Interventions for the treatment of brain radionecrosis after radiotherapy or radiosurgery

  • Protocol
  • Intervention

Authors


Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effectiveness of interventions used in the treatment of brain radionecrosis by considering radiological and clinical (physician- and/or patient-reported) responses, impact on quality of life, and treatment-related toxicities associated with these interventions.

Background

Description of the condition

Brain radionecrosis (tissue death caused by radiation) is a complication that may follow radiotherapy to all or part of the brain (Blonigen 2010; Giglio 2003). This condition can be associated with significant neurological deterioration, functional loss, and in some cases death.

The incidence of brain radionecrosis is increasing because of the growing use of stereotactic radiosurgery and administration of higher cumulative doses of radiation during initial therapy and with salvage radiation therapy for primary and secondary malignant brain tumors. Sterotactic radiosurgery can be thought of as a minimally invasive form of surgical practice using numerous focused radiation beams, or a highly precise radiation treatment using very few fractions (treatment sessions) of radiation. Following radiosurgery, approximately 10% of patients develop radionecrosis, but the risk may be higher following repeated radiation treatments (Blonigen 2010; Mayer 2008; Shaw 2000).

To date, brain radionecrosis has largely been a clinical diagnosis based on clinical and radiological presentation. However, conventional imaging has limited capability to reliably differentiate tumor progression from radionecrosis. Stereotactic biopsy is sometimes used to aid diagnosis, but this approach also fails to have 100% sensitivity or specificity. To avoid the need for invasive surgical procedures for diagnosis, which can be associated with additional risks to the patient, efforts have been invested in improving the capabilities of imaging investigations to confirm a radiological diagnosis. This includes the use of quantitative measures from conventional magnetic resonance imaging (MRI) and use of perfusion and diffusion MRI, MR spectroscopy, and positron emission tomography (PET) imaging. Studies suggest that the best sensitivity and specificity can be achieved by using a combination of these imaging measures to diagnose brain radionecrosis (Barajas 2009; Dequesada 2008; Hoefnagels 2009).

Description of the intervention

Initial therapy for symptomatic brain radionecrosis is typically high-dose corticosteroids (Gonzalez 2007). If symptoms continue to progress despite the initiation of high-dose corticosteroids, surgical resection may be considered (McPherson 2004).

Other interventions have been explored in the context of small single-institution experimental trials and small case series of selected patients. These experimental interventions include anticoagulants, vitamin E and pentoxifylline, hyperbaric oxygen therapy, and antiangiogenic therapy.

How the intervention might work

The underlying pathophysiology of radionecrosis is still unclear. It has been suggested that high-dose radiation results in disruption of the blood-brain barrier, which leads to vasogenic edema (Schultheiss 1995). Accumulation of vasogenic edema can lead to vascular compromise, which can ultimately result in tissue hypoxia (decrease in tissue oxygen levels), which induces release of proteins that stimulate blood vessel growth and leakiness, including vascular endothelial growth factor (VEGF), causing further potentiation of peritumoral vasogenic edema (swelling around the tumor) (Nordal 2004; Plateel 1995).

Treatments have been aimed at stopping and reversing this pathological cascade. For instance, corticosteroids reduce the vasogenic edema and in turn can help prevent vascular compromise and hypoxia, which perpetuate the pathological cascade. Surgical resection immediately relieves the mass effect that is leading to vascular compromise, which is perpetuating the pathological process (Truong 2006). Hyperbaric oxygen has the potential to reverse tissue hypoxia to directly stop any further hypoxic tissue necrosis and decrease the release of the VEGF that is perpetuating the pathological process (Leber 1998; Ohguri 2007). The antiangiogenic agent, bevacizumab, is a monoclonal antibody that binds VEGF and has shown promising results in early clinical reports (Gonzalez 2007; Levin 2011; Wong 2008).

Why it is important to do this review

Because of lack of guidance from larger trials or a systematic review, heterogeneity in the treatment of radionecrosis is significant across institutions. A thorough systematic review will provide an up-to-date evaluation of available scientific information and clinical trial evidence to guide current management of brain radiation necrosis.

Objectives

To assess the effectiveness of interventions used in the treatment of brain radionecrosis by considering radiological and clinical (physician- and/or patient-reported) responses, impact on quality of life, and treatment-related toxicities associated with these interventions.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomized controlled trials (RCTs) of any intervention for the management of brain radionecrosis in adult patients previously treated with radiation therapy to the brain. Because we anticipate a limited number of RCTs, we will also include all comparative prospective intervention trials and quasi trials of any intervention for brain radionecrosis in adult patients. We will include nonrandomized studies in the discussion and will consider them for inclusion in the analysis if we identify an acceptable comparison cohort, adjusted for major prognostic factors.

Types of participants

We will include studies that evaluate adult (> 18 years old) patients previously treated with radiosurgery or fractionated radiotherapy for brain tumor with a diagnosis of brain radionecrosis based on clinical and radiological criteria, with or without pathological confirmation, as tissue confirmation is not frequently acquired in clinical practice.

We will define a clinical and radiological diagnosis of brain radionecrosis as "a growing enhancing lesion with associated edema in the region of prior high-dose radiation in the presence of low suspicion of active tumor due to a long disease control interval, lack of tumor involvement within the brain (e.g., head and neck cancer), or advanced imaging evidence to suggest absence of active tumor.

As the purpose of this review is to provide evidence to guide clinical practice, and as pathological confirmation is often unavailable for patients who may have a combination of radionecrosis and tumor, this review will exclude patients who lack pathological confirmation in the evaluation of any treatment, including treatments that may be active against radionecrosis and tumor.

Types of interventions

Pharmacological interventions

For pharmacological interventions, we will investigate the efficacy and effectiveness of any dose of agent given by any route for the purpose of treating brain radionecrosis. Agents likely to be included are antioxidant agents such as vitamin E and antiangiogenic agents such as bevacizumab. To improve the clinical relevance of this review, we will compare the efficacy and effectiveness of these agents against standard clinical care, which typically includes corticosteroid therapy.

Nonpharmacological Interventions

For nonpharmacological interventions, we will include any treatment given with the aim of treating brain radionecrosis to improve symptoms and prevent progression of the process. These treatments will likely include surgery and hyperbaric oxygen therapy.

Because of the limited number of RCTs anticipated, we will include all prospective intervention trials, including single-arm studies. For these studies, we will report efficacy and effectiveness and will consider these data against outcomes reported for standard care, which typically includes corticosteroid therapy.

Types of outcome measures

Primary outcomes

The primary outcome will be radiological response, defined as any reduction in contrast-enhancing lesions or edema (i.e., T2-weighted hyperintensity on MRI or hypodensity on computed tomography (CT)).

Secondary outcomes
  • Clinical improvement, defined as documented physician-reported or patient-reported improvement in neurological status, symptoms, or functional independent status.

  • Corticosteroid requirements, reported as the ability of patients to decrease their corticosteroid dose or to stop corticosteroids completely.

  • Treatment-related adverse events, including death, hemorrhage, hematological toxicity, pulmonary toxicity, cardiac toxicity, gastrointestinal (GI) toxicity, and infection.

  • Quality of life, using scales such as the M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) and the European Organization for Research and Treatment of Cancer core quality of life questionnaire (EORTC QLQ-C30).

Search methods for identification of studies

Electronic searches

We will search the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL, current issue), MEDLINE (1950 to date), EMBASE (1980 to date), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to date). We have listed the MEDLINE search strategy in Appendix 1.

For databases other than MEDLINE, we will adapt the search strategy as needed. We will identify all relevant articles on PubMed, and we will use the "Related articles" feature to carry out a further search for newly published articles. We will apply no language restrictions in our searches.

Searching other resources

Unpublished and grey literature

We will search Metaregister, Physicians Data Query, www.controlled-trials.com/rct, www.clinicaltrials.gov, and www.cancer.gov/clinicaltrials to search for ongoing trials.

If through these searches we identify ongoing trials that have not been published, we will contact the principal investigators to request relevant data. We will likewise approach the major co-operative trial groups active in this area. We will search conference proceedings and abstracts through ZETOC (http://zetoc.mimas.ac.uk). We will search theses and dissertations through WorldCat (http://firstsearch.oclc.org).

Handsearching

We will handsearch the reference lists of included studies, key textbooks, and previous systematic reviews. We will handsearch journals and conference materials from the past year in the following sources.

  • Annual Meeting of the European Association of Neuro-Oncology (EANO).

  • Annual Congress of the European Society for Radiotherapy and Oncology (ESTRO).

  • Annual Meeting of the World Federation of Neuro-Oncology (WFNO).

  • Annual Meeting of the American Society of Clinical Oncology (ASCO).

  • Annual Meeting of the American Society for Therapeutic Radiation Oncology (ASTRO).

  • Annual Meeting of the American Society of Neuro-Oncology (SNO).

  • Bienniel Congress of the International Stereotactic Radiosurgery Society (ISRS).

  • Biennial Meeting of the Leksell Gamma Knife Society (LGKS).

  • Annual Meeting of the Multinational Association of Supportive Care in Cancer (MASCC).

  • Other resources.

We will undertake personal communication with authors of relevant trials and experts at major hospitals performing clinical trials to identify further data that may or may not have been published. We will seek papers in all languages and will carry out translations if necessary.

Data collection and analysis

Selection of studies

We will download all titles and abstracts retrieved by electronic searching to the reference management database, Endnote. We will remove duplicate references, and two review authors (CC, PB) will independently examine the remaining references. The review authors will not be blinded to study authors or to affiliations of the studies. We will exclude studies that clearly do not meet the inclusion criteria and will obtain copies of the full text of potentially relevant references. Two review authors (CC, PB) will independently assess the eligibility of retrieved papers. Review authors will resolve disagreements by discussion and will document reasons for exclusion.

Data extraction and management

For included trials, data will be abstracted as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Two review authors (CC, PB) will abstract data independently onto a data abstraction form specially designed for the review.

This form will include the following data.

  • Article details (author, year of publication, journal citation, country, and language).

  • Intervention (characteristics and duration).

  • Study design and methodology (including inclusion and exclusion criteria, assignment process, and timing of measurements).

  • Population demographics and total number involved; details of the health status of participants, including tumor histology, prior treatment details, and performance status.

  • Outcome measures (radiological response, clinical improvement, corticosteroid requirements, quality of life, and adverse events).

  • Risk of bias.

Data will be collated and entered into RevMan 5 2014.

When possible, all data extracted will be those relevant to an intention-to-treat (ITT) analysis, in which participants are analyzed in the groups to which they are assigned. The time points at which outcomes were collected and reported will be noted.

For continuous outcomes, we will record the final value and standard deviation of the outcome of interest and the number of participants in each treatment arm assessed at the end of follow-up, and we will use these values to estimate the mean difference between treatment arms and its standard error. We will note time points at which outcomes were collected and reported. We will resolve differences between review authors by discussion. For dichotomous variables, we will record the outcome of interest and the number of participants in each treatment arm assessed for an early time point (within four months of treatment) and at last follow-up.

Assessment of risk of bias in included studies

We will assess the risk of bias in included studies by using the tool of The Cochrane Collaboration (Higgins 2011a). This will include assessment of:

  • selection bias: random sequence generation and allocation concealment;

  • performance bias: blinding of participants and personnel (patients and treatment providers);

  • detection bias: blinding of outcome assessment;

  • attrition bias: incomplete outcome data;

  • reporting bias: selective reporting of outcomes; and

  • other possible sources of bias.

We will interpret all results of meta-analyses in light of findings with respect to risk of bias. We will judge all bias criteria and will report them as having low, high, or unclear risk of bias. We will classify the risk of bias as unclear when insufficient information is provided, or when there is uncertainty over the potential for bias. Two review authors (CC, PB) will apply the risk of bias tool independently and will resolve differences by discussion. We will summarize the results in both a risk of bias graph and a risk of bias summary. We will interpret results of meta-analyses in light of findings with respect to risk of bias.

Measures of treatment effect

Dichotomous data

For dichotomous outcomes (e.g., reduction in lesion volume or not, clinical improvement or not), we will record for each study the number of participants who experience the outcome of interest following treatment at an early time point (within four months of treatment) and at last follow-up.

Continuous data

For continuous outcomes (e.g., lesion volume, quality of life measures), we will express treatment effect as standardized mean differences between treatment arms with 95% confidence intervals, only if appropriate, and if a mean difference method is not possible.

Unit of analysis issues

Two review authors (CC, PB) will review unit of analysis issues according to information provided in the Cochrane Handbook for Systematic Reviews of Interventions and will resolve differences by discussion (Higgins 2011). These may include reports that describe:

  • individuals receiving more than one intervention (e.g., cross-over trial, simultaneous treatment of methods for each individual); or

  • multiple observations for the same outcome (e.g., repeated measurements, recurring events).

Dealing with missing data

We will not impute missing outcome data for any outcome. If data for the primary outcome are missing, we will contact trial authors to request data on outcomes among participants who were assessed.

We will include details of missing data in the narrative summary and "Risk of bias" table, alongside an assessment of the extent to which missing data could have altered the results of the review.

Assessment of heterogeneity

We will assess heterogeneity between studies by visual inspection of forest plots (including the presence of outliers and poor overlap of confidence intervals) and by a formal statistical test of the significance of the heterogeneity (Deeks 2001). When suggested by the forest plot and when I2 is greater than 50%, suggesting substantial heterogeneity (Higgins 2011; Higgins 2011a), we will further explore the causes of heterogeneity.

Assessment of reporting biases

Two review authors (CC, PB) will review and record reporting biases. If suitable, we will examine funnel plots to assess the potential for small-study effects such as publication bias.

Data synthesis

We will pool data in a meta-analysis using RevMan 5 2014 when studies are comparable with respect to participants, interventions, and outcomes.

We will use the random-effects models with inverse variance weighting for all meta-analyses, along with a 95% confidence interval (DerSimonian 1986).

Subgroup analysis and investigation of heterogeneity

As we anticipate a limited number of eligible studies for this review, subgroup analyses may not be feasible but will be attempted for the following subgroups.

  • Radiosurgery versus fractionated radiotherapy.

  • Pathologically confirmed radionecrosis versus clinical-radiological diagnosis alone.

  • Tumor histology for which the initial radiotherapy was provided: brain metastases, primary central nervous system (CNS) tumors, other (likely head and neck cancer).

Sensitivity analysis

Whether sensitivity analysis will be required will be determined by agreement among all review authors and in keeping with information provided in Higgins 2011. We will consider the following factors as possible sources of heterogeneity across studies: variation in study quality (high or low levels of risk of bias), use of different classes of agents, and dosing or scheduling differences. We anticipate that additional possible types of sensitivity analyses will be identified during the conduct of the review.

Acknowledgements

This review is funded in part by a grant from the Society of Neuro-Oncology, USA.

With gratitude to the Cochane Neuro-oncology Group for its contributions, support, and guidance throughout the editorial process. Thanks also to Jane Hayes, Information Manager at the Cochrane Neuro-oncology Group, for designing the search strategy.

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Gynaecological, Neuro-oncology, Orphan Cancer Group. The views and opinions expressed herein are those of the review authors and do not necessarily reflect those of the NIHR, the National Health Service (NHS), or the Department of Health.

Appendices

Appendix 1. MEDLINE search strategy

MEDLINE Ovid
1 exp Brain/
2 exp Brain Neoplasms/
3 brain*.mp.
4 1 or 2 or 3
5 rt.fs.
6 exp Radiotherapy/
7 Radiosurgery/
8 (radiotherap* or radiosurgery).mp.
9 5 or 6 or 7 or 8
10 exp Necrosis/
11 (necrosis or radionecrosis).mp.
12 Radiation Injuries/
13 10 or 11 or 12
14 4 and 9 and 13

key:

[mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]

Contributions of authors

Draft of the protocol: all review authors.

Declarations of interest

Caroline Chung: none.
Paul Brown: none.