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.
Oligodendroglioma and Tumor-Related Epilepsy
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.
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)
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)
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.