Chemotherapy Reduces Seizures in Low-Grade Oligodendroglioma

Share
Print
oligodendroglioma

Temozolomide chemotherapy reduced seizures in 90 percent of patients with World Health Organization (WHO) grade 2 oligodendroglioma and tumor-related epilepsy, according to the results of a recent retrospective study of 39 patients treated at Memorial Sloan Kettering Cancer Center.

Our study, published in the journal Neuro-Oncology Practice, is the first to examine seizure response to temozolomide in a homologous group of adult patients with oligodendroglioma, the glioma subtype that has the highest frequency of seizures. (1)

Notably, seizure frequency improved irrespective of objective tumor response on magnetic resonance imaging in 41 percent of patients (16 of 39); and of those, antiepileptic drug dosage was successfully reduced or eliminated in 26 percent (10 of 39). (1)

Seizure control is essential to improve clinical outcomes and patients’ quality of life. Our findings at MSK confirm and expand on emerging evidence that temozolomide can reduce seizure frequency in a high proportion of patients with oligodendroglioma.

Tumor-related epilepsy occurs in up to 90 percent of patients with low-grade glioma. Seizures are difficult to control in up to 30 percent of patients despite treatment with multiple antiepileptic drugs, which are strongly associated with cognitive impairment issues.
Edward K. Avila Acting Co-Chair and Vice Chair for Clinical Affairs, Department of Neurology; Co-Director, Neuro Advanced Care Unit

Tumor-related epilepsy occurs in up to 90 percent of patients with low-grade glioma(2) Seizures are difficult to control in up to 30 percent of patients despite treatment with multiple antiepileptic drugs, which are strongly associated with cognitive impairment issues. (2), (3), (4), (5)

Treatment with surgery or radiotherapy reduces seizure frequency in low-grade glioma, (6), (7), (8), (9), (10) but chemotherapy alone with procarbazine, lomustine, and vincristine (PCV) or with temozolomide has shown some efficacy in a few prospective and retrospective studies in a subset of patients. (11), (12), (13), (14) However, these studies included a mixture of patients with oligodendroglial and astrocytic tumors, making interpretation difficult. In practice, temozolomide is used more frequently than PCV because it is less toxic and easier to administer.

Back to top

Study Details

Our study focused on oligodendroglioma, given its unique chemosensitivity (13), (15), (16), (17) and the greater anticipated potential for temozolomide to reduce tumor-related seizures. We examined the results for 39 adult patients with oligodendroglioma and tumor-related epilepsy who were treated at MSK between 2005 and 2015. The median age at tumor diagnosis was 41 years (range 22 to 62 years). For 64 percent of patients, the tumors were located in the frontal lobe. (1)

All of the patients underwent surgery as follows: gross total resection in 18 patients (46 percent), biopsy in 11 (28 percent), and subtotal resection in ten (26 percent). All patients were on antiepileptic drugs prior to starting temozolomide, and 21 patients (54 percent) were taking multiple agents. The most common drugs, used either as monotherapy or in combination, were as follows: levetiracetam (n = 26, 67 percent), phenytoin (n = 9, 23 percent), lamotrigine (n = 8, 21 percent), carbamazepine (n = 5, 13 percent), oxcarbazepine (n = 5, 13 percent), phenobarbital (n = 4, 10 percent), lacosamide (n = 4, 10 percent), zonisamide (n = 4, 10 percent), clonazepam (n = 3, 8 percent), valproic acid (n = 3, 8 percent), gabapentin (n = 1, 3 percent), clobazam (n = 1, 3 percent), and topiramate (n = 1, 3 percent). (1)

Before starting temozolomide, nine patients (21 percent) reported daily seizures, and 12 (31 percent) reported more than one seizure weekly. The median time to starting temozolomide was three years after initial surgery (range zero to 17 years). Temozolomide was initiated for various reasons: 21 patients (54 percent) had clinical and radiographic disease progression; seven patients (18 percent) had radiographic progression only; and 11 patients (28 percent) with extensive, persistent tumors after initial surgery were considered high risk. The median number of temozolomide cycles was 12 (range 2 to 24 cycles). (1)

Patients were included if they had experienced a least one seizure on an antiepileptic drug within three months before starting temozolomide, and for which we had seizure frequency data for every clinic visit and after completion of treatment. Patients had not received any other tumor-directed therapy or steroids while taking temozolomide. Thirty patients (77 percent) had not received any tumor-directed chemotherapy before starting temozolomide. (1)

Note that a diagnosis of oligodendroglioma now requires the presence of both an IDH mutation and 1p/19q co-deletion, according to the 2016 WHO classification. All tested tumors in our study were 1p/19q co-deleted or IDH mutated. (1) We included older specimens that had not been analyzed for molecular characteristics based on their classic histology. (18)

Back to top

Study Results

Thirty-five patients (90 percent) showed an improvement in seizure frequency of more than 50 percent compared to baseline. The remaining four patients showed no improvement. (1) Seventeen patients (44 percent) improved as their antiepileptic drug regimen was adjusted during temozolomide therapy. Two patients (5 percent) improved after a second surgical resection of their tumors before initiating temozolomide. (1)

Seizure frequency improved — independent of antiepileptic drug changes or prior antitumor treatment — in 16 patients (41 percent). Of these patients, the antiepileptic drug dosage was successfully reduced or eliminated in ten patients (26 percent) at the end of temozolomide therapy. (1)

Seizure response was observed after a minimum of four cycles of treatment with temozolomide, and 25 patients (64 percent) remained on a stable antiepileptic drug regimen. Objective radiographic response on MRI after completion of temozolomide treatment was observed in five patients (13 percent). (1)

The majority of patients, 32 (82 percent), had radiographically stable disease. Of these, 30 patients showed improvement. Two patients (5 percent) experienced tumor progression and increased seizure frequency during temozolomide treatment. (1)

Back to top

Advancing Neuro-Oncology Care

We hope that our findings will improve the quality of life and clinical outcomes for an increasing number of patients with oligodendroglioma. Seizure frequency may be a useful surrogate marker for evaluating the benefit of tumor-directed therapy. It may also be an independent prognostic factor for survival, (19), (20) but future studies are required to evaluate whether seizure reduction translates to longer progression-free survival or overall survival.

As a neurologist with specialty training in epilepsy and clinical neurophysiology, I treat patients with brain tumors who develop seizures as a result of their cancer as well as patients with neurological complications of systemic cancer. I consult with colleagues in neuro-oncology, neurosurgery, and radiation oncology to create individualized treatment plans for each patient. I also head the electroencephalography and intraoperative neurophysiologic monitoring services at MSK, assisting in the diagnosis and treatment of seizures.

We are currently conducting 19 clinical trials testing new treatment options for patients with glioma. The Brain Tumor Center team is committed to finding new ways to improve patient outcomes and quality of life, and reducing the adverse effects of cancer treatment.

The study was supported by a grant from the National Institutes of Health (P30-CA008748). The author declares no conflict of interest.

Back to top
  1. Haggiagi A, Avila EK. Seizure response to temozolomide chemotherapy in WHO grade II oligodendroglioma: a single-institution descriptive study. Neurooncol Pract. 2019;6(3):203–208.

  2. Armstrong TS, Grant R, Gilbert MR, et al. Epilepsy in glioma patients: mechanisms, management, and impact of anticonvulsant therapy. Neuro Oncol. 2016;18(6):779–789.

  3. Klein M, Engelberts NH, van der Ploeg HM, et al. Epilepsy in low-grade gliomas: the impact on cognitive function and quality of life. Ann Neurol. 2003;54(4):514–520.

  4. Kargiotis O, Markoula S, Kyritsis AP. Epilepsy in the cancer patient. Cancer Chemother Pharmacol. 2011;67(3):489–501.

  5. Maschio M, Sperati F, Dinapoli L, et al. Weight of epilepsy in brain tumor patients. J Neurooncol. 2014;118(2):385–393.

  6. Chang EF, Potts MB, Keles GE, et al. Seizure characteristics and control following resection in 332 patients with low-grade gliomas. J Neurosurg. 2008;108(2):227–235.

  7. Berger MS, Ghatan S, Haglund MM, et al. Low- grade gliomas associated with intractable epilepsy: seizure outcome utilizing electrocorticography during tumor resection. J Neurosurg. 1993;79(1):62–69.

  8. Phi JH, Kim SK, Cho BK, et al. Long-term surgical outcomes of temporal lobe epilepsy associated with low-grade brain tumors. Cancer. 2009;115(24):5771–5779.

  9. Englot DJ, Berger MS, Barbaro NM, Chang EF. Predictors of seizure freedom after resection of supratentorial low-grade gliomas. A review. J Neurosurg. 2011;115(2):240–244.

  10. van den Bent MJ, Afra D, de Witte O, et al; EORTC Radiotherapy and Brain Tumor Groups and the UK Medical Research Council. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet. 2005;366(9490):985–990.

  11. Soffietti R, Rudà R, Bradac GB, Schiffer D. PCV chemotherapy for recurrent oligodendrogliomas and oligoastrocytomas. Neurosurgery. 1998;43(5):1066–1073.

  12. Koekkoek JA, Dirven L, Heimans JJ, et al. Seizure reduction in a low- grade glioma: more than a beneficial side effect of temozolomide. J Neurol Neurosurg Psychiatry. 2015;86(4):366–373.

  13. Pace A, Vidiri A, Galiè E, et al. Temozolomide chemotherapy for progressive low-grade glioma: clinical benefits and radiological response. Ann Oncol. 2003;14(12):1722–1726.

  14. Sherman JH, Moldovan K, Yeoh HK, et al. Impact of temozolomide chemotherapy on seizure frequency in patients with low-grade gliomas. J Neurosurg. 2011;114(6):1617–1621.

  15. van den Bent MJ, Kros JM, Heimans JJ, et al. Response rate and prognostic factors of recurrent oligodendroglioma treated with procarbazine, CCNU, and vincristine chemotherapy. Dutch Neuro-oncology Group. Neurology. 1998;51(4):1140–1145.

  16. Mason WP, Krol GS, DeAngelis LM. Low-grade oligodendroglioma responds to chemotherapy. Neurology. 1996;46(1):203–207.

  17. Buckner JC, Gesme D Jr, O’Fallon JR, et al. Phase II trial of procarbazine, lomustine, and vincristine as initial therapy for patients with low-grade oligodendroglioma or oligoastrocytoma: efficacy and associations with chromosomal abnormalities. J Clin Oncol. 2003;21(2):251–255.

  18. Pallud J, Audureau E, Blonski M, et al. Epileptic seizures in diffuse low- grade gliomas in adults. Brain. 2014;137(Pt 2):449–462.

  19. Avila EK, Chamberlain M, Schiff D, et al. Seizure control as a new metric in assessing efficacy of tumor treatment in low-grade glioma trials. Neuro Oncol. 2017;19(1):12–21.

  20. Koekkoek JA, Dirven L, Heimans JJ, et al. Seizure reduction is a prognostic marker in low-grade glioma patients treated with temozolomide. J Neurooncol. 2016;126(2):347–354.