Bleomicina intraquística para los craneofaringiomas quísticos en los niños
Resumen
Antecedentes
Los craneofaringiomas son los tumores histológicos benignos más frecuentes de la región hipotálamo‐pituitaria en la niñez. Los craneofaringiomas quísticos representan más del 90% de los tumores. El tratamiento óptimo del craneofaringioma quístico sigue siendo polémico. La resección radical es el tratamiento de elección en los pacientes con una localización favorable del tumor. Cuando la localización tumoral no es favorable, la opción de tratamiento principal en los adultos es la resección total o parcial seguida de radioterapia. Sin embargo, la misma presenta un riesgo de morbilidad especialmente para los niños. La bleomicina intraquística se ha utilizado para retrasar potencialmente el uso de radioterapia o de la resección radical para reducir la morbilidad. Esta revisión es la segunda actualización de una revisión Cochrane publicada anteriormente.
Objetivos
Evaluar los beneficios y los efectos perjudiciales de la bleomicina intraquística en niños desde el nacimiento hasta los 18 años de edad con craneofaringioma quístico en comparación con el placebo (sin tratamiento), el tratamiento quirúrgico (con o sin radioterapia adyuvante) u otros tratamientos intraquísticos.
Métodos de búsqueda
Se realizaron búsquedas en las bases de datos electrónicas CENTRAL (2016, Número 1), MEDLINE/PubMed (desde 1966 hasta febrero de 2016) y EMBASE/Ovid (desde 1980 hasta febrero de 2016) con términos preespecificados. Además, se realizaron búsquedas en las listas de referencias de los artículos y revisiones pertinentes, en las actas de congresos (Sociedad Internacional de Oncología Pediátrica 2005‐2015) y en las bases de datos de ensayos en curso (Registro del Instituto Nacional de Salud y Registro del Número de Ensayos Controlados Aleatorios Estándar Internacional (ISRCTN)) en febrero de 2016.
Criterios de selección
Ensayos controlados aleatorizados (ECA), ensayos cuasialeatorizados o ensayos clínicos controlados (ECC) que compararan la bleomicina intraquística y otros tratamientos para los craneofaringiomas quísticos en los niños (desde el nacimiento hasta los 18 años).
Obtención y análisis de los datos
Dos autores de la revisión, de forma independiente, realizaron la selección de los estudios, extrajeron los datos y evaluaron el riesgo de sesgo. Se utilizó el riesgo relativo (RR) para los datos binarios y la diferencia de medias (DM) para los datos continuos. Si uno de los grupos de tratamiento no experimentaba ningún evento y había sólo un estudio disponible para el resultado, se usó la prueba exacta de Fischer. El análisis se realizó según las guías del Manual Cochrane para Revisiones Sistemáticas de Intervenciones (Cochrane Handbook for Systematic Reviews of Interventions).
Resultados principales
No fue posible identificar estudios en los cuales la única diferencia entre los grupos de tratamiento sea el uso del bleomicina intraquística. Se identificó un ECA que comparó la bleomicina intraquística con fósforo32 (32P) intraquístico (siete niños). En esta actualización no se ha identificado ningún estudio adicional. El estudio incluido tuvo alto riesgo de sesgo. No se pudo evaluar la supervivencia. No hubo pruebas claras de una diferencia entre los grupos de tratamiento en la reducción de los quistes (DM ‐0,15, intervalo de confianza (IC) del 95%: ‐0,69 a 0,39, valor de P = 0,59, evidencia de muy baja calidad), el estado neurológico (valor exacto de P de Fisher = 0.429, evidencia de muy baja calidad), parálisis del tercer nervio (valor exacto de P de Fischer = 1,00, evidencia de muy baja calidad), fiebre (RR 2,92, IC del 95%: 0,73 a 11,70, valor de P = 0,13, evidencia de muy baja calidad) o efectos adversos totales (RR 1,75, IC del 95%: 0,68 a 4,53, valor de P = 0,25, evidencia de muy baja calidad). Hubo una diferencia significativa a favor del grupo de 32P en cuanto a la aparición de cefalea y vómitos (valor de p exacto de Fischer = 0,029, evidencia de calidad muy baja para ambos resultados).
Conclusiones de los autores
Debido a que no se identificó ningún ECA, ensayo cuasialeatorizado ni ECC del tratamiento del craneofaringioma quístico en niños en los cuales se observaran diferencias sólo en el uso de bleomicina intraquística entre los grupos de tratamiento, no fue posible establecer una conclusión definitiva acerca de los efectos de la bleomicina intraquística en estos pacientes. Sólo hubo un ECA de poco poder estadístico que comparó la bleomicina intraquística con el tratamiento con 32P intraquístico, aunque no puede establecerse ninguna conclusión definitiva acerca de la efectividad de estos agentes en los niños con craneofaringiomas quísticos. Sobre la base de las pruebas disponibles actualmente, no es posible proporcionar recomendaciones en cuanto al uso de bleomicina intraquística para el tratamiento de los craneofaringiomas quísticos en los niños. Se necesitan más ECA de alta calidad.
PICO
Resumen en términos sencillos
Bleomicina intraquística en niños con craneofaringiomas quísticos
Los craneofaringiomas son tumores benignos poco frecuentes y de crecimiento lento en la región hipotalámica‐pituitaria del cerebro. Aunque son benignos, es decir, el tumor no tiene la capacidad de invadir los tejidos vecinos o de hacer metástasis (propagarse a otros lugares), existe una morbilidad y una discapacidad considerables, incluso cuando el tumor puede ser resecado completamente. Los craneofaringiomas quísticos son el tipo más frecuente de craneofaringiomas. Consisten en una porción sólida que contiene estructuras similares a globos llenos de líquido (quistes). Los quistes son un problema porque la secreción de líquido en ellos permite que el tumor aumente de tamaño, lo que ejerce presión sobre partes del cerebro y puede causar daños. La resección radical (extirpación mediante cirugía) por sí sola no es suficiente porque la tasa de recurrencia es alta y este procedimiento tiene un alto riesgo de deficiencias endocrinológicas/neurológicas como la ceguera; la pérdida de control del apetito, la producción de orina, el comportamiento emocional y la coordinación física; la pérdida de memoria; las alteraciones del sueño; el cese del crecimiento y el desarrollo sexual; los bajos niveles de tiroxina; la hidrocefalia (alta presión dentro del cráneo); y la muerte. Mientras que en los adultos la radioterapia representa un tratamiento complementario (adicional) postoperatorio válido, en los niños tiene un alto riesgo de efectos secundarios que incluyen un mayor daño a cualquier visión que quede, con reducción del cociente intelectual (CI) y la capacidad de realizar tareas complejas más adelante en la vida. La bleomicina intraquística (es decir, un tipo de agente quimioterapéutico que se inyecta en el quiste) se ha utilizado para disminuir potencialmente el daño asociado con el craneofaringioma quístico.
Esta revisión sistemática se centró en los estudios controlados (aleatorizados). No se pudo identificar ensayos controlados aleatorizados (ECA), ensayos cuasialeatorizados ni ensayos clínicos controlados (ECC) en los cuales la única diferencia entre los grupos de control y de intervención fuese el uso de bleomicina intraquística. Sin embargo, se identificó un ECA que comparaba la bleomicina intraquística con el fósforo32 (32P) intraquístico, que es un isótopo radiactivo de fósforo utilizado para la irradiación intraquística. Sólo siete niños fueron incluidos en este estudio. El estudio tiene un alto riesgo de sesgo y el tamaño de la muestra es demasiado pequeño para detectar una diferencia en los resultados. El uso terapéutico de bleomicina intraquística en los niños con craneofaringiomas quísticos actualmente sigue siendo incierto. Aunque no hubo una diferencia significativa en el total de los efectos adversos entre los dos grupos de tratamiento, sí hubo una diferencia significativa tanto en el dolor de cabeza como en los vómitos a favor del grupo 32P. Sin embargo, la calidad de la evidencia es muy baja. Se necesitan más estudios de alta calidad, pero será difícil ya que son pocos los niños que contraen estos tumores.
Authors' conclusions
Summary of findings
| Intracystic bleomycin compared to intracystic radiotherapy with 32P for cystic craniopharyngiomas in children | ||||||
| Patient or population: cystic craniopharyngiomas in children from birth to 18 years old | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with intracystic 32P | Risk with intracystic bleomycin | |||||
| Survival | NA | NA | ‐ | ‐ | ‐ | There was no information on overall survival and event‐free survival reported in this trial |
| Change in cyst size | Mean reduction in cyst size was 65.5% | Mean reduction in cyst size was 50.7% | MD ‐15% (‐69% to 39%) | 7 | ⊕⊝⊝⊝ | MD was 15% reduction in cyst size; the 95% CI mean a 69% reduction to a 39% increase in cyst size |
| Neurological status | See comment | See comment | Not estimable | Not estimable | ⊕⊝⊝⊝ | 1 patient in the bleomycin group had left paralysis, while none of the patients in the 32P group had severe sequelae. There was no significant difference between the 2 groups (Fisher's exact P value = 0.429). |
| Total number of adverse effects | 500 per 1000 | 875 per 1000 | RR 1.75 | 7 | ⊕⊝⊝⊝ | Adverse effects including fever, 3rd nerve paralysis, headache and vomiting were included in this outcome measure |
| Fever | 250 per 1000 | 730 per 1000 | RR 2.92 | 7 | ⊕⊝⊝⊝ | ‐ |
| 3rd nerve paralysis | See comment | See comment | Not estimable | 7 | ⊕⊝⊝⊝ | 1 patient in the 32P group had 3rd nerve paralysis, while none of the patients in the bleomycin group suffered from this. There was no significant difference between the 2 groups (Fisher's exact P value = 1.00). |
| Headache and vomiting | See comment | See comment | Not estimable | 7 | ⊕⊝⊝⊝ | All 3 patients in the bleomycin group had headache and vomiting, while none of the patients in the 32P group did. There was a significant difference in favour of the 32P group (Fisher's exact P value = 0.029). |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1We downgraded a total of 3 levels due to study limitations (the trial had a high risk of performance bias, detection bias and baseline imbalance bias, and an unclear risk of selection bias, attrition bias, reporting bias and early stopping bias), small sample size (the current review includes only one trial with small sample size (n = 7)), and wide confidence intervals including 'no effect', 'appreciable harm' and 'appreciable benefit'. | ||||||
Background
Craniopharyngiomas are usually slow‐growing, benign tumours that originate from epithelial nests or from areas of squamous metaplasia located in the hypothalamic and pituitary regions. Craniopharyngiomas are the most common intracranial tumours of non‐glial origin in the paediatric population, constituting 6% to 13% of all childhood brain tumours and peaking at five to 10 years of age (Sanford 1991; Bunin 1998). Although the tumour is of a benign histological nature, there is considerable morbidity and disability even when the tumour can be resected completely.
Description of the condition
Treatment of childhood craniopharyngioma is an ongoing controversy. The currently accepted therapy is radical tumour resection. However, surgery still remains challenging because the tumour is infiltrative to the tuber cinereum and the hypothalamus. Patient series have demonstrated that gross‐total resection of craniopharyngiomas was achieved in only 50% to 80% of attempted radical resections (Sainte‐Rose 2005; Thompson 2005; Tomita 2005; Zuccaro 2005). Furthermore, even after total resection, the tumour recurrence rate is high (Yasargil 1990; Weiner 1994), especially in the residual cystic portion (Takahashi 1985). Some authors advocate external radiotherapy after partial resection of the tumour (Hetelekidis 1993; Wara 1994), which has resulted in less early morbidity, however, it may increase endocrine disturbance and mortality, especially in children (Gleeson 2003).
Description of the intervention
Bleomycin was first discovered by Hamao Umezawa in 1966 (Umezawa 1966), and was launched in Japan by Nippon Kayaku in 1969. It was found to be effective in various types of epithelial tumours and benign squamous epithelial cells. Kubo 1974 confirmed the toxicity of bleomycin to cultured craniopharyngioma cells in 1971. In 1985, Takahashi 1985 published a paper concerning seven patients with craniopharyngioma treated with intratumoural bleomycin, which indicated that the local injection of bleomycin was not as effective against craniopharyngioma of the mixed or solid type, but was markedly effective against tumours of the cystic type. After that, other research confirmed that intracystic bleomycin used to treat cystic craniopharyngioma may eliminate cysts completely with few complications (Broggi 1989; Mettolese 2001).
How the intervention might work
Bleomycin is an antitumour antibiotic secreted by Streptomyces verticillus. It is composed of two main glycopeptides, bleomycin A2 and B2. Its action is based on inhibition of DNA and RNA synthesis through the formation of metal complexes with copper and iron serving as co‐factors. These effects on the cell cycle are the G, M and S phases.
Bleomycin is very effective in squamous cell carcinomas. The squamous epithelium associated with keratinisation is characteristically found in the cyst walls of craniopharyngiomas and in its solid component. Therefore, it is believed that it can be used to treat cystic craniopharyngiomas.
Why it is important to do this review
Although some researchers have advocated bleomycin for the treatment of cystic craniopharyngioma, it is a neurotoxic drug and if leakage occurs severe complications may develop, including death. The aim of this review is to evaluate the existing evidence on intracystic bleomycin in the treatment of children with craniopharyngioma. This is an update of the previous systematic reviews evaluating the use of intracystic bleomycin for cystic craniopharyngiomas in children (Fang 2012; Zheng 2014).
Objectives
To assess the benefits and harmful effects of intracystic bleomycin in children from birth to 18 years with cystic craniopharyngioma.
Specific objectives are to compare:
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intracystic bleomycin with placebo (no treatment);
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intracystic bleomycin with surgical treatment (with or without adjuvant radiotherapy);
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intracystic bleomycin with other intracystic treatments.
Methods
Criteria for considering studies for this review
Types of studies
We planned to include all randomised controlled trials (RCTs), quasi‐randomised trials or controlled clinical trials (CCTs) as defined by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), which compared intracystic bleomycin with placebo/no treatment or surgical treatment (with or without adjuvant radiotherapy) or other intracystic treatments. We did not consider any other uncontrolled observational trials.
Types of participants
Participants had to meet the following criteria.
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Between the ages of 0 to 18 years (age at onset of intracystic bleomycin treatment).
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Diagnosed as having cystic craniopharyngioma by brain computerised tomography (CT) or magnetic resonance imaging (MRI).
Types of interventions
Intracystic bleomycin. Procedure: the catheter is inserted inside the tumour with the help of a surgical microscope or stereotactically or via a neuroendoscopic technique, and is connected to a subcutaneous reservoir. After catheter insertion, contrast agents are injected into the cyst to verify that there is no fluid leakage. Intratumoural fluid is aspired and bleomycin is injected into the cyst. The control group is given placebo/no treatment or surgical treatment (with or without adjuvant radiotherapy) or other intracystic treatments. The dose, frequency and duration can vary.
Types of outcome measures
Primary outcomes
The primary endpoint is overall survival (OS) or event‐free survival (EFS) at the end of the follow‐up.
OS is defined as the time to death from any cause. EFS is defined as the time to recurrence or progression of primary disease or death from any cause.
Secondary outcomes
We grouped time points into 'short‐term' (less than one year) or 'long‐term' (more than one year) outcomes. We evaluated the measurements as follows at pre‐specified time points.
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The response of the cyst to treatment: sensitive or insensitive (as defined by the authors).
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The size of the cystic component: the rate of decrease in the size of the cystic component.
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Endocrine function: the comparison between pre‐ and postoperative endocrine deficits including: hypopituitarism, short stature, weight alterations, diabetes insipidus. The change is classified as improved, stable, worsened and new cases.
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Neurological status: no disability; moderate disability; severe disability (the criteria of disability as defined by the authors).
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Visual outcome: classified as improved, stable, worsened and new cases.
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Quality of life: measured using a scale that has been validated through reporting of norms in a peer‐reviewed publication.
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Adverse effects: such as death, cerebrovascular event, new neurological deficit, new hypothalamic dysfunction, new visual dysfunction, the recurrence of craniopharyngioma, headache, nausea, vomiting, transient fever, arthralgia, chronic fatigue syndrome etc.; number of patients who withdrew due to adverse events compared with placebo, no treatment, surgical treatment (with or without adjuvant radiotherapy) or other intracystic chemotherapy groups.
Search methods for identification of studies
Electronic searches
We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 1), MEDLINE/PubMed (from 1945 to 10 February 2016) and EMBASE/Ovid (from 1980 to 10 February 2016). We have presented the sensitive search strategies used for CENTRAL, MEDLINE/PubMed and EMBASE/Ovid in Appendix 1, Appendix 2 and Appendix 3.
Searching other resources
We located information about trials not registered in CENTRAL, MEDLINE or EMBASE, either published or unpublished, by searching the reference lists of relevant articles and reviews. We scanned electronically the proceedings abstracts of the International Society for Paediatric Oncology (SIOP) (from 2005 up to and including 2015) on 3 March 2016. We searched the International Standard Randomised Controlled Trial Number (ISRCTN) register (http://www.isrctn.com) and the register of the National Institutes of Health (http://www.clinicaltrials.gov) for ongoing trials on 3 March 2016. We did not impose any language restrictions. For details of these search strategies see Appendix 4 and Appendix 5. We will update the searches every two years.
Data collection and analysis
Selection of studies
Two review authors independently screened the titles and abstracts of studies identified through the searches and selected trials that met the inclusion criteria. We retrieved full articles for further assessment. We used discussion and consultation with a third review author to resolve any disagreement. The selection process is outlined in a flow chart (see Figure 1)
Study flow diagram.
Data extraction and management
For included studies, two review authors independently extracted the following information using a standard form:
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General information: title, authors, published/unpublished, year of publication, language of publication, duplicate publications, study design, country, reference/source, contact address, urban/rural, sponsoring, setting.
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Intervention: dose, route, timing, control intervention (placebo, no treatment, surgical treatment (with or without adjuvant radiotherapy), some other intracystic chemotherapies).
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Participants: sampling, total number and number in comparison groups, sex, age, trial inclusion and exclusion criteria; withdrawals/losses to follow‐up (reasons/description), subgroups.
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Outcomes: outcomes specified above, length of follow‐up, quality of reporting of outcomes.
If there were differences in data extraction, we resolved these by discussion, referring back to the original paper, or by consulting a third person.
Assessment of risk of bias in included studies
Two authors planned to assess independently the risk of bias in included RCTs and CCTs using Cochrane's 'Risk of bias' tool (Higgins 2011). The tool considers six domains of bias: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other issues. For each domain, the study method is described using verbatim quotes and judged for adequacy (high, low, unclear risk of bias). We added items for the assessment of risk of bias as described in the module of Cochrane Childhood Cancer (Kremer 2010). We resolved any disagreements by discussion or using a third party arbitrator, and presented the results in the 'Risk of bias' table and also in both graph and written summary form.
Risk of bias assessment for non‐randomised clinical trials is a complex topic. However, since no non‐randomised trials (i.e. CCTs) were identified, using a modification of the Methodological Index for Non‐Randomised Studies (MINORS) was not applicable (Slim 2003).
Measures of treatment effect
For time‐to‐event data (e.g. overall survival and event‐free survival), we used the hazard ratio (HR). If HRs were not explicitly presented in the study, we planned to use Parmar's method (Parmar 1998).
For dichotomous outcomes (e.g. response of cyst to treatment, adverse events, visual outcome, neurological status and endocrine function), we calculated risk ratios (RR) with 95% confidence intervals (CI) for each trial.
For continuous outcomes (e.g. the rate of decrease of the size of the cystic component, quality of life), we intended to evaluate mean difference (MD) or standardised mean difference (SMD) with 95% CI. We only analysed one continuous outcome, reduction of cyst size, and for this we reported the MD.
Unit of analysis issues
We planned to consider each individual study included in the meta‐analysis as a unit for analysis.
Dealing with missing data
We analysed all data on an intention‐to‐treat basis. We did not contact authors for missing data.
Assessment of heterogeneity
Since only one eligible study was identified, assessing the presence of substantial heterogeneity (i.e. I² > 50% (Higgins 2011)) was not applicable.
Assessment of reporting biases
We planned to construct a funnel plot (Egger 1997), to ascertain graphically the existence of publication bias. However, as a rule of thumb, tests for funnel plot asymmetry should be used only when there are at least 10 studies included in the meta‐analysis, because when there are fewer studies the power of the tests is too low to distinguish chance from real asymmetry (Higgins 2011). Since only one RCT could be included in this review, we did not construct funnel plots.
Data synthesis
We performed data synthesis and analyses using the Cochrane Review Manager software, RevMan 5.3 (RevMan 2014). We performed the analyses according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We used the Mantel‐Haenszel method to perform the analysis. Since only one RCT could be included in this review, we used a fixed‐effect model. Also, because there was only one study available, we were unable to calculate a RR if one of the treatment groups experienced no events and we therefore used the Fisher's exact test instead (in SPSS 18.0). For each comparison we prepared a 'Summary of findings' table using the GRADE profiler software (www.gradepro.org), in which we presented the following outcomes: survival, size reduction of cyst, neurological status, total number of adverse effects, fever, third nerve paralysis and headache in combination with vomiting. For each outcome two review authors independently assessed the quality of the evidence by using the five GRADE considerations, i.e. study limitations, inconsistency, indirectness, imprecision and publication bias as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and the GradePro Handbook (Schünemann 2013).
Subgroup analysis and investigation of heterogeneity
As only one eligible study was identified and the sample size was small, subgroup analysis was not applicable. Otherwise we would have looked at:
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age at onset of intracystic bleomycin treatment;
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gender;
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dosage (or the concentration of the dose) of treatment;
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multicystic craniopharyngioma.
Sensitivity analysis
Since only one eligible study was identified, performing sensitivity analyses for the quality criteria used was not applicable.
Results
Description of studies
Results of the search
For the original review, we identified a total of 295 references through electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (n = 2), PubMed (n = 202) and EMBASE (n = 91). We screened one study in full text and only this randomised controlled trial was eligible for inclusion in the original review (Jiang 2002) (see Characteristics of included studies).
For the previous update, we identified an additional 68 references through electronic searches of CENTRAL (n = 0), PubMed (n = 50) and EMBASE (n = 18). From reading the titles and abstracts, we were not able to identify any eligible study from the references. No additional studies or trials was eligible for inclusion.
For this update, we identified an additional 51 references through electronic searches of CENTRAL (n = 0), PubMed (n = 39) and EMBASE (n = 12). From reading the titles and abstracts, we were not able to identify any eligible study from the references. Scanning the reference lists of relevant studies and reviews, and scanning the conference proceedings of SIOP, did not identify any other eligible studies. Scanning the ongoing trials databases did not identify any eligible (ongoing) studies. In summary, only one RCT could be included in this review. We identified no eligible CCTs or ongoing studies (See Figure 1).
Included studies
See Characteristics of included studies.
This study also included adults, but we only extracted data for children in the intracystic bleomycin and intracystic phosphorus32 (32P) groups. The total number of children was seven. Three children received intracystic bleomycin and four children received intracystic 32P. In the bleomycin group, a 1.0 ml solution of bleomycin was injected through the tube into the cysts daily for eight days. In the 32P group, 0.9% saline was injected daily into the cysts for seven days and 32P was administered to the patients in the 32P group on the eighth day. The dose of bleomycin started at 5.0 mg and was increased by 2.5 mg or 5.0 mg each day, depending on the tolerance of the patient to the drug. The largest daily dose was no more than 15 mg. The largest total dose received by any patient was 120 mg, while the least was 14.5 mg. The radioactive dose of 32P to the cyst wall was 200 Gy. The outcomes reported in the trial were size reduction of the cyst, neurological status and adverse effects (headache, fever, vomiting and third nerve paralysis). The trial did not report survival, response of the cyst to treatment, endocrine function, visual outcome or quality of life.
Excluded studies
There were no excluded studies.
Risk of bias in included studies
The risk of bias is summarised in the 'Risk of bias' summary (Figure 2) and 'Risk of bias' graph (Figure 3). For more detailed information see the 'Risk of bias' table in the Characteristics of included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Allocation
The generation of allocation sequence and allocation concealment was unclear.
Blinding
Blinding of participants was performed. However, blinding of personnel and outcome assessors for the clinical outcomes was not performed.
Incomplete outcome data
The numbers and reasons for dropouts and withdrawals in all intervention groups were not described. We considered the trial to have an unclear risk of bias.
Selective reporting
The protocol for this study was unavailable, therefore the trial was at unclear risk of bias.
Other potential sources of bias
Baseline imbalance
The patients in the bleomycin group were all multicystic, while the patients in the 32P group were not. Hence, the trial did have a risk of baseline imbalance.
Early stopping
The sample size calculations for the trial were not reported. Hence, it was unclear whether the trial was stopped early.
Summary of quality assessment of included trial
We considered the trial to have a high risk of performance bias, detection bias and baseline imbalance bias, and an unclear risk of selection bias, attrition bias, reporting bias and early stopping bias.
Effects of interventions
Overall survival or event‐free survival
There was no information on overall survival and event‐free survival reported in this trial.
The response of the cyst to treatment
There was no information about the response of the cyst to treatment.
The size of the cystic component
There was no significant difference in cyst size reduction between the bleomycin and phosphorus32 (32P) groups (mean difference (MD) ‐0.15, 95% confidence interval (CI) ‐0.69 to 0.39, P value = 0.59, very low quality of evidence) (see Analysis 1.1 and summary of findings Table for the main comparison).
Endocrine function
The data for endocrine function could not be extracted.
Neurological status
One child in the bleomycin group had left paralysis after two episodes of epilepsy. None of the children in the 32P group had severe sequelae. There was no significant difference between the groups (Fisher's exact P value = 0.429, very low quality of evidence).
Visual outcome
There was no visual outcome reported in this trial.
Quality of life
There was no quality of life outcome reported in this trial.
Adverse effects
All three children in the bleomycin group had complications of fever, headache and vomiting, however, in the 32P group there was only one patient who had transient fever; none of the patients in that group suffered from headache or vomiting. There was no significant difference in fever between the two groups (risk ratio (RR) 2.92, 95% CI 0.73 to 11.70, P value = 0.13, very low quality of evidence) (see Analysis 1.2 and summary of findings Table for the main comparison), but there was a significant difference in headache (Fisher's exact P value = 0.029, very low quality of evidence) and vomiting (Fisher's exact P value = 0.029, very low quality of evidence) in favour of the 32P group. A patient in the 32P group had third nerve paralysis, while none of the patients in the bleomycin group suffered from this. There was no significant difference between the two groups (Fisher's exact P value = 1.00, very low quality of evidence). In summary, there was no significant difference in total adverse effects between the groups (RR 1.75, 95% CI 0.68 to 4.53, P value = 0.25, very low quality of evidence) (see Analysis 1.3 and summary of findings Table for the main comparison).
Subgroup analysis
It was not possible to perform subgroup analysis due to the small sample size.
Discussion
The occurrence of cysts is one of the typical characteristics of craniopharyngioma, occurring in more than 90% of tumours (Blacklund 1994). The treatment of cystic craniopharyngioma is controversial. Puget 2007 used a preoperative classification system to grade hypothalamic involvement and stratify treatment. For tumours that do not involve the hypothalamus and that are amenable to complete resection without hypothalamic injury, radical resection should be attempted. For tumours that appear to invade the hypothalamus on magnetic resonance imaging (MRI), especially if children with these tumours already have clinical evidence of hypothalamic dysfunction, the risks of radical resection are higher and partial resection followed by radiotherapy might be feasible. However, for any type of radiotherapy, the potential complications are higher the younger the child is, therefore intracystic treatment that delays the use of radiotherapy or is followed by resection may be beneficial. Another systematic review has concluded that intracystic interferon currently seems to have the best benefit‐risk ratio, but the evidence on which this was based was from non‐randomised controlled trials (Bartels 2012). This is an update of the previous systematic reviews evaluating the use of intracystic bleomycin for cystic craniopharyngiomas in children (Fang 2012; Zheng 2014).
There were no eligible randomised controlled trials (RCTs), quasi‐randomised trials or controlled clinical trials (CCTs) in which only the use of intracystic bleomycin in children differed between groups. Even though RCTs are the highest level of evidence, it should be recognised that data from non‐randomised studies on the use of intracystic bleomycin in cystic craniopharyngioma are available. The results are promising (Frank 1995; Hader 2000; Mettolese 2001; Park 2002; Lena 2005; Kim 2007; Hukin 2007). Most of these studies were retrospective cohort studies and they mentioned that intracystic bleomycin has potential advantages, such as inducing the shrinkage of the cyst size and allowing the delay of radiotherapy or radical resection.
There was only one eligible randomised trial that compared two different types of intracystic treatments: intracystic bleomycin and intracystic phosphorus32 (32P). No survival or duration of follow‐up data were provided to compare the two groups. There was no significant difference in the size reduction of the cyst, neurological status, fever or third nerve paralysis. There was a significant difference in the occurrence of headache and vomiting in favour of the 32P group. There was no significant difference in total adverse effects. However, the quality of the evidence is very low; the groups were small and relevant patient characteristics (i.e. characteristics of the cysts) were different between the two groups. Furthermore, there is a high risk of bias. We considered the trial to have a high risk of performance bias, detection bias and baseline imbalance bias and an unclear risk of selection bias, attrition bias, reporting bias and early stopping bias. In addition, the trial did not calculate the sample size, involved only seven patients and was therefore grossly underpowered to detect clinically important differences in outcome.
However, the role of intracystic bleomycin as a primary curative technique compared with radical therapy, partial resection plus radiotherapy, or other intracystic treatment in children with cystic craniopharyngioma can only be adequately determined through evaluation within prospective RCTs. Intracystic bleomycin is associated with a significant risk of morbidity. The acute adverse effects of intracystic bleomycin include headache, nausea, vomiting and transient mild fever, which occur in as many as 70% of patients, typically 24 hours after each instillation, and are self‐limiting (Hukin 2007). Even more serious are the reported delayed complications. There have been cases where MRI revealed signs of bleomycin leakage consistent with the extensive vasogenic oedema surrounding the cyst, which resulted in hypothalamic injury (Lafay‐Cousin 2007). The following complications have also been reported: diabetes insipidus (Park 2002), progressive panhypopituitarism (Hukin 2007), precocious puberty (Hukin 2007), and hypothalamic dysfunction resulting in transient hypersomnolence and poor memory (Park 2002), visual deficits (Mettolese 2001; Park 2002), neurocognitive deficits (Hukin 2007), sensorineural hearing loss (Broggi 1989; Frank 1995), peritumoral oedema (Hukin 2007), cerebral ischaemia (Broggi 1989), cerebral artery stenosis/occlusion (Cho 2012), hemiparesis (Jiang 2002; Park 2002), moyamoya disease after the combined treatment of intracystic bleomycin and radiotherapy (Hukin 2007), and death possibly related to a high individual and cumulative dose (Savas 2000).
Hence, surgeons have to realise that intracystic bleomycin for cystic craniopharyngioma in children currently has to be regarded as an experimental treatment that should only be performed in the context of a trial and requires close clinical monitoring. Imaging evaluation should be performed using MRI during treatment to ensure the safety of the therapy.
Comparing two intracystic treatments (with or without post‐treatment therapy) is an appropriate consideration for a future randomised trial. For example, the use of intracystic interferon alpha (IFNα) (Cavalheiro 2005; Ierardi 2007) and beta‐emitting radionuclides (Cáceres 2005), such as phosphorus32 (32P), yttrium90, rhenium186 and aurum198, are also available to provide control of the cystic tumour. Compared to the morbidity associated with intracystic bleomycin, IFNα seems to have similar advantages, but does not appear to have any significant major toxicity, even if it spills into the subarachnoid space. Therefore, further trials on intracystic treatment of cystic craniopharyngiomas are very much needed.
Study flow diagram.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Comparison 1 Intracystic bleomycin versus intracystic 32P, Outcome 1 Reduction of cyst size.
Comparison 1 Intracystic bleomycin versus intracystic 32P, Outcome 2 Fever.
Comparison 1 Intracystic bleomycin versus intracystic 32P, Outcome 3 Total adverse effects.
| Intracystic bleomycin compared to intracystic radiotherapy with 32P for cystic craniopharyngiomas in children | ||||||
| Patient or population: cystic craniopharyngiomas in children from birth to 18 years old | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with intracystic 32P | Risk with intracystic bleomycin | |||||
| Survival | NA | NA | ‐ | ‐ | ‐ | There was no information on overall survival and event‐free survival reported in this trial |
| Change in cyst size | Mean reduction in cyst size was 65.5% | Mean reduction in cyst size was 50.7% | MD ‐15% (‐69% to 39%) | 7 | ⊕⊝⊝⊝ | MD was 15% reduction in cyst size; the 95% CI mean a 69% reduction to a 39% increase in cyst size |
| Neurological status | See comment | See comment | Not estimable | Not estimable | ⊕⊝⊝⊝ | 1 patient in the bleomycin group had left paralysis, while none of the patients in the 32P group had severe sequelae. There was no significant difference between the 2 groups (Fisher's exact P value = 0.429). |
| Total number of adverse effects | 500 per 1000 | 875 per 1000 | RR 1.75 | 7 | ⊕⊝⊝⊝ | Adverse effects including fever, 3rd nerve paralysis, headache and vomiting were included in this outcome measure |
| Fever | 250 per 1000 | 730 per 1000 | RR 2.92 | 7 | ⊕⊝⊝⊝ | ‐ |
| 3rd nerve paralysis | See comment | See comment | Not estimable | 7 | ⊕⊝⊝⊝ | 1 patient in the 32P group had 3rd nerve paralysis, while none of the patients in the bleomycin group suffered from this. There was no significant difference between the 2 groups (Fisher's exact P value = 1.00). |
| Headache and vomiting | See comment | See comment | Not estimable | 7 | ⊕⊝⊝⊝ | All 3 patients in the bleomycin group had headache and vomiting, while none of the patients in the 32P group did. There was a significant difference in favour of the 32P group (Fisher's exact P value = 0.029). |
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1We downgraded a total of 3 levels due to study limitations (the trial had a high risk of performance bias, detection bias and baseline imbalance bias, and an unclear risk of selection bias, attrition bias, reporting bias and early stopping bias), small sample size (the current review includes only one trial with small sample size (n = 7)), and wide confidence intervals including 'no effect', 'appreciable harm' and 'appreciable benefit'. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Reduction of cyst size Show forest plot | 1 | 7 | Mean Difference (IV, Fixed, 95% CI) | ‐0.15 [‐0.69, 0.39] |
| 2 Fever Show forest plot | 1 | 7 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.92 [0.73, 11.70] |
| 3 Total adverse effects Show forest plot | 1 | 7 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.75 [0.68, 4.53] |
