tablas -
Comparison 1. Retinoic acid versus no further therapy