Intracystic bleomycin for cystic craniopharyngiomas in children
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the benefits and harmful effects of intracystic bleomycin in children aged 0 to 18 years with cystic CP.
Specific objectives are to assess:
(1) comparison of intracystic bleomycin to placebo (no treatment);
(2) comparison of intracystic bleomycin to surgical treatment (with or without adjuvant radiotherapy);
(3) comparison of intracystic bleomycin to some other intracystic chemotherapies.
Background
Craniopharyngiomas (CP) are usually slow‐growing benign tumors that originate from epithelial nests or from areas of squamous metaplasia located in hypothalamic and pituitary regions. CP are the most common intracranial tumors of non‐glial origin in the pediatric population, constituting 6% to 13% of all childhood brain tumors and peaking at five to 10 years of age (Sanford 1991; Bunin 1996). Although the tumor is of benign histological nature, there is considerable morbidity and disability even when the tumor can be resected completely.
Description of the condition
Treatment of childhood craniopharyngioma is an ongoing controversy. Currently accepted therapies are radical tumor resection or partial resection followed by radiation therapy or other chemotherapies. However, surgery still remains challenging because the tumor is infiltrative to the tuber cinereum and the hypothalamus. Furthermore, even after total resection, the tumor's 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 tumors(Hetelekidis 1993,Wara 1994). However, that 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 on various types of epithelial tumors and benign squamous epithelial cells. Kubo 1971 confirmed the toxicity of bleomycin to cultured CP cells in 1971. In 1985, Takahashi 1985 published a paper concerning seven patients with CP treated with intratumoral bleomycin, and it indicated that the local injection of bleomycin was not as effective against CP of the mixed or solid type but was markedly effective against tumors of the cystic type. After that, other research confirmed that the intracystic bleomycin to treat cystic CP may eliminate cysts completely with few complications (Broggi 1989; Mettolese 2001).
How the intervention might work
Bleomycin is an antitumor antibiotic secreted by Streptomyces verticillus. It is composed of two main glycopeptides, bleomycin A2 and B2. Its action was based on inhibition of DNA and RNA synthesis through the formation of metal complexes with copper and iron serving as cofactors. 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 keratinization 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
To our knowledge there has been no previous systematic review of this subject. Although some researches advocated its effect in treating cystic CP, 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 CP.
Objectives
To assess the benefits and harmful effects of intracystic bleomycin in children aged 0 to 18 years with cystic CP.
Specific objectives are to assess:
(1) comparison of intracystic bleomycin to placebo (no treatment);
(2) comparison of intracystic bleomycin to surgical treatment (with or without adjuvant radiotherapy);
(3) comparison of intracystic bleomycin to some other intracystic chemotherapies.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs), quasi‐randomised trials or controlled clinical trials (CCTs) as defined by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009 ) that compared intracystic bleomycin with placebo/no treatment or surgical treatment (with or without adjuvant radiotherapy) or some other intracystic chemotherapies. We will not consider any other uncontrolled observational trials.
Types of participants
Participants should meet criteria below.
(1) Participants are between the ages of 0 to 18 years (age at onset of intracystic bleomycin treatment).
(2) Diagnosed as cystic craniopharyngioma by brain CT or MRI.
Types of interventions
Intracystic bleomycin. Procedure: the catheter was inserted inside the tumor with the help of a surgical microscope or stereotactically, and was connected to a subcutaneous reservoir. After catheter insertion, contrast agents were injected into the cyst to verify there was no fluid leakage. Intratumoral fluid was aspired and bleomycin was injected in it. The control group is given placebo/no treatment or surgical treatment (with or without adjuvant radiotherapy) or some other intracystic chemotherapy.
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 will group time‐points into "short‐term" (less than one year) or "long‐term" (more than one year) outcomes. We will evaluate the measurements as follows at pre‐specified time points.
(1) The response of cyst to treatment: sensitive or insensitive.
(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 post‐operative endocrine deficits include: hypopituitarism; short stature; weight alterations; diabetes insipidus. The change is classified as improved,stable,worsened and new cases.
(4) Neurological status: no disability; moderate disability; severe disability.
(5) Quality of life (QoL): measured using a scale that has been validated through reporting of norms in a peer‐reviewed publication.
(6) Adverse effects: such as death; new neurological deficit; new hypothalamic dysfunction; new visual dysfunction; the recurrence of craniopharyngioma; headache, nausea, and vomiting along with transient fever; arthralgia; chronic fatigue syndrome, etc.; number of patients who withdraw due to adverse events compared to 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 will search the following electronic databases: The Cochrane Central Library of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue); MEDLINE/PubMed (from 1945 to present); and EMBASE/Ovid (from 1980 to present). We have presented the sensitive search strategies used for MEDLINE/PubMEd, EMBASE/Ovid and CENTRAL in Appendix 1, Appendix 2 and Appendix 3.
Searching other resources
We will locate 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 will scan the Proceedings abstracts of the International Society for Paediatric Oncology (SIOP) (from 2005 to 2009), and of the International Symposium of Pediatric Neuro‐Oncology (ISPNO) conferences and pediatric neurosurgical conferences (from 2005 to 2009), electronically or otherwise by handsearching. We will search the International Standard Randomised Controlled Trial Number (ISRCTN) register and the register of the National Institute of Health (http://www.controlled‐trials.com) for ongoing trials. We will not impose language restrictions. We will update the searches every two years.
Data collection and analysis
Selection of studies
Two authors will independently screen titles and abstracts of studies identified through the searches and select trials that meet the inclusion criteria. We will then retrieve full articles (and translated into English where required) for further assessment. We will use discussion and consultation with a third reviewer to resolve any disagreement.
Data extraction and management
For included studies, two authors will independently extract the following information using a standard form:
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 above, length of follow‐up, quality of reporting of outcomes.
If there are differences in data extraction, we will solve the differences by discussion, referring back to the original paper, or by consulting a third person. Also, we will contact authors about missing information in their trials if necessary.
Assessment of risk of bias in included studies
Two authors will assess the methodological quality of included RCTs and CCTs using The Cochrane Collaboration 'Risk of bias' tool (Higgins 2009). 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 (Yes, No, Unclear). A judgment of 'Yes' indicates low risk of bias, while 'No' indicates high risk of bias. We will add items for the assessment of risk of bias as described in the module of the Cochrane Childhood Cancer Group (Kremer 2010). We will resolve any disagreements by discussion or using a third party arbitrator, and will present results in the ‘Risk of bias’ table and also in both graph and written summary form.
Quality assessment for non‐randomised clinical trials is a complex topic. In this review we will also use a modification of the Methodological Index for Non‐Randomised Studies (MINORS) (Slim 2003). This tool is one of the few validated and tested methods specifically developed for the assessment of the quality of non‐randomised trials. The tool includes 12 domains: a clearly stated aim; inclusion of consecutive patients; prospective collection of data; endpoints appropriate to the aim of the study; unbiased assessment of the study endpoint; follow‐up period appropriate to the aim of the study; loss to follow‐up less than 5%; prospective calculation of the study size; an adequate control group; contemporary groups; baseline equivalence of groups; adequate statistical analyses.
Measures of treatment effect
For time to event (e.g. the overall survival and event‐free survival) data, we will use the hazard ratio (HR). If HRs are not explicitly presented in the study, we will use Parmar's method (Parmar 1998).
For dichotomous outcomes (e.g. the decrease rate of the size of the cystic component,the response of cyst to treatment, adverse events and the endocrine function), we will calculate risk ratios (RR) with 95% confidence intervals (CI) for each trial.
For continuous outcomes (e.g. quality of life), we will evaluate mean difference (MD) or standardised mean difference (SMD) with 95% CI.
Unit of analysis issues
We will consider each individual study that is included in the meta‐analysis as a unit for analysis.
Dealing with missing data
We will analyse all data on an intention‐to‐treat principle. We will contact the authors of the respective trials directly by email, letter or fax to ask for the missing data.
Assessment of heterogeneity
We will construct a forest plot to display the results and to examine possible heterogeneity between the studies. We will use the I2 test to
measure the amount of heterogeneity, where I2 values of 50% and more indicate a substantial level of heterogeneity (Higgins 2009). If there is evidence of substantial heterogeneity, we will use a random‐effects model.
Assessment of reporting biases
We will use funnel plots (Egger 1997) to assess the presence of publication bias.
Data synthesis
We will carry out data synthesis and analyses using the Cochrane Review Manager software, RevMan 5 (RevMan 2008).
For time‐to‐event data, we will pool HRs using the generic inverse variance facility of RevMan 5.
For any dichotomous outcomes (e.g. rate of decrease in the size of the cystic component, the response of the cyst to treatment, adverse events), we will pool the RR.
For continuous outcomes (e.g. quality of life), we will pool the mean differences between the treatment arms at the end of follow‐up using the MD method if all trials measured the outcome on the same scale, or, if otherwise, the standardised mean difference method.
If there is no evidence of statistical heterogeneity and the pooling of results is clinically appropriate, we will calculate a combined estimate using the Mantel‐Haenszel method (Mantel 1959) for fixed‐effect models and the methods of DerSimonian & Laird (DerSimonian 1986) for random‐effects models. If pooling is not possible, then we will not do a meta‐analysis, but describe the trials narratively.
Subgroup analysis and investigation of heterogeneity
If possible, we will carry out the following subgroup analyses:
1. age at onset of intracystic bleomycin treatment;
2. gender;
3. dosage(or the concentration of the dose) of treatment;
4. multicystic craniopharyngioma.
Sensitivity analysis
We will perform sensitivity analyses excluding studies at high risk of bias.
