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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 1  |  Page : 17-23

Antiepileptic drug usage in neuro-oncology: A practice survey


1 Tata Memorial Centre, Clinical Research Secretariat, Mumbai, Maharashtra, India
2 Tata Memorial Centre, Neuro-Oncology Disease Management Group, Mumbai, Maharashtra, India

Date of Submission18-Feb-2019
Date of Acceptance17-Mar-2019
Date of Web Publication3-Jun-2019

Correspondence Address:
Dr. Tejpal Gupta
ACTREC, Tata Memorial Centre, Homi Bhabha National Institute, Kharghar, Navi Mumbai - 410 210, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJNO.IJNO_3_19

Rights and Permissions
  Abstract 


Purpose: Despite the lack of high-quality evidence, anti-epileptic drugs (AEDs) are very commonly prescribed for seizure prophylaxis in patients with brain tumors even without prior history of seizures. We sought to review the current practices of prescribing AEDs among neuro-oncology health-care professionals.
Materials and Methods: An e-mail with online link to a 15-item questionnaire regarding AED prophylaxis was sent to members of major academic societies representing the Indian Neuro-Oncology Community to assess the prevalent patterns of practice.
Results: The online survey was completed by 318 of 3320 health-care professionals that were mailed for an overall response rate of 9.6%. Majority (68.9%) of respondents were radiation oncologists followed by neurosurgeons (22.9%) and medical oncologists/neurologists (8.2%). The practice setting spanned across the health-care spectrum, and over 75% reported having ≥ 5-year of experience in managing patients with brain tumors. Even for seizure-naïve patients, 65.1% of respondents routinely prescribed prophylactic AEDs with significant variability in the duration of such prophylaxis. Levetiracetam was the most preferred AED (60%) followed by phenytoin (35%) in the survey. Most respondents believed that tumor type, histological grade, and anatomic location influenced the risk of seizures. Despite widespread use in clinical practice, only 27.3% of the respondents strongly believed that prophylactic AEDs significantly reduced the risk of seizures. Over 93% of respondents agreed that a large randomized controlled trial would better inform therapeutic decision-making regarding AED prophylaxis.
Conclusions: This survey of the Indian Neuro-Oncology Community demonstrates widespread variability in the frequency and duration of AED prophylaxis in seizure-naive brain tumor patients in contemporary practice.

Keywords: Antiepileptic drugs, brain tumors, prophylaxis, seizures


How to cite this article:
Parhi A, Gupta T. Antiepileptic drug usage in neuro-oncology: A practice survey. Int J Neurooncol 2019;2:17-23

How to cite this URL:
Parhi A, Gupta T. Antiepileptic drug usage in neuro-oncology: A practice survey. Int J Neurooncol [serial online] 2019 [cited 2019 Jun 20];2:17-23. Available from: http://www.Internationaljneurooncology.com/text.asp?2019/2/1/17/259557




  Introduction Top


Seizures, one of the common symptoms in neuro-oncologic practice,[1],[2] occur in approximately 20%–45% of patients with primary or metastatic brain tumors and are associated with significant morbidity and negative impact on health-related quality of life.[2],[3] Brain tumor patients who have never experienced a seizure previously also carry a 20%–30% risk of developing new-onset seizures during the evolution of their disease.[3],[4] The occurrence of seizures can precipitate neurological/functional impairment (cerebral edema resulting in raised intracranial pressure) and secondary morbidities (aspiration and brain hypoxia) in the affected patient, as well as cause psychological distress (anxiety, depression, suicidal ideation, isolation, and stigmatization) to the patient and caregivers. While it is justified and appropriate to use antiepileptic drugs (AEDs) therapeutically in brain tumor patients with prior history of seizures, there is no high-quality evidence[5] supporting the use of prophylactic AEDs in patients who have never experienced seizures in the past. The duration of AED usage, the need for a uniform tapering schedule before AED withdrawal, and therapeutic monitoring of serum AED levels remain highly variable and are largely based on personal and institutional biases leading to widespread variation and nonuniformity in the patterns of practice.[5] However, despite lack of any quality evidence, patients with brain tumors continue to receive AED prophylaxis across the world with potential for harm and toxicity. Common AED-induced side effects include cognitive impairment, myelosuppression, liver dysfunction, and dermatologic reactions (ranging from minor rashes to life-threatening Stevens–Johnson syndrome), drug interactions with other concomitant medication, apart from the cost and inconvenience.[6],[7] Hence, there is an unmet need for the development of consensus guidelines for the judicious and appropriate usage of AEDs in neuro-oncologic practice.

Aims

The aim of our study was to review the current practices of prescribing AEDs in patients diagnosed with brain tumors (primary or metastatic) among health-care professionals and subsequently facilitate the development of appropriate research questions and/or consensus guidelines for their usage in contemporary neuro-oncologic practice.


  Materials and Methods Top


We sent an e-mail to members of major national societies, i.e., Indian Society of Neuro-Oncology (ISNO), Neurological Society of India (NSI), and Association of Radiation Oncologists of India (AROI) representing the Indian Neuro-Oncology Community in the 1st week of January 2018 with link to a 15-item questionnaire [Online Supplementary File S1][Additional file 1] on SurveyMonkey, an online survey tool. Respondents could complete the questionnaire online through the link that was active till February 28, 2018. The survey questionnaire was divided into two parts: the first part comprising three general questions asking respondents about their specialty, practice setting, and years of experience in managing patients with brain tumors. The second part comprising 12 specific questions was largely structured around existing controversies regarding AED usage in patients with brain tumors that had not been adequately addressed by high-quality evidence-based medicine. Participants were asked about their usage or nonusage of AEDs in the peri- and post-operative period in patients with brain tumors with and without prior history of seizures. Survey questions focused on the frequency, duration, choice of AED, tapering schedule, and necessity of therapeutic drug monitoring. Tumor-related factors that could influence epileptogenicity such as tumor type, grade, and anatomic location were also queried. Finally, respondents were asked whether they believed that prophylactic AEDs reduced the risk of seizures in patients with brain tumors and whether a large randomized controlled trial (RCT) could inform clinical practice regarding AED prophylaxis in neuro-oncology. Responses were analyzed descriptively as well as quantitatively wherever appropriate. Respondents were de-identified to maintain anonymity. Owing to the nature of the study, with no potential for harm whatsoever, our institutional review board which functions in accordance with the Principles of Helsinki provided exemption from ethical review for the conduct of the study.


  Results Top


An e-mail requesting the recipient's informed response with the link to the questionnaire-based survey was sent out to 3320 health-care professionals affiliated to one of the three major national societies (ISNO, NSI, and AROI) primarily responsible for the management of patients with brain tumors. The survey was completed by 318 respondents for an overall response rate of 9.6%, with every single respondent answering all 15 questions.

Survey sample description

Among the 318 respondents, who participated in the survey, majority (n = 219, 68.9%) were radiation oncologists followed neurosurgeons (n = 73, 22.9%) with remaining 26 (8.2%) being medical oncologists or neurologists [Figure 1]. The predominant practice setting of the respondents spanned the entire health-care spectrum including academic/teaching hospitals (n = 152, 47.8%); private/corporate hospitals (n = 109, 34.3%); individual private practice (n = 26, 8.2%); trust-aided/charitable hospitals (n = 22, 6.9%); and nonteaching government hospitals (n = 9, 2.8%). Over 75% of the respondents had over 5-year experience in managing patients with brain tumors, with nearly 50% reporting over 10-year experience.
Figure 1: Distribution of survey respondents by practice specialty

Click here to view


Specific responses to anti-epileptic drug-usage

Even for seizure-naïve patients (never experienced seizures in the past), 207 of 318 (65.1%) respondents routinely (always, almost always, and mostly) prescribed prophylactic AEDs in the peri-/post-operative period [Figure 2]. Only 50 (15.7%) respondents never prescribed prophylactic AEDs, while 42 (13.2%) respondents rarely prescribed prophylactic AEDs in this setting [Figure 2]. Nineteen (6%) respondents stated that this question was not applicable. The duration of such AED prophylaxis was quite variable [Figure 3], with nearly half of the respondents prescribing prophylactic AEDs in patients without any history of seizures for at least 6 months or more including 15% for ≥2 years. In patients with prior history of seizures, 98% of respondents routinely prescribed AEDs in the perioperative setting and continued them postoperatively as expected. Only 2% of respondents reported to rarely or never prescribing AEDs in the peri-/post-operative setting even for patients with prior history of seizures. The preferred duration of AED prophylaxis in this setting was longer as expected; nearly 75% of respondents recommended AEDs for at least 2 years from last seizure episode (2-year seizure-free interval), including 15% offering life-long prophylaxis. Only 6% of respondents prescribed AEDs for a short duration (perioperatively up to 4 weeks) in patients with prior history of seizures.
Figure 2: General frequency of prescribing prophylactic antiepileptic drugs in brain tumor patients without prior history of seizures. Note that over 65% of respondents routinely (always, almost always, mostly) prescribe prophylactic antiepileptic drugs in the peri-/post-operative period even in seizure-naïve patients

Click here to view
Figure 3: Pie chart demonstrating widespread variability in the duration of anti-epileptic drug prophylaxis in seizure-naïve brain tumor patients

Click here to view


Levetiracetam emerged as the most preferred AED in the survey, with 60% of respondents recommending it in first-line therapy followed by phenytoin (35%) with the remaining 5% comprising of other drugs such as valproate, carbamazepine, and phenobarbitone. Nearly 55% of respondents generally (always, almost always, and mostly) prescribed AEDs based on the type of seizures (generalized tonic–clonic, complex partial, absence, or focal seizures), whereas 43% of respondents did not base their choice of AEDs on seizure type. Nearly 31% of respondents always tapered AEDs before stopping, whereas 11% of respondents never used a tapering schedule for AED withdrawal. About 6% of respondents stated that tapering of AEDs was not applicable. Therapeutic drug monitoring of AED levels was rarely used in clinical practice with < 8% of respondents checking serum levels regularly and 10.5% only when clinically indicated. Most respondents reported that tumor type, histological grade, and anatomic location of tumor influenced the risk of seizures. Respondents reported glioblastoma (47.2%) and brain metastases (46.2%) to be associated with the highest risk of seizures followed by oligodendroglioma (39.6%), astrocytoma (34.9%), and meningioma (14.8%). Embryonal tumors were associated with the lowest risk of seizures (4.4%). Respondents also reported that tumors located in the parietal (66.7%) and frontal lobe (63.8%) were likely to be associated with the highest risk of seizures, while tumors in the posterior fossa (4.4%) and pineal region (1.9%) were likely to be associated with the lowest risk of seizures [Figure 4]. Unfortunately, temporal lobe location (the common cause of seizures) was inadvertently missing an option in the final electronic version of that particular question, although it was listed in our original draft questionnaire. Despite widespread use in clinical practice, only 27.3% of the respondents strongly believed that prophylactic AEDs significantly reduced the risk of seizures, while 21.3% of respondents completely disagreed with the statement. Over 93% of respondents agreed that a large RCT could potentially (yes, probably, and possibly) inform therapeutic decision-making and shape clinical practice regarding AED prophylaxis in neuro-oncology [Figure 5].
Figure 4: Bar diagram showing perceived relative risk of seizures as reported by respondents based on the anatomic tumor location

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Figure 5: Pie chart showing general agreement (yes, probably, possibly) in the vast majority of respondents to the statement that a large randomized controlled trial could shape clinical practice regarding antiepileptic drug prophylaxis in neuro-oncology

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  Discussion Top


This practice survey of major representatives of the Indian Neuro-Oncology Community clearly demonstrates prevalent widespread variability regarding AED usage including significant gaps in knowledge and practice. Despite the lack of high-quality evidence regarding AED prophylaxis in brain tumor patients without any prior history of seizures,[5] nearly two-thirds of the respondents continue to prescribe prophylactic anticonvulsants routinely in the peri-/post-operative period. Only about one-quarter of the respondents strongly believed that prophylactic AEDs reduced the risk of seizures significantly in patients without any prior seizure episode, yet nearly two-thirds of the respondents prescribed prophylactic AEDs in that setting. The duration of such prophylaxis was also somewhat variable with just under 50% of the respondents prescribing AEDs for 6 months or more. There was the general consensus regarding AED usage in patients with prior history of seizures with a whopping majority (98%) of respondents prescribing them in the peri-/post-operative period. The suggested duration of AED usage in patients with prior seizure history was also longer, with 75% respondents recommending a 2-year seizure-free interval before attempting AED withdrawal. Levetiracetam emerged as preferred first-line AED for primary and secondary prophylaxis in patients with brain tumors regardless of the type of seizure in accordance with accumulating data suggesting its improved therapeutic ratio (at least equivalent if not superior efficacy as well as favorable toxicity profile) compared to phenytoin.[8],[9] A systematic review of 21 studies,[10] albeit with a high risk of bias, reporting seizure frequency data regarding levetiracetam use either as monotherapy or add-on agent in patients with brain tumors showed that levetiracetam was effective in reducing seizure frequency and was associated with favorable safety outcomes.

It is widely accepted that seizures in patients with brain tumors can increase health-care costs, impair their quality of life, and even negatively impact on survival.[11] Immediate postoperative seizures (within the first 2 weeks of surgery) have been associated with either prolongation of hospital length of stay or unplanned/emergency readmissions.[11] Hence, prophylactic AEDs are commonly administered in the perioperative period to reduce the risk of such postoperative complications, although their efficacy in patients without a seizure history has always been disputed. Several nonrandomized studies have demonstrated a benefit to this practice, resulting in very low rates (<2.5%) of early postoperative seizures. However, this putative benefit of AED prophylaxis has never been proven by prospective clinical trials,[12],[13],[14] systematic reviews and meta-analyses[15],[16],[17],[18],[19] including the most recently updated Cochrane review,[20] all of whom have shown no significant reduction in the risk of seizures with such peri- /post-operative AED prophylaxis in seizure-naïve patients with brain tumors. Separate systematic reviews in brain metastases[21] and meningiomas[22] have also failed to demonstrate significant reduction in seizure risk with prophylactic AEDs. In the largest retrospective multi-center study on the patterns of practice, Youngerman et al.[23] analyzed 5985 patients undergoing resection or biopsy for an intracranial neoplasm between 2009 and 2013. They reported the use of prophylactic AEDs in 1671 of 4110 (40.7%) seizure-naïve patients with levetiracetam as the most preferred agent (72%). On multivariable analysis, anatomic location, tumor pathology, and geographic region of neurosurgery were significantly associated with AED prophylaxis.

In the year 2000, a Position Statement by the American Academy of Neurology recommended against the routine use of prophylactic AEDs in seizure-naïve patients,[5] citing lack of any demonstrable clinical benefit. However, AED prophylaxis still continues to be used widely across the world despite guidelines from the premier neurology society. Since then, five practice surveys[24],[25],[26],[27],[28] addressing this issue have been published, which show very variable prevalence (25%–70%) of AED prophylaxis in this setting [Table 1]. The physician-reported practice of AED prophylaxis and actual anticonvulsant use has moderately declined[29] since the publication of the position statement. Our survey, though, suggests relative high frequency (65%) of prescribing prophylactic AEDs similar to many prior surveys with levetiracetam emerging as the most preferred agent. The vast majority of respondents agreed that a large RCT on this question would shape clinical practice by generating high-quality evidence to support or refute the usage of prophylactic AEDs. However, such an RCT is easier said than done. Assuming a 10% baseline expected incidence of perioperative seizures, one would require over 1250 patients (625 patients in each arm) to be enrolled in an RCT to demonstrate an absolute seizure reduction of 5% (relative risk reduction of 50%) with 80% power using a non-inferiority design at the 0.05 significance level.[17] This number would increase to 1500 patients if the baseline risk of perioperative seizures was assumed to be 6%,[27] keeping all other parameters same. Given the time-frame, logistics, and significant resource implications including cost considerations, such a trial may not be practical and merits further nuanced consideration and debate. Researchers at the Duke University are presently enrolling patients on a single-center three-arm, open-label, randomized Phase II trial of perioperative seizure prophylaxis using lacosamide or levetiracetam (test arms) versus no AED (control arm) in suspected glioma patients undergoing craniotomy[30] using visits to the emergency/hospital re-admission within 30-day of surgery as the primary endpoint with a target accrual of 232 patients over 2-year period. However, the choice of primary endpoint in this study is inappropriate and likely to be influenced by other causes or perioperative morbidity (wound complications including infections and thromboembolic events) and the sample size inadequate and grossly underpowered to detect any meaningful difference.
Table 1: Surveys of health-care professionals regarding patterns of practice of antiepileptic drug prophylaxis in patients with
brain tumors


Click here to view


Strengths and limitations

The biggest strength of our survey lies in the fact that it was not restricted to any particular specialty but represents the opinion and practice of the major stakeholders of the neuro-oncology community of the country (ISNO, NSI, and AROI). Over 300 members responded to our questionnaire-based survey making it one of the largest such surveys on AED prophylaxis in neuro-oncology. However, several caveats and limitations inherent to such online practice surveys remain. Less than 10% of the recipients actually responded to our questionnaire-based survey; hence, it may be inappropriate to assume that this represents the majority view of members of the three academic societies who were polled. Second, we did not attempt to analyze the difference in the responses, if any, based on the specialty, years of experience, or practice setting of the respondents. The number of neurologists among the respondents was miniscule and clearly under-represented. It is possible that the survey results could have been quite different if many more neurologists (specialists who deal and prescribe AEDs to patients with seizures including brain tumors) would have responded. The survey lacked specific questions regarding the choice of AED given their potential interaction with chemotherapeutic agents and corticosteroids.[31] Finally, emerging data suggest a significant albeit small survival benefit with the use of prophylactic AEDs (mostly valproate) in malignant gliomas;[29],[32] questions regarding such perceived benefit were not included in our survey precluding any such analysis.


  Conclusionsu Top


Our practice survey of the Indian Neuro-Oncology Community demonstrates widespread variability in the frequency and duration of AED prophylaxis in seizure-naive brain tumor patients in contemporary practice. Most respondents believe that tumor type, histological grade, and anatomic tumor location influence epileptogenicity and that levetiracetam should be the drug of the first choice for AED prophylaxis. Given the current lack of high-quality evidence, universal acceptance of consensus guidelines or position statement is unlikely until a large RCT on this topic informs therapeutic decision-making in the future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.


  Supplementary File Top


Supplementary File S1: Anti-Epileptic Drugs in Neuro-Oncology Practice Survey

Principal Investigator: XXXX

Research Team: YYYY



Part A: General Information

  1. What is your practice specialty?


    1. Neurosurgery
    2. Radiation Oncology
    3. Medical Oncology
    4. Neurology
    5. Psychiatry
    6. Others, specify _____________


  2. What is your practice setting? (In case of multiple practice settings, please tick on the predominant setting defined as consuming >50% of total practice time)


    1. Academic (Teaching) Hospital
    2. Nonteaching Government Hospital
    3. Trust-aided/Charitable Hospital
    4. Corporate Hospital
    5. Private (Individual) Practice
    6. Others (please specify ___________________________)


  3. What is your experience in treating patients with brain tumors?


    1. <1 year
    2. 1–5 years
    3. 5–10 years
    4. 10–15 years
    5. >15 years
    6. Others (please specify____________________________)


    Part B: Antiepileptic Drug usage specific

  4. Do you prescribe prophylactic antiepileptic drugs in the peri-/postoperative setting in patients with brain tumors who have never experienced any seizure?


    1. Never
    2. Rarely
    3. Mostly
    4. Almost always
    5. Always


  5. Not Applicable


  6. How long do you give prophylactic antiepileptic drugs in the postoperative period for patients with brain tumors without any seizure? (answer to the closest duration)

    1. <7 days
    2. 1–4 weeks
    3. >4 weeks but < 6 months
    4. ≥6 months but < 2 years
    5. ≥2 years
    6. Not Applicable


  7. Do you prescribe antiepileptic drugs in the postoperative period for patients with brain tumors who have experienced seizures previously?


    1. Never
    2. Rarely
    3. Mostly
    4. Almost always
    5. Always


  8. Not Applicable


  9. How long do you prescribe antiepileptic drugs in the postoperative period for patients with brain tumor who have experienced seizures previously? (answer to the closest duration)

    1. <4 weeks
    2. 4 weeks–6 months
    3. >6 months but < 2 years
    4. ≥2 years
    5. 2 years from last seizure (2-year seizure-free interval)
    6. Life-long


  10. Which of the following is your first-line antiepileptic drug of choice in patients with brain tumors?


    1. Phenytoin
    2. Levetiracetam
    3. Valproate
    4. Lacosamide
    5. Carbamazepine
    6. Clobazam
    7. Lamotrigine
    8. Phenobarbitone
    9. Others (please specify _________________________)


  11. Is your choice of antiepileptic drug influenced by the type of seizure? (generalized seizures, complex partial seizures, absence seizures, and focal seizures)


    1. No
    2. Rarely
    3. Mostly
    4. Almost always
    5. Always
    6. Not Applicable


  12. Do you taper antiepileptic drugs before stopping?


    1. Never
    2. Rarely
    3. Mostly
    4. Almost always
    5. Always


  13. Not applicable


  14. How frequently do you test therapeutic levels of antiepileptic drugs in patients with brain tumors?

    1. Never
    2. Rarely
    3. Only if needed
    4. Regularly
    5. Always
    6. Not applicable


  15. According to you, which brain tumor type carries a high risk of seizures? (You can select more than one option)


    1. Oligodendroglioma
    2. Astrocytoma
    3. Metastases
    4. Meningioma
    5. Glioblastoma
    6. Embryonal tumor
    7. Others (please specify____________________________)


  16. According to you, which tumor location carries a high risk of seizures?


  17. (You can select more than one option)

    1. Frontal lobe
    2. Parietal lobe
    3. Occipital lobe
    4. Sellar/Suprasellar
    5. Pineal region
    6. Posterior fossa
    7. Intraventricular
    8. Leptomeningeal


  18. Others (please specify_____________________________)


  19. Do you strongly believe that prophylactic antiepileptic drugs reduce the risk of seizures?

    1. No
    2. Somewhat
    3. Possibly
    4. Probably
    5. Yes


  20. Do you think that a large randomized controlled trial can shape clinical practice regarding antiepileptic drug prophylaxis in neuro-oncology?


    1. No
    2. Not sure
    3. Possibly
    4. Probably
    5. Yes




 
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