TOPIC

REVIEW REVIEW

Intracystic Bleomycin for Cystic Craniopharyngiomas in Children (Abridged Republication of Cochrane Systematic Review)
Wenke Liu, MD* Yuan Fang, MD* Bowen Cai, MD Jianguo Xu, MD Chao You, MD Heng Zhang, MD
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China *These authors contributed equally to this article. Correspondence: Heng Zhang, MD, Department of Neurosurgery, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, 610041, Chengdu, Sichuan, China. E-mail: zhangheng_doctor@126.com Received, May 23, 2012. Accepted, July 24, 2012. Published Online, August 16, 2012. Copyright 2012 by the Congress of Neurological Surgeons

BACKGROUND: Craniopharyngiomas are the most common benign histological tumors to involve the hypothalamopituitary region in childhood. When the tumor location is unfavorable, a gross total or partial resection followed by radiotherapy is the main treatment option in adults. However, it presents the risk of morbidity, especially for children. Intracystic bleomycin has been used to potentially delay the use of radiotherapy or radical resection to decrease morbidity. OBJECTIVE: To determine the benefit and harm of intracystic bleomycin vs other treatments for cystic craniopharyngiomas in children. METHODS: We searched the electronic databases of CENTRAL, MEDLINE/PubMed, and EMBASE/Ovid with prespecified terms. In addition, we searched reference lists of relevant articles and reviews, conference proceedings, and ongoing trial databases. RESULTS: We could not identify any studies in which the only difference between the treatment groups was the use of intracystic bleomycin. We did identify a randomized, controlled trial comparing intracystic bleomycin with intracystic 32P (n = 7 children). The trial had a high risk of bias. Survival could not be evaluated. There was no evidence of a significant difference in cyst reduction, neurological status, third nerve paralysis, fever, or total adverse effects between the treatment groups. There was a significant difference in favor of the 32P group for the occurrence of headache and vomiting. CONCLUSION: Based on the currently available evidence, we are not able to give recommendations for the use of intracystic bleomycin in the treatment of cystic craniopharyngiomas in children. High-quality randomized, controlled trials are needed.
KEY WORDS: Bleomycin, Cochrane review, Craniopharyngiomas, Intracystic, Randomized, controlled trials, Systematic review
Neurosurgery 71:909915, 2012
DOI: 10.1227/NEU.0b013e31826d5c31

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raniopharyngiomas are usually slowgrowing benign tumors that originate in epithelial nests or areas of squamous metaplasia located in hypothalamic and pituitary regions. Craniopharyngiomas are the most common intracranial tumors of nonglial origin in the pediatric population, constituting 6% to 13% of all childhood brain tumors and peaking at 5 to 10 years of age.1,2 Although the tumor is of a benign histological nature, there is considerable

ABBREVIATIONS: CCT, controlled clinical trial; CI, confidence interval; EFT, event-free survival; OS, overall survival; RCT, randomized, controlled trial; RR, risk ratio

morbidity and disability even when the tumor can be resected completely. Treatment of childhood craniopharyngiomas is an ongoing controversy. The currently accepted therapy is radical tumor resection. However, surgery still remains challenging because the tumor infiltrates the tuber cinereum and the hypothalamus. A recent patient series demonstrated that gross total resection of craniopharyngiomas was achieved in only 50% to 80% of attempted radical resections.3-6 Furthermore, even after total resection, the tumors recurrence rate is high,7,8 especially in the residual cystic portion.9 Some authors advocate external radiotherapy after partial resection of the tumors,10,11 which has resulted in less early morbidity; however, that may increase endocrine disturbance and mortality, especially in children.12

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Bleomycin was first discovered by Hamao Umezawa in 196613 and was launched in Japan by Nippon Kayaku in 1969. It was found to be effective for various types of epithelial tumors and benign squamous epithelial cells. Kubo et al14 confirmed the toxicity of bleomycin to cultured craniopharyngioma cells in 1971. In 1985, Takahashi et al9 reported on 7 patients with craniopharyngioma treated with intratumoral 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 tumors of the cystic type. After that, other research confirmed that intracystic bleomycin to treat cystic craniopharyngiomas may eliminate cysts completely with few complications.15,16 Although some researchers advocated its effect in treating 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 treating children with craniopharyngiomas. We conducted a Cochrane systematic review,17 which is summarized here.

PATIENTS AND METHODS

Criteria for Considering Studies for This Review Types of Studies
We planned to include all randomized, controlled trials (RCTs), quasirandomized trials, or controlled clinical trials (CCTs) as defined by the Cochrane Handbook for Systematic Reviews of Interventions,18 which compared intracystic bleomycin with placebo/no treatment or surgical treatment (with or without adjuvant radiotherapy) or some other intracystic treatments. Any other uncontrolled observational trials were not considered.

Secondary Outcomes. We grouped time points into short term (,1 year) or long term (.1 year) outcomes. We evaluated the measurements as follows at prespecified time points. 1. The response of the cyst to treatment: sensitive or insensitive (as defined by the authors). 2. The size of the cystic component: the rate of decrease in the size of the cystic component. 3. Endocrine function: the comparison between pre- and postoperative endocrine deficits includes hypopituitarism, short stature, weight alterations, and diabetes insipidus. The change is classified as improved, stable, worsened, and new cases. 4. Neurological status: no disability, moderate disability, severe disability (the criteria of disability as defined by the authors). 5. Visual outcome: classified as improved, stable, worsened and new cases. 6. Quality of life: measured using a scale that has been validated via reporting of norms in a peer-reviewed publication. 7. Adverse effects: death; new neurological deficit; new hypothalamic dysfunction; new visual dysfunction; the recurrence of craniopharyngioma, headache, nausea, vomiting, transient fever, arthralgia, chronic fatigue syndrome, etc.; the number of patients who withdrew because of adverse events compared with placebo, no treatment, surgical treatment (with or without adjuvant radiotherapy), or some other intracystic chemotherapy groups.

Search Methods for Identification of Studies Electronic Searches

We searched the following electronic databases: The Cochrane Central Library of Controlled Trials (CENTRAL) (The Cochrane Library, 2010, Issue 4); MEDLINE/PubMed (from 1945 to October 2010); and EMBASE/Ovid (from 1980 to October 2010).

Searching Other Resources

We located information about trials not registered in MEDLINE, EMBASE, or CENTRAL, either published or unpublished, by searching the reference lists of relevant articles and reviews. We scanned the proceedings abstracts of the International Society for Paediatric Oncology (from 2005 to 2010) on October 16, 2010 electronically. We searched the International Standard Randomised Controlled Trial Number register and the register of the National Institutes of Health (http://www.controlled-trials.com) for ongoing trials on October 16, 2010. We did not impose language restrictions. The search strategies can be obtained from the corresponding author.

Types of Participants
Participants had to meet the following criteria: (1) between the ages of 0 and 18 years (age at onset of intracystic bleomycin treatment) and having a diagnosis of cystic craniopharyngioma by brain computed tomography or magnetic resonance imaging.

Types of Interventions
Intracystic Bleomycin. The procedure is as follows: the catheter is inserted in the tumor with the help of a surgical microscope or stereotactically 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. Intratumoral 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 some other intracystic treatments. The dose, frequency, and duration can vary.

Data Collection and Analysis Selection of Studies

Two review authors independently screened 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.

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 of any cause. EFS is defined as the time to recurrence or progression of primary disease or death of any cause.

Data Extraction and Management

For included studies, 2 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. Intervention: dose, route, timing, control intervention (placebo, no treatment, surgical treatment [with or without adjuvant radiotherapy], some other intracystic chemotherapies). Participants: sampling, total number and number in comparison groups, sex, age, trial inclusion and exclusion criteria, withdrawals/losses to follow-up (reasons/description), subgroups. Outcomes: outcomes specified previously, length of follow-up, quality of reporting of outcomes. If there were differences in data extraction, we resolved the differences by discussion, referring to the original paper, or consulting a third person.

Assessment of Reporting Biases

We planned to construct a funnel plot22 to graphically ascertain 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.18 Because only 1 RCT could be included in this review, funnel plots were not constructed.

Data Synthesis
We performed data synthesis and analyses using the Cochrane Review Manager software RevMan 5.23 We performed the analyses according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions.18 We used the Mantel-Haenszel method to perform the analysis. Because only 1 RCT could be included in this review, we used a fixed-effect model. Also, because there was only 1 study available, we were unable to calculate an RR if one of the treatment groups experienced no events, and the Fisher exact test was used instead (in SPSS version18.0; SPSS Inc., Chicago, Illinois).

Assessment of Risk of Bias in Included Studies

Two authors planned to assess the methodological quality of included RCTs and CCTs using The Cochrane Collaboration Risk of Bias tool18 independently. The tool considers 6 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 (yes, no, unclear). A judgment of yes indicates low risk of bias, whereas no indicates high risk of bias. We added items for the assessment of risk of bias as described in the module of the Cochrane Childhood Cancer Group.19 We resolved any disagreements by discussion or using a thirdparty arbitrator, and presented the results in the risk of bias (Table) and also in both graphic and written summary form. Quality assessment for nonrandomized clinical trials is a complex topic. However, since no nonrandomized trials (ie, CCTs) were identified, using a modification of the Methodological Index for Non-Randomised Studies20 was not applicable.

Subgroup Analysis and Investigation of Heterogeneity

Because only 1 eligible study was identified and the sample size was small, a subgroup analysis was not applicable.

Sensitivity Analysis
Because only 1 eligible study was identified, performing sensitivity analyses for the used quality criteria was not applicable.

RESULTS
Measures of Treatment Effect
For time to event (eg, the OS and EFS) data, we used the hazard ratio. If hazard ratios were not explicitly presented in the study, we used the Parmar method.21 For dichotomous outcomes (eg, the response of the cyst to treatment, adverse events, visual outcome, neurological status, and endocrine function), we calculated risk ratios (RRs) with 95% confidence intervals (CIs) for each trial. For continuous outcomes (eg, the decrease rate of the size of the cystic component, quality of life), we intended to evaluate the mean difference or standardized mean difference with a 95% CI. We only analyzed 1 continuous outcome, reduction of cyst size, and for this we reported the mean difference.

Unit of Analysis Issues

We planned to consider each individual study included in the metaanalysis as a unit for analysis.

Dealing With Missing Data

We analyzed all data on an intent-to-treat principle. We did not contact authors for missing data.

Assessment of Heterogeneity
Since only 1 eligible study was identified, assessing the presence of heterogeneity (ie, I2 . 50%18) was not applicable.

Description of Studies Characteristics of Included Studies Results of the Search. We identified a total of 295 references through electronic searches of The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (n = 2), EMBASE (n = 91), and PubMed (n = 202). It was clear from reading titles and abstracts that only the trial by Jiang et al,24 an RCT, was eligible for inclusion (see Characteristics of Included Studies section). We were not able to identify any quasi-randomized trial or CCTs from the references. Scanning the reference lists of relevant studies and reviews and scanning the conference proceedings of International Society for Paediatric Oncology did not identify any other eligible studies. Scanning the ongoing trials databases did not identify any eligible (ongoing) studies. In summary, only 1 RCT could be included in this review. No eligible CCTs or ongoing studies were identified. Included Studies. This study also included adults, but we only extracted data on children in the intracystic bleomycin and intracystic 32P group. The total number of children was 7. Three children received intracystic bleomycin and 4 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

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TABLE. Risk of Bias Table Bias Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants (performance bias) Blinding of personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Free of baseline imbalance? Free of early stopping? Was the trial free of source of funding bias? Authors Judgment Unclear risk Support for Judgment Quote: The patients were randomly allocated. Comment: The trial is described as randomized, but the method of sequence generation was not specified. Quote: The patients were randomly allocated. Comment: The trial was described as randomized, but the method used to conceal the allocation was not described. Quote: The patients were semiblinded (both the patients and their families did not know which therapy they received). Comment: The blinding of patients was performed. Comment: The blinding of personnel was not performed, and the trial was of high risk of performance risk. Comment: The blinding of outcome assessment was not performed, and the trial was of high risk of detection bias. Comment: The numbers and reasons for dropouts and withdrawals in all intervention groups were not given. Comment: The protocol is unavailable, and it is unclear whether data on survival, the response of the cyst to treatment, endocrine function, visual outcome, and quality of life were recorded. Comment: The patients in bleomycin group were all polycystic, whereas not all the patients in the 32P group were. Comment: Sample size calculation was not reported, and it is not clear whether the trial was stopped early. Comment: The trial was free of source of funding bias.

Unclear risk

Low risk

High risk High risk Unclear risk Unclear risk

High risk Unclear risk Low risk

8 days. In the 32P group, 0.9% saline solution was injected daily into the cysts for 7 days, and 32P was administered to the patients in 32P group on day 8. The dose of bleomycin started at 5.0 mg and was increased by 2.5 mg or 5.0 mg each day, depending on patient tolerance of the drug. The largest daily dose was no more than 15 mg. The largest total dose received by any patient was 120 mg, whereas the lowest dose 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 See the Table for the characteristics of the included studies. Summary of Quality Assessment of Included Trials The trial was considered to have a high risk of performance bias, detection bias, and bias of baseline imbalance and an unclear risk of selection bias, attrition bias, reporting bias, and bias of early stopping. There was source of funding bias.

Effects of Interventions Survival There was no information on OS and EFS reported in this trial. Response of the Cyst to Treatment There was no information about the response of the cyst to treatment. Size Reduction of the Cyst There was no significant difference in size reduction between bleomycin and 32P (mean difference, 20.15; 95% CI: 20.69 to 0.39; P = .59). Endocrine Function The data on endocrine function could not be extracted. Neurological Status One child in the bleomycin group had left-side paralysis after 2 episodes of epilepsy, and none of the children in the 32P group had severe sequelae. There was no significant difference (Fisher exact test, P = .429) between the groups. Visual Outcome There was no visual outcome reported in this trial.

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Quality of Life There was no quality of life information reported in this trial. Adverse Effects All 3 children in the bleomycin group had complications of fever, headache, and vomiting; however, in the 32P group, there was only 1 patient who had transient fever; none of the patients in that group experienced headache or vomiting. There was no significant difference in fever (RR: 2.92; 95% CI: 0.73-11.70; P = .13) between the 2 groups, but there was a significant difference in headache (Fisher exact test, P = .029) and vomiting (Fisher exact test, P = .029) in favor of the 32P group. A patient in the 32P group had third nerve paralysis, whereas none of the patients in the bleomycin group experience this. There was no significant difference (Fisher exact test, P = 1.00) between the 2 groups. In summary, there was no significant difference in total adverse effects (RR: 1.75; 95% CI: 0.68-4.53; P = .25) between the groups. Subgroup Analysis It was not possible to perform subgroup analysis because of the small sample size.

DISCUSSION
The occurrence of cysts is one of the typical characteristics of craniopharyngiomas, occurring in more than 90% of tumors.25 The treatment of cystic craniopharyngiomas is controversial. Puget et al26 used a preoperative classification system to grade hypothalamic involvement and stratify treatment. For tumors that do not involve the hypothalamus and are amenable to complete resection without hypothalamic injury, attempted radical resection should be advised. For tumors that appear to invade the hypothalamus on magnetic resonance imaging, especially if children with these tumors 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, so that intracystic treatment that delays the use of radiotherapy or is followed by resection may be beneficial. This review was undertaken to evaluate the existing evidence of intracystic bleomycin in treating children with cystic craniopharyngiomas. There were no eligible RCTs, quasi-randomized trials, or CCTs in which only the use of intracystic bleomycin differed between groups in children. Even though RCTs are the highest level of evidence, it should be recognized that data from nonrandomized studies on the use of intracystic bleomycin in cystic craniopharyngioma are available. The results are promising.16,27-32 Most of these studies were retrospective cohort studies. They mentioned that intracystic bleomycin has potential advantages, such as inducing a decrease in cyst size and allowing radiotherapy or radical resection to be delayed.

There was only 1 eligible randomized trial that compared 2 different types of intracystic treatments: intracystic bleomycin and intracystic 32P. There was no significant difference in size reduction of cyst, neurological status, fever, or third nerve paralysis. There was a significant difference in the occurrence of headache and vomiting in the 32P group. There was no significant difference in total adverse effects. No survival or duration of follow-up information was provided to compare the 2 groups. The quality of the RCT is low; groups are small and relevant patient characteristics (ie, cyst characteristics) were different between the 2 groups. Furthermore, there is a high risk of bias. The trial was considered to have a high risk of performance bias, detection bias, and bias of baseline imbalance and an unclear risk of selection bias, attrition bias, reporting bias, and bias of early stopping. It was free of source of funding bias. In addition, the trial did not calculate the sample size, involved only 7 patients, and therefore was 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 some other intracystic treatment in children with cystic craniopharyngiomas 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.32 Even more serious are reported delayed complications. There have been cases in which magnetic resonance imaging revealed the signs of bleomycin leakage consistent with the extensive vasogenic edema surrounding the cyst, which resulted in hypothalamic injury.33 The following complications have also been reported: diabetes insipidus,29 progressive panhypopituitarism,32 precocious puberty,32 and hypothalamic dysfunction resulting in transient hypersomnolence and poor memory,29 visual deficits,16,29 neurocognitive deficits,32 sensorineural hearing loss,15,27 peritumoral edema,32 cerebral ischemia,15 hemiparesis,29 moyamoya disease after the combined treatment of intracystic bleomycin and radiotherapy,32 and death possibly related to a high single and cumulative dose.34 Therefore, surgeons must realize that currently intracystic bleomycin for cystic craniopharyngioma in children needs 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 magnetic resonance imaging during treatment to ensure the safety of the therapy. Comparing 2 intracystic treatments (with or without posttreatment therapy) is an appropriate consideration for a future randomized trial. For example, the use of intracystic interferon alfa35,36 and b-emitting radionuclide,37 such as 32P, yttrium 90, rhenium 186, and aurum 198, are also available to provide control of the cystic tumor. Compared with the morbidity of intracystic bleomycin, interferon alfa seems to have advantages similar to those of intracystic bleomycin, but does not appear to have any significant major toxicity, even if it spills into the subarachnoid space.

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CONCLUSION
Implications for Practice There are no RCTs, quasi-randomized trials, or CCTs assessing the role of intracystic bleomycin vs no treatments, surgical treatment (with or without adjuvant radiotherapy), or some other intracystic treatments for patients with cystic craniopharyngiomas in children. We cannot make definitive conclusions about the effects on antitumor efficacy (ie, OS and EFS), the response of the cyst to treatment, size reduction, endocrine function, neurological status, visual outcome, quality of life, or adverse effects of this treatment. Based on the currently available evidence, we are not able to give recommendations for clinical practice. We identified only 1 RCT comparing intracystic bleomycin with intracystic 32P. No definitive conclusions can be made about the effects of these agents on antitumor efficacy, morbidity, and mortality in children with cystic craniopharyngiomas. No significant difference in cyst size reduction, neurological status, or total adverse effects between the 2 groups was identified. With regard to the individual adverse effects, no significant difference in fever and 3rd nerve paralysis was seen, but there was a significant difference in both headache and vomiting in favor of the 32P group. Based on the currently available evidence, we are not able to promote treatment with intracystic bleomycin or intracystic 32P in children with cystic craniopharyngiomas. Implications for Research High-quality RCTs (with more homogeneous samples and adequate power) are necessary to determine the efficacy and adverse effects of intracystic bleomycin for cystic craniopharyngiomas in children. Such trials ought to be reported according to the Consort Statement (http://www.consort-statement.org). Disclosure
The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.

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(from the Cochrane Childhood Cancer Review Group) for helping with the development of the search strategy and for the electronic search of the databases CENTRAL, MEDLINE, and EMBASE. This article is based on a Cochrane Review published in the Cochrane Database of Systematic Reviews 2012, Issue 4. No.:CD008890 DOI: 10.1002/14651858.CD008890.pub2 (see www.thecochranelibrary.com for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and the Cochrane Database of Systematic Reviews should be consulted for the most recent version of the review.

Acknowledgments
The authors thank the Cochrane Childhood Cancer Review Group for their support in publishing the Cochrane Review. We thank Dr Edith Leclerq

COMMENTARY
Commentary provided by Plastaras et al, Wisoff, available at www.neurosurgery-online.com.

NEUROSURGERY

VOLUME 71 | NUMBER 5 | NOVEMBER 2012 | 915

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