TY - JOUR
T1 - Epilepsy meets cancer
T2 - When, why, and what to do about it?
AU - Weller, Michael
AU - Stupp, Roger
AU - Wick, Wolfgang
N1 - Funding Information:
Because of their enzyme-inducing activity, older antiepileptic drugs such as phenytoin, phenobarbital, or carbamazepine can enhance the metabolism of many commonly given chemotherapy agents and thus decrease their efficacy ( panel ). Accordingly, non-enzyme-inducing antiepileptic drugs are now favoured for patients with cancer, to allow effectively the administration of chemotherapy and targeted agents that often show increased hepatic metabolism in patients given enzyme-inducing antiepileptic drugs. Conversely, investigators have not shown that the enzyme inhibitory activity of valproic acid results in clinically relevant increases in anticancer drug concentrations, which increases their activity through a pharmacokinetic mechanism. Intrinsic antitumour activities or pharmacodynamic potentiation of radiotherapy or chemotherapy have been proposed to be mediated by some antiepileptic drugs. However, there is only limited data from in-vitro studies indicating additive or synergistic activity of antiepileptic drugs with cancer therapeutics. For example, we did not record a modulation of the cytotoxic or antiproliferative effects of several anticancer drugs, including vincristine, cytarabine, doxorubicin, cisplatin, carmustine, and teniposide, by either carbamazepine, phenytoin, or valproic acid in cultured glioma cells at concentrations that are likely to be achieved in vivo. 41 Levetiracetam has been proposed to sensitise glioblastoma cells to temozolomide via suppression of O 6 -methylguanine-DNA-methyltransferase (MGMT) expression, 48 thus targeting one of the major resistance pathways of alkylating agent chemotherapy. 49 Since the lifetime risks of patients with glioblastoma to have epileptic seizures and toxicity associated with antiepileptic drugs are considerable, and since these patients are now commonly exposed to chemotherapy, there has traditionally been significant interest in the choice of antiepileptic drug in glioblastoma. A retrospective analysis of three trials undertaken by the North Central Cancer Treatment Group indicated a possible association of use of enzyme-inducing antiepileptic drugs, but not of seizure history, with a favourable outcome in patients with glioblastoma. 50 Yet, the implications of this finding remain unclear in that the chemotherapy regimens used in these trials are not considered active. 51 Accordingly, we retrospectively assessed a potential predictive association with outcome of antiepileptic drug use within the pivotal trial of radiotherapy alone versus radiotherapy plus concomitant and adjuvant temozolomide for newly diagnosed glioblastoma that was undertaken by the European Organization for Research and Treatment of Cancer and the National Cancer Institute of Canada Clinical Trials Group. 52 We identified 387 patients (68% of all patients) who received any antiepileptic drugs; 110 patients (28% of those receiving antiepileptic drugs) were prescribed exclusively non-enzyme-inducing antiepileptic drugs, mostly valproic acid, whereas the others received at least one enzyme-inducing antiepileptic drug, either phenytoin, carbamazepine, oxcarbazepine, or phenobarbital. We specifically compared three groups of patients: those without antiepileptic drugs, those given valproic acid alone, and those given enzyme-inducing antiepileptic drugs only. After controlling for potentially confounding factors, we still noted a significant increase in overall survival of patients given valproic acid in the chemoradiotherapy group, but not in the radiotherapy alone group, suggesting a specific interaction between valproic acid and temozolomide chemotherapy. This association remains after adjustment for potentially confounding factors and inbalances. Moreover, haematological toxicity in patients given chemoradiotherapy and valproic acid was increased. 44 Nevertheless, our analysis has some limitations and should be interpreted with caution. The data were generated from an unplanned and insufficiently powered retrospective analysis with insufficient statistical power. Use of antiepileptic drugs for the purpose of this analysis refers only to baseline use—ie, at study entry when patients were treated with radiotherapy with or without temozolomide chemotherapy—but no detailed data for further treatment with such drugs were collected during the course of the study. The reason for the prescription of antiepileptic drugs was not recorded; thus, patients could have been receiving this treatment because of a seizure at disease presentation or as primary prophylaxis during the perioperative and postoperative phase. We assume that only a few patients were maintained on valproic acid throughout the planned six cycles of adjuvant temozolomide, raising the possibility that any sensitisation to chemoradiotherapy by valproic acid might have been underestimated. At least two mechanisms for this improved efficacy of temozolomide chemotherapy conferred by co-medication with valproic acid can be considered. Temozolomide is a prodrug converted to 3-methyl-(triazen-1-yl)imidazole-4-carboxamide, which is either hydrolysed or unchanged before excretion. No effect of phenytoin, carbamazepine, or phenobarbital on temozolomide clearance has been reported, whereas valproic acid decreased its clearance by 5%. To some extent, the increased haematological toxicity during adjuvant temozolomide chemotherapy with valproic acid could thus be related to an increased bioavailability of temozolomide. Yet, thrombocytopenia is not an uncommon side-effect in patients given valproic acid alone. Moreover, the negative result for temozolomide dose intensification in the Radiation Therapy Oncology Group 0525 trial 53 provides strong support against the hypothesis that valproic acid simply increases the biologically active dose of temozolomide. Increased haematological toxicity has been noted when patients with glioma were co-treated with valproic acid and nitrosourea-based chemotherapy, but survival data by use of antiepileptic drug were not reported. 43 Alternatively, our finding may lend support to the notion that histone deacetylase inhibitory properties of valproic acid sensitise glioma cells for temozolomide. The EC 50 for valproic acid-induced inhibition of histone deacetylase is 500 μmol/L, 36 which probably exceeds the clinically achieved plasma concentrations. Yet, some patients with glioblastoma who were reoperated after exposure to valproic acid show evidence of histone deacetylase inhibition. 54 A prolonged survival of 14 months versus 11 months was reported in patients with glioblastoma treated with adjuvant lomustine who received a non-enzyme-inducing antiepileptic drug, mainly valproic acid, compared with patients who received an enzyme-inducing antiepileptic drug, mainly carbamazepine. 55 A phase 1 dose escalation trial of valproic acid combined with fluorouracil, epirubicin, and cyclophosphamide confirmed that histone deacetylase inhibition could be achieved in vivo. 56 Yet, a phase 1 trial exploring valproic acid plus dacarbazine and interferon-α chemoimmunotherapy in metastatic melanoma showed only moderate tolerability, but no indication of enhanced activity. 57 Exploratory trials with histone deacetylase inhibitors more potent than valproic acid, such as vorinostat in combination with temozolomide radiochemotherapy, might provide further support for this hypothesis. Selective histone deacetylase inhibitors might also have a preferred tolerability profile compared with valproic acid, which induces weight gain, alopecia, and tremor in some patients ( table ). In any case, this analysis from a randomised phase 3 trial lends supports to the view that the choice of antiepileptic drugs in patients with brain tumours could affect survival. 44
PY - 2012/9
Y1 - 2012/9
N2 - The lifetime risk of having epileptic seizures is profoundly increased in patients with cancer: about 20% of all patients with systemic cancer may develop brain metastases. These patients and those with primary brain tumours have a lifetime risk of epilepsy of 20-80%. Moreover, exposure to chemotherapy or radiotherapy to the brain, cancer-related metabolic disturbances, stroke, and infection can provoke seizures. The management of epilepsy in patients with cancer includes diagnosis and treatment of the underlying cerebral pathological changes, secondary prophylaxis with antiepileptic drugs, and limiting of the effect of epilepsy and its treatment on the efficacy and tolerability of anticancer treatments, cognitive function, and quality of life. Because of the concern of drug-drug interactions, the pharmacological approach to epilepsy requires a multidisciplinary approach, specifically in a setting of rapidly increasing choices of agents both to treat cancer and cancer-associated epilepsy.
AB - The lifetime risk of having epileptic seizures is profoundly increased in patients with cancer: about 20% of all patients with systemic cancer may develop brain metastases. These patients and those with primary brain tumours have a lifetime risk of epilepsy of 20-80%. Moreover, exposure to chemotherapy or radiotherapy to the brain, cancer-related metabolic disturbances, stroke, and infection can provoke seizures. The management of epilepsy in patients with cancer includes diagnosis and treatment of the underlying cerebral pathological changes, secondary prophylaxis with antiepileptic drugs, and limiting of the effect of epilepsy and its treatment on the efficacy and tolerability of anticancer treatments, cognitive function, and quality of life. Because of the concern of drug-drug interactions, the pharmacological approach to epilepsy requires a multidisciplinary approach, specifically in a setting of rapidly increasing choices of agents both to treat cancer and cancer-associated epilepsy.
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U2 - 10.1016/S1470-2045(12)70266-8
DO - 10.1016/S1470-2045(12)70266-8
M3 - Review article
C2 - 22935237
AN - SCOPUS:84865568082
SN - 1470-2045
VL - 13
SP - e375-e382
JO - The Lancet Oncology
JF - The Lancet Oncology
IS - 9
ER -
