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## Complete Summary

#### GUIDELINE TITLE

The use of prophylactic anticonvulsants in patients with brain tumours:
a clinical practice guideline.

#### BIBLIOGRAPHIC SOURCE(S)

Perry J, Zinman L, Laperriere N, Chambers A, Lloyd N, Spithoff K,
Neuro-oncology Disease Site Group. The use of prophylactic
anticonvulsants in patients with brain tumours: a clinical practice
guideline. Toronto (ON): Cancer Care Ontario (CCO); 2006 Oct 11. 23
p. (Evidence-based series; no. 9-4). \[16 references\]

#### GUIDELINE STATUS

This is the current release of the guideline.

The EVIDENCE-BASED SERIES report, initially the full original guideline,
over time will expand to contain new information emerging from their
reviewing and updating activities.

Please visit the [Cancer Care Ontario Web
site](http://www.cancercare.on.ca/pdf/pebc9-4s.pdf) for details on any
new evidence that has emerged and implications to the guidelines.

### COMPLETE SUMMARY CONTENT

 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Brain tumors

#### GUIDELINE CATEGORY

Assessment of Therapeutic Effectiveness\
Prevention\
Treatment

#### CLINICAL SPECIALTY

Neurological Surgery\
Neurology\
Oncology\
Radiation Oncology

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

-   To evaluate whether patients with newly diagnosed brain tumours
    should receive prophylactic anticonvulsants to reduce seizure risk

-   To evaluate the best practice for patients with brain tumours who
    are taking anticonvulsant medications but who have never had a
    seizure

#### TARGET POPULATION

Adult patients with newly diagnosed brain tumours in the peri- and
postoperative period and beyond

This document will focus upon patients with brain tumours who have never
had a seizure.

#### INTERVENTIONS AND PRACTICES CONSIDERED

Prophylactic anticonvulsants:\*

1.  Phenytoin

2.  Divalproex sodium

3.  Phenobarbital

\*Routine use is not recommended (see \"Major Recommendations\" for
context).

#### MAJOR OUTCOMES CONSIDERED

-   Incidence of seizures

-   Adverse effects

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Hand-searches of Published Literature (Primary Sources)\
Hand-searches of Published Literature (Secondary Sources)\
Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

**Literature Search Strategy**

MEDLINE (1966 to June 2005) and the Cochrane Library (2005 Issue 2)
databases were searched using \"anticonvulsant\" (Medical subject
heading (MeSH) or \"antiepileptic drugs\" (MeSH) combined with the
keywords \"glioma\", \"glioblastoma\" and \"brain tumours\". These terms
were then combined with the search terms for the following study
designs: practice guidelines, systematic reviews, meta-analyses,
reviews, randomized controlled trials, and controlled clinical trials.
The Canadian Medical Association (CMA) Infobase
(<http://www.cma.ca/cpgs/index.asp>), the National Guideline
Clearinghouse
([http://www.guideline.gov/index.asp](http://www.guideline.gov/)), and
other Web sites were searched for existing evidence-based practice
guidelines. Relevant articles and abstracts were selected and reviewed
by three reviewers, and the reference lists from these sources were
searched for additional trials, as were the reference lists from
relevant review articles.

**Study Inclusion Criteria**

Fully published articles or abstracts were selected for inclusion in
this systematic review if they:

1.  Reported results of randomized controlled trials (RCTs) or
    meta-analyses of RCTs comparing patients with brain tumours treated
    with prophylactic anticonvulsants with patients with brain tumours
    not treated with prophylactic anticonvulsants or comparing various
    anticonvulsant-tapering strategies in patients with brain tumours.
    Sufficient follow-up time was required.

2.  Included patients without a history of seizures.

3.  Reported data on the incidence of seizures for each intervention
    group or adverse effects.

4.  Clinical practice guidelines from other guideline development groups
    evaluating the use of prophylactic anticonvulsants in brain tumour
    patients were also eligible for inclusion.

**Study Exclusion Criteria**

1.  Due to resource limitations, publications in languages other than
    English were excluded.

2.  Letters and editorials were excluded.

#### NUMBER OF SOURCE DOCUMENTS

One evidence-based practice guideline, five randomized controlled
trials, one systematic review, and one retrospective review were
identified.

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Expert Consensus (Committee)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

Not applicable

#### METHODS USED TO ANALYZE THE EVIDENCE

Meta-Analysis of Randomized Controlled Trials\
Review of Published Meta-Analyses\
Systematic Review with Evidence Tables

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

To estimate the overall effect of prophylactic anticonvulsants in
patients treated with or without anticonvulsants, the incidence of
seizures (the number of patients who suffered from at least one seizure
by the end of the study and the number of patients included in the
analysis by the investigators) were abstracted from the published
reports of individual randomized controlled trials (RCTs). The study
results were pooled using Review Manager 4.2.7 (RevMan Analyses 1.0.2;
version date: May 2004; © 2004 the Cochrane Collaboration), which is
freely available through the Cochrane Collaboration. Combining data in
this manner assumes a constant hazard ratio of risks for the groups
being compared. Results are expressed as relative risks (RR) (also known
as risk ratios) with 95% confidence intervals (CI), where an RR for the
incidence of seizures less than one indicates fewer seizures in the
experimental group. Conversely, an RR greater than one suggests that
patients in the control group experienced fewer seizures. The RR is
calculated by taking the ratio of the proportion of patients who have
had a seizure in the experimental treatment group to the proportion of
patients who have had a seizure in the control group. The random-effects
model was used for pooling across studies in preference to the
fixed-effects model, as the more conservative estimate of effect.

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

Only five randomized controlled trials (RCTs) have tested the effects of
anticonvulsants for the primary prophylaxis of seizures in patients with
newly diagnosed brain tumours. No studies have been disease-specific,
and all included a mixture of both primary and secondary brain tumours.
All were heterogeneous with respect to inclusion criteria and the
anticonvulsants used in the study.

Anticonvulsants are problematic in brain tumour patients. The studies of
Glantz et al and Forsyth et al. demonstrate that the rate and intensity
of anticonvulsant-related side effects may be higher in patients with
brain tumours when compared to patients with seizure disorders from
other causes. In addition, the anticonvulsants tested in those RCTs were
in the class of enzyme-inducing anticonvulsants and are expected to have
pharmacodynamic interactions with other medications commonly used in the
treatment of those patients. In particular, interactions between
enzyme-inducing anticonvulsants and chemotherapy are of significant
concern. No studies have tested the newer generation of anticonvulsants
that, in general, are characterized by fewer adverse effects and minimal
drug interactions.

Because those clinical trials were all small, it is not possible to
determine if there are special subgroups of patients at increased risk
of seizures. Intuitively, patients with tumours near the motor strip,
with cortically based tumours, or hemorrhagic tumours may be at
increased risk of seizures; however there are no data to support this
assumption. Clinicians must therefore individualize treatment for those
patients. Tumour-related factors such as location must be integrated
with patient preferences and quality of life (QOL), in addition to
concomitant medications, in order to reach treatment decisions.

From the larger RCTs and the meta-analysis, it is clear that
conventional anticonvulsants (phenytoin, valproic acid, and
phenobarbital) confer at best a 25% reduction in the risk of seizures,
with the incremental risk of adverse effects and drug interactions. The
Neurology Disease Site Group (DSG) felt that the statistical power of
those trials reliably excluded a clinically important reduction in
seizure risk for seizure-naïve patients with newly diagnosed primary and
secondary brain tumours. Thus, the routine use of postoperative
anticonvulsants is not recommended in those patients, especially in
light of a significant risk of serious adverse effects and problematic
drug interactions. This recommendation is in agreement with the American
Academy of Neurology (AAN) practice parameter.

The newer anti-epileptic medications may overcome some of these issues
but have not been tested in clinical trials. No recommendations can be
made regarding the use of those medications; however, a randomized
controlled clinical trial, informed by the analysis and the suggestions
by Forsyth et al., should be considered.

In the survey of Ontario practitioners, 74% of respondents indicated
that they did not recommend the routine use of anticonvulsants in
seizure-naïve patients with newly diagnosed brain tumours. Thus, the
current practice is consistent with the recommendation of this
guideline. The pre-guideline survey is presented in Appendix 1 in the
original guideline document, and the results of the two case scenarios
are shown in Table 3 in the original guideline document. Respondents
were asked to indicate which response most closely matched their usual
practice.

For patients who are already on anticonvulsants but have never had a
seizure, there is very little evidence to guide treatment. The AAN
practice parameter recommends considering a taper and discontinuation of
anticonvulsants; however, only one small retrospective clinical trial
has attempted to address that issue. There is insufficient evidence to
recommend for or against the tapering of anticonvulsants in this
situation, and, therefore, treatment must be individualized. In the
Ontario practice survey, essentially equal numbers of practitioners
would maintain anticonvulsants, withdraw them, or have a discussion and
allow a patient-based decision. Thus, current practice appears to
reflect the lack of data that addresses this very specific question.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

Not applicable

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

**Development and Internal Review**

This evidence-based series was developed by the Neuro-oncology Disease
Site Group (DSG) of Cancer Care Ontario\'s Program in Evidence-Based
Care (PEBC).

**Report Approval Panel**

Prior to submission of this evidence-based series report for external
review, the report was reviewed and approved by the PEBC Report Approval
Panel, which consists of two members, including an oncologist, with
expertise in clinical and methodology issues.

**External Review by Ontario Clinicians**

Following review and discussion of Sections 1 and 2 of the original
guideline document and review and approval of the report by the PEBC
Report Approval Panel, the Neuro-oncology DSG circulated the clinical
practice guideline and systematic review to clinicians in Ontario for
review and feedback.

*Methods*

Feedback was obtained through an electronic survey of 55 practitioners
in Ontario (medical oncologists, radiation oncologists, neurologists and
neurosurgeons). The survey consisted of items evaluating the methods,
results, and discussion used to inform the draft recommendations and
whether the draft recommendations should be approved as a practice
guideline. Written comments were invited. The survey was emailed on June
22, 2006. Follow-up reminders were sent on July 21 and August 4, 2006.
The Neuro-oncology DSG reviewed the results of the survey.

This report reflects the integration of feedback obtained from the
Report Approval Panel of the PEBC and through the external review
process, with final approval given by the Neuro-oncology DSG.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

-   The routine use of postoperative anticonvulsants is not recommended
    in seizure-naïve patients with newly diagnosed primary or secondary
    brain tumours, especially in light of a significant risk of serious
    adverse effects and problematic drug interactions. This
    recommendation is in agreement with the American Academy of
    Neurology (AAN) practice parameter.

-   There is insufficient evidence to support or refute the use of
    anticonvulsants in the perioperative period for patients with brain
    tumours who have never had a seizure.

-   There is very little evidence to guide treatment for patients who
    are already on anticonvulsants but have never had a seizure. There
    is insufficient evidence to recommend whether or not anticonvulsants
    should be tapered in this situation and therefore treatment must be
    individualized.

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The recommendations are supported by one evidence-based practice
guideline, five randomized controlled trials, one systematic review, and
one retrospective review.

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   Results of four randomized controlled trials (RCTs) that compared
    anticonvulsants to placebo or no treatment in patients with brain
    tumours and no history of seizures suggested no benefit for the
    long-term use of prophylactic anticonvulsants. The trials were small
    and insufficiently powered.

-   Pooled results of 518 brain tumour patients from five RCTs
    demonstrated no benefit for anticonvulsants (relative risk \[RR\]
    1.04, 95% confidence interval \[CI\] 0.70-1.54, p=0.84), reliably
    ruling out a clinically significant reduction in the incidence of
    seizures for patients who received anticonvulsants compared to no
    anticonvulsants.

-   A published meta-analysis of RCTs including patients with no history
    of seizures indicated no benefit for prophylactic anticonvulsant
    treatment for early-onset seizures within one week of treatment
    initiation (odds ratio \[OR\] 0.91; 95% CI, 0.45-1.83, p\>0.05).
    Analysis of long-term efficacy also showed no benefit for
    prophylactic anticonvulsants (OR 1.01; 95% CI, 0.51-1.98, p\>0.05).

#### POTENTIAL HARMS

Anticonvulsant use in patients with brain tumours is associated with
potential adverse effects and drug interactions, particularly when used
in combination with radiotherapy or chemotherapy. Adverse effects
reported in clinical trials include rash, nausea, and hypotension.
Clinicians should be aware of emerging evidence for the interaction
between enzyme-inducing anticonvulsants and newer systemic chemotherapy
agents in the experimental setting.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

-   Although there is insufficient evidence to support or refute the use
    of perioperative anticonvulsants in patients with brain tumours,
    there is evidence to suggest a role for perioperative
    anticonvulsants in general patient populations undergoing craniotomy
    to prevent early seizures.

-   The anticonvulsants tested in randomized controlled trials (RCTs)
    are in the class of enzyme-inducing anticonvulsants, including
    phenytoin, phenobarbital, and divalproex sodium. No RCTs have been
    published that examine the efficacy of the newer generation of
    anticonvulsants for the prevention of seizures in patients with
    brain tumours.

-   Anticonvulsant use in patients with brain tumours is associated with
    potential adverse effects and drug interactions, particularly when
    used in combination with radiotherapy or chemotherapy. Adverse
    effects reported in clinical trials include rash, nausea, and
    hypotension. Clinicians should be aware of emerging evidence for the
    interaction between enzyme-inducing anticonvulsants and newer
    systemic chemotherapy agents in the experimental setting.

-   Patients with tumours near the motor strip, cortically based
    tumours, or hemorrhagic tumours may be at increased risk of seizure;
    however, there are no data to support this assumption. The RCTs
    included in this review were small and heterogeneous with respect to
    patient inclusion; therefore, it was impossible to determine whether
    subgroups of patients might benefit from prophylactic
    anticonvulsants.

-   Care has been taken in the preparation of the information contained
    in this document. Nonetheless, any person seeking to apply or
    consult the evidence-based series is expected to use independent
    medical judgment in the context of individual clinical circumstances
    or seek out the supervision of a qualified clinician. Cancer Care
    Ontario makes no representation or guarantees of any kind whatsoever
    regarding their content or use or application and disclaims any
    responsibility for their application or use in any way.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Living with Illness\
Staying Healthy

#### IOM DOMAIN

Effectiveness\
Safety

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Perry J, Zinman L, Laperriere N, Chambers A, Lloyd N, Spithoff K,
Neuro-oncology Disease Site Group. The use of prophylactic
anticonvulsants in patients with brain tumours: a clinical practice
guideline. Toronto (ON): Cancer Care Ontario (CCO); 2006 Oct 11. 23
p. (Evidence-based series; no. 9-4). \[16 references\]

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2006 Oct

#### GUIDELINE DEVELOPER(S)

Program in Evidence-based Care - State/Local Government Agency
\[Non-U.S.\]

#### GUIDELINE DEVELOPER COMMENT

The Program in Evidence-based Care (PEBC) is a Province of Ontario
initiative sponsored by Cancer Care Ontario and the Ontario Ministry of
Health and Long-Term Care.

#### SOURCE(S) OF FUNDING

Cancer Care Ontario\
Ontario Ministry of Health and Long-Term Care

#### GUIDELINE COMMITTEE

Neuro-oncology Disease Site Group

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

For a current list of past and present members, please see the [Cancer
Care Ontario Web
site](http://www.cancercare.on.ca/english/toolbox/qualityguidelines/diseasesite/neuro-ebs/neuro-dsg/).

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

The members of the Neuro-oncology Disease Site Group (DSG) were asked to
disclose potential conflicts of interest relating to the topic of this
systematic review and meta-analysis. No conflicts were declared.

#### GUIDELINE STATUS

This is the current release of the guideline.

The EVIDENCE-BASED SERIES report, initially the full original guideline,
over time will expand to contain new information emerging from their
reviewing and updating activities.

Please visit the [Cancer Care Ontario Web
site](http://www.cancercare.on.ca/pdf/pebc9-4s.pdf) for details on any
new evidence that has emerged and implications to the guidelines.

#### GUIDELINE AVAILABILITY

Electronic copies: Available in Portable Document Format (PDF) from the
[Cancer Care Ontario Web
site](http://www.cancercare.on.ca/pdf/pebc9-4f.pdf).

#### AVAILABILITY OF COMPANION DOCUMENTS

None available

#### PATIENT RESOURCES

None available

#### NGC STATUS

This summary was completed by ECRI on March 28, 2008.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is subject to
the guideline developer\'s copyright restrictions. Please refer to the
[Copyright and Disclaimer
Statements](http://www.cancercare.on.ca/ontariocancernews/copyright.html)
posted at the Program in Evidence-Based Care section of the Cancer Care
Ontario Web site.

### DISCLAIMER

#### NGC DISCLAIMER

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Date Modified: 11/3/2008