Anticonvulsive therapy. Roberta Rudà Division of Neuro-Oncology, Dept. of Neuroscience City of Health and Science and University of Turin, Italy

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1 Anticonvulsive therapy Roberta Rudà Division of Neuro-Oncology, Dept. of Neuroscience City of Health and Science and University of Turin, Italy Symposium on Brain Metastases, Zurich, 19 Jan 2018

2 DISCLOSURE I have received grants and honoraria for Lectures and Advisory Boards from: Mundipharma Italfarmaco UCB

3 Frequency of epileptic seizures by tumor histology Tumor histology At presentation Overall Astrocytoma 60-80% 60-80% Oligodendroglioma 70-80% 80-90% Anaplastic astrocytoma 40-50% 60-70% Glioblastoma 30-40% 40-60% Ganglioglioma 80-90% 80-90% DNT 80-90% 80-90% CNS lymphoma 10-15% 10-15% Meningioma 30-40% 50-60% Brain metastasis 20% 25-40% Neoplastic meningitis 15% 20% Modified from Glantz and Edwards, Cancer Neurology in Clinical Practice, 2003

4 Cancer Control, 2017

5 Systematic review to identify articles from MRI era that reported seizure rate in patients with BM A total of 2012 patients were identified from 18 studies 294 out of 2012 had seizures (14.6 %) 184/236 (78%) had seizures at the time of presentation 52/236 (22%) had seizures after diagnosiskk

6 Chan et al, J of Neurooncol, 2017

7 Chan et al, J of Neurooncol, 2017

8 Epilepsy in brain tumors: different mechanisms in different hystologies Glioneuronal tumors: several studies have suggested an intrinsic epileptogenicity, indicating the presence of a hyperxcitable neuronal component High grade gliomas: abrupt tissue damage leading to necrosis and haemosiderin deposition and to oedema Low grade gliomas: multifactorial factors including infiltrative growth and alteration of the balance between Glutammate (excitatory) and GABAergic pathways Brain metastasis: cortical location, oedema, haemorrhage (notably in patients with metastatic melanoma)

9 Handbook of Clinical Neurology; Gliomas, 2016 DJ Englot, EF Chang, and C Vecht

10 Wu et al, World Neurosurgery, 2017

11 Wu et al, World Neurosurgery, 2017

12 Epilepsy prophylaxis in Neuro- Oncology A consensus statement from the Quality Standards Subcommittee of the American Academy of Neurology recommends not to use antiepileptic drugs routinely as prophylaxis in patients with brain tumors, and to withdraw these drugs in the first week after surgery if patients have never had seizures (Glantz et al., 2000). Temkin et al, 2001; Sirven et al, 2004

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14 Mikkelsen T et al, J Neurooncol, 2010

15 Recommendations from the AANS Level 3 For adults with brain metastases who have not experienced a seizure due to their metastatic brain disease, routine prophylactic use of anticonvulsants is NOT recommended. Only a single underpowered randomized controlled trial (RCT), which did not detect a difference in seizure occurrence, provides evidence for decision-making purposes. Mikkelsen T et al, J Neurooncol, 2010

16 How to chose an antiepileptic drug? There are no firm Guidelines to chose an AED to treat BTRE Should be considered: Side effects Interaction with antitumor treatments Type of seizures Efficacy (trials & studies)

17 AEDs side effects Adverse effects of old AEDs are more frequent in patients with tumor-related epilepsy than in the rest of the epileptic population. A meta-analysis showed that adverse events warranted interruption or modification of AEDs in 24% of BT patients opposed to % of patients without brain tumor (Glantz et al., 2000). Cognitive deficits, hematotoxicity and skin reactions are the most important.

18 AEDs side effects PB: seems to be associated with the worst cognitive profile and can cause megaloblastic anemia and scapular-humeral periarthritis. CBZ: can cause dizziness, diplopia and sedation. Idiosyncratic effect: hematological toxicity. Use during RT seems to be associated with a higher risk of developing severe cutaneous reactions. PHT: can cause agranulocytosis and acute encephalopathy. Use during RT seems to be associated with a higher risk of developing severe cutaneous reactions. VPA: can cause acute encephalopathy, coagulation deficits and thrombocytopenia. Increased hematological toxicity has also been reported in combined therapy with VPA and nitrosoureas.

19 Interactions The risk of interactions between AEDs and anticancer agents is a major concern. Enzyme-inducing AEDs such as carbamazepine, phenytoin and barbiturates stimulate the activity of drugmetabolizing enzymes and enhance the metabolic clearance of many concomitantly administered drugs, including several chemotherapeutics, targeted agents and corticosteroids This is the reason why in NeuroOncology consensus exists to avoid enzyme-inducing AEDs in favour of NEI-AEDs

20 Interactions of cancer therapy and AEDs Weller, Stupp and Wick, Lancet Oncol 2012

21 ILAE Guidelines on management of partial seizures For partial seizures the ILAE has updated the most appropriate AED choices for monotherapy based on a meta-analysis of a large number of randomized control trials Levetiracetam, carbamazepine, phenytoin and zonisamide score as level A? VPA represent the only level B Gabapentin, lamotrigine,oxcarbazepine,phenobarbital, topiramate and vigabatrin are level C Glauser et al, Epilepsia 2013

22 EFFICACY of newer AEDs in BTRE Study AEDs Study Design No. Histology Siddiqui. Epilepsia 2002 Wagner et al. Seizure 2003 Newton et al. J Neurooncol 2006 Maschio et al. J Neurooncol Rosati et al. Arch Neurol 2010 Maschio et al. J Neurooncol 2008 Perry et al. Can J Neurol 1996 Striano et al. Epilepsy Res 2002 Novy J et al. Clin Neurol Neurosurg 2009 Maschio et al. Acta Neurol Scand 2009 Saria et al. J Neurosurg 2013 Levetiracetam add-on Levetiracetam add-on Levetiracetam add-on/mono Levetiracetam add-on Levetiracetam monotherapy Topiramate add-on/mono Gabapentin add-on Tiagabine add-on Pregabalin add-on/mono Zonisamide add-on Lacosamide add-on Retrospective 41 Prospective 26 Retrospective 41 Prospective 19 Prospective 82 Prospective 47 Prospective 14 Prospective 11 Retrospective 9 Prospective 6 Retrospective GBM 5 AA 2 MTS 2 MEN 12 LGGs 18 HGGs 8 LGGs 12 GBM 13 AA 7 MTS 7 LGGs 2 PCNSL 7 GBM 5 AA 1 MEN 6 LGGs 13 LGGs 69 HGGs 28 HGGs 13 LGGs 4 MEN 2 MTS 7 GBM 4 MTS 1 AA 1 LGGs 1 MEN 1 GBM 9 LGGs 6 GBM 2 LGGs 1 PCNSL 3 LGGs 1 HGGs 2 gliomatosis 28 GBM 25 LGGs 15 grade III gliomas 2 others Concomitant Therapy Rate of Response Seizure Freedom ne 51% 27% TMZ + RT (GBM) 65% 15% Most of pts RT; sometimes TMZ, MTX in PCNSL 90% 58.50% Most of pts CT 47% 47% nr 60% 89% 38/47 CT (TMZ, PCV, FTM, other) 20/47 RT 20% 56% 4 RT/1 SRT 100% 57% ne 63.30% 27% RT + TMZ (GBM) 100% 67% 3/6 FTM 83% ne 54% ne

23 Patients (n = 30) Mean seizure frequency prior initiating new AED (events/months) Mean seizure frequency at the last evaluation (events/months) p value Whole population (n = 30) 6.5 (± SD) 1.3 (± 5.50 SD) < Oxcarbazepine (n = 16) 5.69 (± 8.19 SD) 0.43 (± 0.93 SD) Topiramate (n = 8) 3.75 (± 3.24 SD) 0.08 (± 0.24) Levetiracetam (n = 6) 12.2 (± SD) 5.33 (± SD) 0.027

24 EANO Guidelines on brain metastases Anticonvulsants should NOT be prescribed prophylactically (Level A) In patients who suffer from seizure and need a concomitant treatment with chemotherapeutics or targeted agents, enzymeinducing AEDs should be avoided (Level B) Soffietti et al, Neuro-Oncol 2017

25 AEDs treatment of BTRE: Conclusions Need for prospective studies investigating prophylaxis in subgroups at higher risk of seizures (i.e. brain mets from melanoma, etc) Absence of high-level evidence specifically addressing treatment in this patients population: in general, the most commonly used drug is levetiracetam Need for preclinical studies

26 IMPACT OF AEDs on survival?

27 Prognostic significance of continued VPA use Prognostic significance of baseline (A B) and continued (C D) LEV use

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29 Reddy JP et al, Radiotherapy and Oncology, 2015

30 Reddy JP et al, Radiotherapy and Oncology, 2015

31 Epilepsy in the end of life The risk of seizure in the end of life phase is higher in patients presenting previous history of epilepsy and surprisingly, epilepsy is one of the most frequent symptoms in the last stage of disease of brain tumor patients (36.9% Pace et al, 2013) Uncontrolled seizures may lead to rehospitalization, which is often not preferred by patients in the EOL phase and caregiver Seizure management during the EOL phase is often hampered by swallowing difficulties or an impaired consciusness At present, there are no data regarding the preferred drug: intramuscolar phenobarbital in patients assisted at home or intravenous levetiracetam in hospitalized patients may represent an option. Intranasal midazolam appeared to be a feasible way to treat acute seizures (Koekkoek et al, 2016) EANO Guidelines on Palliative care in adults with glioma (Lancet Oncol,2017)

32 Single brain met in a young patients with lung adenocarcinoma receiving SRT: MRI after 3 months from the SRT Partial motor seizures MRI after 6 months From SRT: Increasing number of seizures AEDs: LEV, VPA, increasing doses of desamethasone SEIZURES RELATED TO TREATMENTS

33 MRI before surgery MRI after surgery: near total resection Histological diagnosis: radiation necrosis Seizure-free and withdrawal of steroids and AEDs

34 Seizures in a cancer patient Vascular disease Metabolic disorders Infections Paraneoplastic disease Brain Metastasis Leptomeningeal metastasis Side effects of antineoplastic treatments (radiotherapy/radiosurgery, chemoterapy or targeted agents)