Category Archives: Drugs

Progesterone for acute traumatic brain injury

Systematic reviews

2016

Ma et al., updated the searches of the following databases: the Cochrane Injuries Group’s Specialised Register (30 September 2016), the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 9, 2016), MEDLINE (Ovid; 1950 to 30 September 2016), Embase (Ovid; 1980 to 30 September 2016), Web of Science Core Collection: Conference Proceedings Citation Index-Science (CPCI-S; 1990 to 30 September 2016); and trials registries: Clinicaltrials.gov (30 September 2016) and the World Health Organization (WHO) International Clinical Trials Registry Platform (30 September 2016).

They included randomised controlled trials (RCTs) of progesterone versus no progesterone (or placebo) for the treatment of people with acute TBI.

Two review authors screened search results independently to identify potentially relevant studies for inclusion. Independently, two review authors selected trials that met the inclusion criteria from the results of the screened searches, with no disagreement.

They included five RCTs in the review, with a total of 2392 participants. We assessed one trial to be at low risk of bias; two at unclear risk of bias (in one multicentred trial the possibility of centre effects was unclear, whilst the other trial was stopped early), and two at high risk of bias, due to issues with blinding and selective reporting of outcome data.All included studies reported the effects of progesterone on mortality and disability. Low quality evidence revealed no evidence of a difference in overall mortality between the progesterone group and placebo group (RR 0.91, 95% CI 0.65 to 1.28, I² = 62%; 5 studies, 2392 participants, 2376 pooled for analysis). Using the GRADE criteria, we assessed the quality of the evidence as low, due to the substantial inconsistency across studies.There was also no evidence of a difference in disability (unfavourable outcomes as assessed by the Glasgow Outcome Score) between the progesterone group and placebo group (RR 0.98, 95% CI 0.89 to 1.06, I² = 37%; 4 studies; 2336 participants, 2260 pooled for analysis). We assessed the quality of this evidence to be moderate, due to inconsistency across studies.Data were not available for meta-analysis for the outcomes of mean intracranial pressure, blood pressure, body temperature or adverse events. However, data from three studies showed no difference in mean intracranial pressure between the groups. Data from another study showed no evidence of a difference in blood pressure or body temperature between the progesterone and placebo groups, although there was evidence that intravenous progesterone infusion increased the frequency of phlebitis (882 participants). There was no evidence of a difference in the rate of other adverse events between progesterone treatment and placebo in the other three studies that reported on adverse events.

This updated review did not find evidence that progesterone could reduce mortality or disability in patients with TBI. However, concerns regarding inconsistency (heterogeneity among participants and the intervention used) across included studies reduce our confidence in these results.There is no evidence from the available data that progesterone therapy results in more adverse events than placebo, aside from evidence from a single study of an increase in phlebitis (in the case of intravascular progesterone).There were not enough data on the effects of progesterone therapy for our other outcomes of interest (intracranial pressure, blood pressure, body temperature) for us to be able to draw firm conclusions.Future trials would benefit from a more precise classification of TBI and attempts to optimise progesterone dosage and scheduling 1).

2012

Ma et al., searched: the Cochrane Injuries Group’s Specialised Register (13 July 2012), Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 7, 2012), MEDLINE (Ovid) (1950 to August week 1, 2012), EMBASE (Ovid) (1980 to week 32 2012), LILACS (12 August 2012), Zetoc (13 July 2012), Clinicaltrials.gov (12 August 2012), Controlled-trials.com (12 August 2012). SELECTION CRITERIA: We included published and unpublished randomised controlled trials (RCTs) of progesterone versus no progesterone (or placebo) for the treatment of people with acute TBI. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results to identify the full texts of potentially relevant studies for inclusion. From the results of the screened searches two review authors independently selected trials meeting the inclusion criteria, with no disagreement. MAIN RESULTS: Three studies were included with a total of 315 people. Two included studies were of high methodological quality, with low risk of bias in allocation concealment, blinding and incomplete outcome data. One study did not use blinding and had unclear risk of bias in allocation concealment and incomplete outcome data. All three studies reported the effects of progesterone on mortality. The pooled risk ratio (RR) for mortality at end of follow-up was 0.61, 95% confidence interval (CI) 0.40 to 0.93. Three studies measured disability and found the RR of death or severe disability in patients treated with progesterone to be 0.77, 95% CI 0.62 to 0.96. Data from two studies showed no difference in mean intracranial pressure or the rate of adverse and serious adverse events among people in either group. One study presented blood pressure and temperature data, and there were no differences between the people in the progesterone or control groups. There was no substantial evidence for the presence of heterogeneity.

Current clinical evidence from three small RCTs indicates progesterone may improve the neurologic outcome of patients suffering TBI. This evidence is still insufficient and further multicentre randomised controlled trials are required 2).

2011

Junpeng et al., searched: the Cochrane Injuries Group’s Specialised Register (to April 2010), Cochrane Central Register of Controlled Trials 2010, Issue 1 (The Cochrane Library), MEDLINE (Ovid) (1950 to April week 1 2010), EMBASE (Ovid) (1980 to week 14 2010), LILACS (to 17 April 2010 ), Zetoc (to 21 April 2010), Clinicaltrials.gov (17 April 2010 ), Controlled-trials.com (17 April 2010).

They included published and unpublished randomised controlled trials (RCTs) of progesterone versus no progesterone (or placebo) for the treatment of acute TBI.

Two authors independently screened search results to identify the full texts of potentially relevant studies for inclusion. From the results of the screened searches two authors independently selected trials meeting the inclusion criteria, with no disagreement.

Three studies were included with 315 patients. All three studies reported the effects of progesterone on mortality. The pooled relative risk (RR) for mortality at end of follow-up is 0.61, 95% confidence interval (CI) 0.40 to 0.93. Three studies measured disability and found the RR of death or severe disability in patients treated with progesterone was 0.77, 95% confidence interval (CI) 0.62 to 0.96. Two studies presented data on intracranial pressure and adverse events. One study presented blood pressure and temperature data. There was no substantial evidence for the presence of heterogeneity.

Current clinical evidence from three small RCTs indicates progesterone may improve the neurologic outcome of patients suffering TBI. This evidence is still insufficient and further multicentre randomised controlled trials are required 3).


Progesterone has been associated with robust positive effects in animal models of traumatic brain injury (TBI) and with clinical benefits in two phase 2 randomized controlled trials. Skolnick et al, investigated the efficacy and safety of progesterone in a large, prospective, phase 3 randomized controlled trial.

A multinational placebo controlled study, in which 1195 patients, 16 to 70 years of age, with severe traumatic brain injury TBI (Glasgow Coma Scale score, ≤8 (on a scale of 3 to 15, with lower scores indicating a reduced level of consciousness and at least one reactive pupil) were randomly assigned to receive progesterone or placebo. Dosing began within 8 hours after injury and continued for 120 hours. The primary efficacy end point was the Glasgow Outcome Scale score at 6 months after the injury.

Proportional-odds analysis with covariate adjustment showed no treatment effect of progesterone as compared with placebo (odds ratio, 0.96; confidence interval, 0.77 to 1.18). The proportion of patients with a favorable outcome on the Glasgow Outcome Scale (good recovery or moderate disability) was 50.4% with progesterone, as compared with 50.5% with placebo. Mortality was similar in the two groups. No relevant safety differences were noted between progesterone and placebo.

Primary and secondary efficacy analyses showed no clinical benefit of progesterone in patients with severe TBI. These data stand in contrast to the robust preclinical data and results of early single-center trials that provided the impetus to initiate phase 3 trials. (Funded by BHR Pharma; SYNAPSE ClinicalTrials.gov number, NCT01143064 .) 4).

There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P=0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes. Conclusions This clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. (Funded by the National Institute of Neurological Disorders and Stroke and others; PROTECT III ClinicalTrials.gov number, NCT00822900 .) 5).


There is significant theoretical evidence for the potential role of estrogen and progesterone use in altering the pathogenesis of SAH. Nevertheless, this has received mixed reviews in both case controlled studies and cohort analysis within the literature 6)


1) Ma J, Huang S, Qin S, You C, Zeng Y. Progesterone for acute traumatic brain injury. Cochrane Database Syst Rev. 2016 Dec 22;12:CD008409. doi: 10.1002/14651858.CD008409.pub4. [Epub ahead of print] Review. PubMed PMID: 28005271.
2) Ma J, Huang S, Qin S, You C. Progesterone for acute traumatic brain injury. Cochrane Database Syst Rev. 2012 Oct 17;10:CD008409. doi: 10.1002/14651858.CD008409.pub3. Review. PubMed PMID: 23076947.
3) Junpeng M, Huang S, Qin S. Progesterone for acute traumatic brain injury. Cochrane Database Syst Rev. 2011 Jan 19;(1):CD008409. doi: 10.1002/14651858.CD008409.pub2. Review. Update in: Cochrane Database Syst Rev. 2012;10:CD008409. PubMed PMID: 21249708.
4) Skolnick BE, Maas AI, Narayan RK, van der Hoop RG, MacAllister T, Ward JD, Nelson NR, Stocchetti N; the SYNAPSE Trial Investigators. A Clinical Trial of Progesterone for Severe Traumatic Brain Injury. N Engl J Med. 2014 Dec 10. [Epub ahead of print] PubMed PMID: 25493978.
5) Wright DW, Yeatts SD, Silbergleit R, Palesch YY, Hertzberg VS, Frankel M, Goldstein FC, Caveney AF, Howlett-Smith H, Bengelink EM, Manley GT, Merck LH, Janis LS, Barsan WG; the NETT Investigators. Very Early Administration of Progesterone for Acute Traumatic Brain Injury. N Engl J Med. 2014 Dec 10. [Epub ahead of print] PubMed PMID: 25493974.
6) Young AM, Karri SK, Ogilvy CS. Exploring the use of estrogen & progesterone replacement therapy in subarachnoid hemorrhage. Curr Drug Saf. 2012 Jul;7(3):202-6. Review. PubMed PMID: 22950381.

Levetiracetam for hemifacial spasm

Levetiracetam proved its effectiveness and safety in the treatment of a case of HFS.Nevertheless, there is a need for further controlled studies with larger samples 1).


Kuroda et al., experienced two elderly hemifacial spasm (HFS) patients who exhibited a marked response to levetiracetam (LEV) without side effects. Although the exact underlying pharmacological mechanism remains unknown, we assume anti-kindling effect as one of the important pharmacological mechanism underlying the effect of LEV against HFS. Moreover, LEV is considered to be suitable for use in elderly patients because of its good tolerability. In addition, the lack of hepatic induction or inhibition makes it an easy and safe drug when used in addition to other anticonvulsants. Although the long-term benefit remains unknown, LEV may represent an alternative treatment for elderly HFS patients who are unable to undergo or decline surgical intervention and/or botulinum toxin injections or are intolerant to other anticonvulsants 2).


1) Biagio Carrieri P, Petracca M, Montella S. Efficacy of levetiracetam in hemifacial spasm: a case report. Clin Neuropharmacol. 2008 May-Jun;31(3):187-8. doi: 10.1097/WNF.0b013e3180ed44c8. PubMed PMID: 18520988.
2) Kuroda T, Saito Y, Fujita K, Yano S, Ishigaki S, Kato H, Murakami H, Ono K. Efficacy of levetiracetam in primary hemifacial spasm. J Clin Neurosci. 2016 Dec;34:213-215. doi: 10.1016/j.jocn.2016.05.025. PubMed PMID: 27460515.

Spontaneous intracranial epidural hematoma during rivaroxaban treatment

Rivaroxaban (BAY 59-7939) is an oral anticoagulant invented and manufactured by Bayer; in a number of countries it is marketed as Xarelto. In the United States, it is marketed by Janssen Pharmaceutica.

It is the first available orally active direct factor Xa inhibitor. Rivaroxaban is well absorbed from the gut and maximum inhibition of factor Xa occurs four hours after a dose. The effects last approximately 8–12 hours, but factor Xa activity does not return to normal within 24 hours so once-daily dosing is possible 1).

Thrombolysis and/or endovascular thrombectomy might be safe for patients treated with the new anticoagulant rivaroxaban 2).

Complications

Direct factor Xa inhibitors rivaroxaban and apixaban are efficacious alternatives to warfarin and confer a lower risk of spontaneous intracranial hemorrhage (ICH).

Despite several advantages rivaroxaban compared with vitamin K antagonists (VKA), its lack of specific antidotes to reverse anticoagulant effects may increase the risk profile of patients with bleeding complications.

There are few studies in the literature regarding the presence of intracerebral hemorrhage and the volume and prognosis of bleeding associated with rivaroxaban 3).

The results suggest that rivaroxaban may exacerbate intracranial haemorrhage in patients with mild traumatic brain injury (TBI)4).

Case series

A total of 70 patients with traumatic intracranial hemorrhage (tICH) after mild traumatic brain injury (TBI) were included in a retrospective analysis and were categorized into three groups: group A (no antithrombotics n=37), group B (antiplatelet medication n=22, VKA=5), and group C (rivaroxaban n=6). Medical charts were reviewed for baseline characteristics, laboratory values, intracranial haemorrhage, repeated computed tomography (CT) scans, re-haemorrhage, Glasgow Coma Scale (GCS) scores and in-hospital mortality.

No significant differences were observed for baseline characteristics. The rate of re-haemorrhage was significantly higher in group C (50%) than in group A (11%) (p<0.05). Two patients died and both had been treated with rivaroxaban which resulted in a significantly higher mortality rate of 33% in group C compared with groups A (0%) and B (0%). No significant differences were observed for GCS at discharge and length of hospital stay between survivors of groups A-C.

Despite major limitations of retrospective design and small patient numbers, the results suggest that rivaroxaban may exacerbate intracranial hemorrhage in patients with mild TBI. Further studies are needed to characterize the risk profile of this drug in patients with tICH 5).

Case reports

2016

First case described in the literature of spontaneous intracranial epidural hematoma secondary to the use of Xareltor. Spontaneous intracranial epidural hematomas are rarely described in the literature. They are associated with infectious diseases of the skull, coagulation disorders, vascular malformations of the dura mater and metastasis to the skull. Long-term post-marketing monitoring and independent reports will probably detect the full spectrum of hemorrhagic complications of the use of rivaroxaban 6).

2015

The clinical and radiologic findings and follow-up of an 80-year-old male patient with intracerebral hemorrhage who uses rivaroxaban for anticoagulation are presented in the article of Çalışkan et al. 7).

2014

Ishihara et al. report an acute stroke patient taking rivaroxaban who received intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA). An 80-year-old man with a history of nonvalvular atrial fibrillation, who had been receiving 10 mg of rivaroxaban showed abrupt onset of aphasia and right hemiparesis. National Institutes of Health Stroke Scale score was 10. Onset of neurologic deficits occurred 4 hours after the last dose of rivaroxaban. Clinical data on admission were as follows: blood pressure, 170/90 mm Hg; prothrombin time (PT), 22.6 seconds (control, 12.9 seconds); international normalized ratio, 2.03; activated partial thromboplastin time, 46 seconds (normal, 23-32 seconds); and creatinine level, 1.11 mg/dL. Magnetic resonance angiography revealed occlusion of the superior trunk of the left middle cerebral artery. Intravenous infusion of .6 mg/kg of rt-PA (total dose, 36 mg) was performed 6 hours after the last rivaroxaban administration with informed consent. The neurologic deficit improved during infusion of rt-PA. Repeat brain computed tomography showed left frontal cortical infarction without hemorrhagic changes. In the case of rivaroxaban, it is difficult to accurately determine the drug activity. As the anticoagulant activity of rivaroxaban can be estimated from its pharmacokinetics and PT, it is clinically important to obtain accurate information about the timing of medication and blood sampling 8).


A 83-year-old woman had a medical history with ischemic stroke due to paroxysmal atrial fibrillation and was then administered 10 mg of rivaroxaban daily. Although she took rivaroxaban in the morning, ischemic stroke recurred at midnight of that day. Soon after transferring to the hospital, Kimura et al. confirmed right middle cerebral artery (MCA) occlusion in the patient and then initiated treatment with intravenous rt-PA. Although no hemorrhagic complication occurred, recovery of her symptoms was not seen, and endovascular thrombectomy was performed. Although the inferior branch of the MCA was recanalized, an infarct was seen in her left frontal lobe. Hemorrhagic transformation was not observed during or after these combined treatments 9).


1) Komotar RJ, Starke RM, Connolly ES Jr. Orally administered factor xa inhibitor, rivaroxaban: a novel thromboembolic prophylaxis agent. Neurosurgery. 2008 Oct;63(4):N10-1. doi: 10.1227/01.NEU.0000339454.55968.F0. PubMed PMID: 18981864.
2) , 9) Kimura S, Ogata T, Fukae J, Okawa M, Higashi T, Iwaasa M, Inoue T, Tsuboi Y. Revascularization for acute ischemic stroke is safe for rivaroxaban users. J Stroke Cerebrovasc Dis. 2014 Oct;23(9):e427-31. doi: 10.1016/j.jstrokecerebrovasdis.2014.05.015. Epub 2014 Aug 20. PubMed PMID:25149204.
3) , 7) Çalışkan F, Akdemir HU, Nurata H, Akdemir N, Başara G, Yavuz Y.Rıvaroxaban-induced severe diffuse ıntracerebral hemorrhage. Am J Emerg Med. 2015 Mar;33(3):475.e1-5. doi: 10.1016/j.ajem.2014.08.028. Epub 2014 Aug 21. PubMed PMID: 25218622.
4) , 5) Beynon C, Potzy A, Sakowitz OW, Unterberg AW. Rivaroxaban and intracranial haemorrhage after mild traumatic brain injury: A dangerous combination? Clin Neurol Neurosurg. 2015 May 30;136:73-78. doi: 10.1016/j.clineuro.2015.05.035. [Epub ahead of print] PubMed PMID: 26070116.
6) Ruschel LG, Rego FM, Milano JB, Jung GS, Silva LF Jr, Ramina R. Spontaneous intracranial epidural hematoma during rivaroxaban treatment. Rev Assoc Med Bras (1992). 2016 Nov;62(8):721-724. doi: 10.1590/1806-9282.62.08.721. PubMed PMID: 27992010.
8) Ishihara H, Torii H, Imoto H, Oka F, Sadahiro H, Suzuki M. Intravenous thrombolysis with recombinant tissue plasminogen activator in a stroke patient treated with rivaroxaban. J Stroke Cerebrovasc Dis. 2014 Nov-Dec;23(10):e457-9. doi: 10.1016/j.jstrokecerebrovasdis.2014.07.008. Epub 2014 Oct 3. PubMed PMID: 25280819.

Update: Sunitinib

The failure of hormonal and cytotoxic chemotherapy in the treatment of recurrent meningioma and increasing understanding of potential molecular targets in meningioma has resulted in multiple studies utilizing single-agent targeted therapy directed at biologically relevant signaling pathways, such as somatostatin (Sandostatin(®) LAR, SOM230c), PDGF (imatinib), EGF (erlotinib) and VEGF (sunitinib and vatalanib)1).

Sunitinib targets vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor, abundant in meningioma.

Andrae et al analysed the effects of sunitinib in two benign (BenMen-1, HBL52) and two malignant (IOMM-Lee, KT21MG) human meningioma cell lines and found that DNA synthesis was significantly (p ≤ 0.001) inhibited following 1, 2 or 5 μM sunitinib, with IC(50) values between 2 and 5 μM in all cell lines. This effect was associated with a G(2)M-arrest at 10 μM for BenMen-1, HBL52 and IOMM-Lee, and 20 μM in KT21MG cells. Nuclear bisbenzimide staining revealed chromatin condensation following treatment with sunitinib concentrations of 10 μM or higher. Corresponding, cell viability assays showed a significant (p ≤ 0.001) short term decrease of viable cells (24h) only for high sunitinib concentrations with IC(50)-values between 10 and 20 μM. However, pre-irradiated meningioma cells (5 Gy) showed a sensitivity shift towards IC(50)-values around 5 μM sunitinib. We also found that 5 μM strongly reduced meningioma cell migration in vitro. Western blot analyses showed abolished platelet derived growth factor receptor (PDGFR)-autophosphorylation after sunitinib. Interestingly, the drug also inhibited the autophosphorylation of the receptor tyrosine kinase fms-like tyrosine kinase 3 (Flt3) in a dose-dependent manner. Taken together, the present data show that micromolar sunitinib has strong cytostatic and anti-migratory effects on human meningioma cells 2).

Potential activity of VEGF (vascular endothelial growth factor) inhibitors such as sunitinib, vatalanib, and bevacizumab is suggested in small non-controlled studies and requires validation in randomized trials 3) 4) 5) 6) 7) 8).

The PDGFRβ inhibitors gambogic acid and tandutinib equally impaired the migration of meningioma cells 9).

Case series

2016

A clinical trial of sunitinib for treatment of recurrent World health organization grade 2 meningioma and World health organization grade 3 meningioma suggested potential efficacy in this population, but only 2 patients exhibited significant radiographic response with tumor volume reduction.

Raheja et al illustrate another such case and discuss a complication related to this dramatic tumor volume reduction in aggressive skull base meningiomas. The authors describe the case of a 39-year-old woman who had undergone repeat surgical interventions and courses of radiotherapy over the previous 11 years for recurrent cranial and spinal meningiomas. Despite 4 operations over the course of 4 years on her right petroclival meningioma with cavernous sinus and jugular fossa extensions, she had progressive neurological deficits and tumor recurrences. The specimen histology progressed from WHO Grade I initially to Grade II at the time of the third recurrence. The lesion was then irradiated 3 times using stereotactic radiosurgery for further recurrences. More recently, the tumor size increased rapidly on imaging, in association with progressive neurological symptoms arising from brainstem compression and vasogenic edema. Institution of sunitinib therapy yielded a dramatic radiographic response, with marked reduction in the tumor volume and reduction of brainstem vasogenic edema within a few weeks of initiation of treatment. The significant radiographic response of tumor in the clival region was also associated with CSF rhinorrhea from a dural breach created by resolution of the invasive skull base meningioma, which necessitated withholding the sunitinib medication. To address the leak, the authors undertook surgical exploration and transsphenoidal packing using an autologous fat graft and a vascularized pedicled nasoseptal flap. The patient has done well during follow-up of 3 months after packing, with no evidence of recurrent CSF leak, and the medication was subsequently restarted. Prior clinical data and the dramatic radiographic response in this patient suggest that sunitinib holds promising therapeutic potential in carefully selected patients with recurrent atypical meningiomas where conventional strategies have been exhausted. There is a potential risk of associated CSF rhinorrhea, especially in more invasive skull base lesions showing dramatic radiographic response 10).

2015

Thirteen patients with temozolomide-refractory recurrent anaplastic glioma or low-grade glioma were treated with sunitinib malate in combination with lomustine. The most frequent grade 3 and 4 adverse events were fatigue, thrombocytopenia, neutropenia and lymphopenia. The best objective tumor response by Response Assessment in Neuro-Oncology (RANO) criteria was one complete response, one unconfirmed partial response and three cases of stable disease. The median progression-free survival was 1.8 months (95% confidence interval=1.0-2.7 months) with 6-month progression-free survival of 15% (95% confidence interval=0-35%). The median overall survival was 6.7 months (95% confidence interval=0.7-12 months). The investigated combination regimen of sunitinib and lomustine is well-tolerated but insufficiently active to warrant further investigation in an unselected population of patients with temozolomide-refractory recurrent anaplastic and low-grade glioma 11).


A prospective, multicenter, investigator-initiated single-arm phase II trial. The primary cohort enrolled patients with surgery and radiation-refractory recurrent World Health Organization (WHO) grades II-III meningioma. An exploratory cohort enrolled patients with WHO grade I meningioma, hemangiopericytoma, or hemangioblastoma. Sunitinib was administered at 50 mg/d for days 1-28 of every 42-day cycle. The primary endpoint was the rate of 6-month progression-free survival (PFS6), with secondary endpoints of radiographic response rate, safety, PFS, and overall survival. Exploratory objectives include analysis of tumoral molecular markers and MR perfusion imaging.

Thirty-six patients with high-grade meningioma (30 atypical and 6 anaplastic) were enrolled. Patients were heavily pretreated (median number of 5 recurrences, range 2-10). PFS6 rate was 42%, meeting the primary endpoint. Median PFS was 5.2 months (95% CI: 2.8-8.3 mo), and median overall survival was 24.6 months (95% CI: 16.5-38.4 mo). Thirteen patients enrolled in the exploratory cohort. Overall toxicity included 1 grade 5 intratumoral hemorrhage, 2 grade 3 and 1 grade 4 CNS/intratumoral hemorrhages, 1 grade 3 and 1 grade 4 thrombotic microangiopathy, and 1 grade 3 gastrointestinal perforation. Expression of VEGFR2 predicted PFS of a median of 1.4 months in VEGFR2-negative patients versus 6.4 months in VEGFR2-positive patients (P = .005).

Sunitinib is active in recurrent atypical/malignant meningioma patients. A randomized trial should be performed. TRIAL REGISTRATION: ClinicalTrials.gov NCT01125046 12).


1) Chamberlain MC, Barnholtz-Sloan JS. Medical treatment of recurrent meningiomas. Expert Rev Neurother. 2011 Oct;11(10):1425-32. doi: 10.1586/ern.11.38. Review. PubMed PMID: 21955199.
2) Andrae N, Kirches E, Hartig R, Haase D, Keilhoff G, Kalinski T, Mawrin C. Sunitinib targets PDGF-receptor and Flt3 and reduces survival and migration of human meningioma cells. Eur J Cancer. 2012 Aug;48(12):1831-41. doi: 10.1016/j.ejca.2012.01.032. PubMed PMID: 22391574.
3) Le Rhun E, Taillibert S, Chamberlain MC. Systemic therapy for recurrent meningioma. Expert Rev Neurother. 2016 Aug;16(8):889-901. doi: 10.1080/14737175.2016.1184087. PubMed PMID: 27123883.
4) Hundsberger T, Surbeck W, Hader C, Putora PM, Conen K, Roelcke U. [Meningioma: management of the most common brain tumour]. Praxis (Bern 1994). 2016 Apr 13;105(8):445-51. doi: 10.1024/1661-8157/a002320. Review. German. PubMed PMID: 27078728.
5) Mawrin C, Chung C, Preusser M. Biology and clinical management challenges in meningioma. Am Soc Clin Oncol Educ Book. 2015:e106-15. doi: 10.14694/EdBook_AM.2015.35.e106. PubMed PMID: 25993161.
6) Rahman A. Sunitinib for atypical and anaplastic meningioma. Lancet Oncol. 2014 Sep;15(10):e424. PubMed PMID: 25328951.
7) Baumgarten P, Brokinkel B, Zinke J, Zachskorn C, Ebel H, Albert FK, Stummer W, Plate KH, Harter PN, Hasselblatt M, Mittelbronn M. Expression of vascular endothelial growth factor (VEGF) and its receptors VEGFR1 and VEGFR2 in primary and recurrent WHO grade III meningiomas. Histol Histopathol. 2013 Sep;28(9):1157-66. doi: 10.14670/HH-28.1157. PubMed PMID: 23475388.
8) Chamberlain MC. The role of chemotherapy and targeted therapy in the treatment of intracranial meningioma. Curr Opin Oncol. 2012 Nov;24(6):666-71. doi: 10.1097/CCO.0b013e328356364d. Review. PubMed PMID: 22759739.
9) Pfister C, Pfrommer H, Tatagiba MS, Roser F. Vascular endothelial growth factor signals through platelet-derived growth factor receptor β in meningiomas in vitro. Br J Cancer. 2012 Nov 6;107(10):1702-13. doi: 10.1038/bjc.2012.459. PubMed PMID: 23047550; PubMed Central PMCID: PMC3493872.
10) Raheja A, Colman H, Palmer CA, Couldwell WT. Dramatic radiographic response resulting in cerebrospinal fluid rhinorrhea associated with sunitinib therapy in recurrent atypical meningioma: case report. J Neurosurg. 2016 Dec 9:1-6. [Epub ahead of print] PubMed PMID: 27935362.
11) Duerinck J, DU Four S, Sander W, VAN Binst AM, Everaert H, Michotte A, Hau P, Neyns B. Sunitinib Malate plus Lomustine for Patients with Temozolomide-refractory Recurrent Anaplastic or Low-grade Glioma. Anticancer Res. 2015 Oct;35(10):5551-7. PubMed PMID: 26408725.
12) Kaley TJ, Wen P, Schiff D, Ligon K, Haidar S, Karimi S, Lassman AB, Nolan CP, DeAngelis LM, Gavrilovic I, Norden A, Drappatz J, Lee EQ, Purow B, Plotkin SR, Batchelor T, Abrey LE, Omuro A. Phase II trial of sunitinib for recurrent and progressive atypical and anaplastic meningioma. Neuro Oncol. 2015 Jan;17(1):116-21. doi: 10.1093/neuonc/nou148. PubMed PMID: 25100872; PubMed Central PMCID: PMC4483051.

Update: Temozolamide for intracranial ependymoma

Few data are available on temozolomide (TMZ) in ependymomas.

Case series

2016

Eighteen patients (median age, 42 y), with either WHO grade III (10) or grade II (8) ependymoma were evaluable. Tumor location at diagnosis was supratentorial in 11 patients and infratentorial in 7. Progression before TMZ was local in 11 patients, local and spinal in 6 patients, and spinal only in one patient. A median of 8 cycles of TMZ (1-24) was administered. Response to TMZ consisted of complete response (CR) in one (5%) patient, partial response (PR) in 3 (17%) patients, stable disease (SD) in 7 (39%) patients, and progressive disease (PD) in 7 (39%) patients. Maximum response occurred after 3, 10, 14, and 15 cycles, respectively, with neurological improvement in 2 patients. All 4 responding patients were chemotherapy naïve. Both anaplastic (2) and grade II (2) tumors responded. Median progression-free survival and overall survival were 9.69 months (95% CI, 3.22-30.98) and 30.55 months (95% CI, 12.85-52.17), respectively. MGMT methylation was available in 11 patients and was not correlated with response or outcome.

TMZ has a role in recurrent chemo-naïve adult patients with intracranial ependymoma, regardless of tumor grade and MGMT methylation. We suggest that, after failure of surgery and radiotherapy, TMZ should be considered as a possible first-line treatment for recurrent ependymoma 2).

2009

A total of 25 patients, ages 28 to 63 years, with recurrent ependymoma were treated. All patients had previously been treated with surgery, radiotherapy, and platinum-based chemotherapy (cisplatin in 15 patients and carboplatin in 10 patients). Nine patients underwent repeat surgery. Patients were treated at the time of second recurrence with TMZ (5 consecutive days), once every 4 weeks, which was defined as a single cycle. Neurologic evaluation was performed every 4 weeks and neuroradiographic assessment every 8 weeks.

A total of 68 cycles of TMZ (median, 2 cycles; range, 1-6 cycles) was administered. TMZ-related toxicity included leukopenia (7 patients; 1 with grade 3 [grade was determine according to National Cancer Institute Common Toxicity Criteria [version 3.0]), constipation (6 patients; none with grade 3), fatigue (5 patients; none with grade 3), anemia (2; none with grade 3), thrombocytopenia (2; none with grade 3), and deep vein thrombosis (2; none with grade 3). One patient (4%) demonstrated a partial radiographic response, 9 (36%) had stable disease, and 15 (60%) developed progressive disease after 2 cycles of TMZ. Time to tumor progression ranged from 1 to 7 months (median, 2 months). Survival ranged from 2 to 8 months (median, 3 months). The 6-month and 12-month PFS were 2% and 0%, respectively.

TMZ in this dose schedule demonstrated little efficacy in a cohort of adults with recurrent, intracranial, platinum-refractory ependymoma 3).

Case reports

2011

A 25-year-old female patient with multifocal recurrence of a supratentorial malignant ependymoma administered temozolomide as second-line therapy is reported. Currently, 5 months after initiation of temozolomide treatment, there is no evidence of radiographic progression 4).

2006

A case report of a recurrent intracranial ependymoma treated with temozolomide in remission 10 years after completing chemotherapy 5).


1) Friedman HS, Dolan ME, Pegg AE, Marcelli S, Keir S, Catino JJ, Bigner DD, Schold SC Jr. Activity of temozolomide in the treatment of central nervous system tumor xenografts. Cancer Res. 1995 Jul 1;55(13):2853-7. PubMed PMID: 7796412.
2) Rudà R, Bosa C, Magistrello M, Franchino F, Pellerino A, Fiano V, Trevisan M, Cassoni P, Soffietti R. Temozolomide as salvage treatment for recurrent intracranial ependymomas of the adult: a retrospective study. Neuro Oncol. 2016 Feb;18(2):261-8. doi: 10.1093/neuonc/nov167. Epub 2015 Aug 30. PubMed PMID: 26323606; PubMed Central PMCID: PMC4724181.
3) Chamberlain MC, Johnston SK. Temozolomide for recurrent intracranial supratentorial platinum-refractory ependymoma. Cancer. 2009 Oct 15;115(20):4775-82. doi: 10.1002/cncr.24524. PubMed PMID: 19569246.
4) Freyschlag CF, Tuettenberg J, Lohr F, Thomé C, Schmieder K, Seiz M. Response to temozolomide in supratentorial multifocal recurrence of malignant ependymoma. Anticancer Res. 2011 Mar;31(3):1023-5. PubMed PMID: 21498732.
5) Rehman S, Brock C, Newlands ES. A case report of a recurrent intracranial ependymoma treated with temozolomide in remission 10 years after completing chemotherapy. Am J Clin Oncol. 2006 Feb;29(1):106-7. PubMed PMID: 16462515.

Update: Rivaroxaban in neurosurgery

Rivaroxaban

J.Sales-Llopis

Neurosurgery Department, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Alicante, Spain

Rivaroxaban (BAY 59-7939) is an oral anticoagulant invented and manufactured by Bayer; in a number of countries it is marketed as Xarelto. In the United States, it is marketed by Janssen Pharmaceutica.

It is the first available orally active direct factor Xa inhibitor. Rivaroxaban is well absorbed from the gut and maximum inhibition of factor Xa occurs four hours after a dose. The effects last approximately 8–12 hours, but factor Xa activity does not return to normal within 24 hours so once-daily dosing is possible 1).

Thrombolysis and/or endovascular thrombectomy might be safe for patients treated with the new anticoagulant rivaroxaban 2).

Complications

Despite several advantages of the novel anticoagulant rivaroxaban compared with vitamin K antagonists (VKA), its lack of specific antidotes to reverse anticoagulant effects may increase the risk profile of patients with bleeding complications.

There are few studies in the literature regarding the presence of intracerebral hemorrhage and the volume and prognosis of bleeding associated with rivaroxaban 3).

The results suggest that rivaroxaban may exacerbate intracranial haemorrhage in patients with mild traumatic brain injury (TBI) 4).

Case series

A total of 70 patients with traumatic intracranial hemorrhage (tICH) after mild traumatic brain injury (TBI) were included in a retrospective analysis and were categorized into three groups: group A (no antithrombotics n=37), group B (antiplatelet medication n=22, VKA=5), and group C (rivaroxaban n=6). Medical charts were reviewed for baseline characteristics, laboratory values, intracranial haemorrhage, repeated computed tomography (CT) scans, re-haemorrhage, Glasgow Coma Scale (GCS) scores and in-hospital mortality.

No significant differences were observed for baseline characteristics. The rate of re-haemorrhage was significantly higher in group C (50%) than in group A (11%) (p<0.05). Two patients died and both had been treated with rivaroxaban which resulted in a significantly higher mortality rate of 33% in group C compared with groups A (0%) and B (0%). No significant differences were observed for GCS at discharge and length of hospital stay between survivors of groups A-C.

Despite major limitations of retrospective design and small patient numbers, the results suggest that rivaroxaban may exacerbate intracranial hemorrhage in patients with mild TBI. Further studies are needed to characterize the risk profile of this drug in patients with tICH 5).

Case reports

2015

The clinical and radiologic findings and follow-up of an 80-year-old male patient with intracerebral hemorrhage who uses rivaroxaban for anticoagulation are presented in the article of Çalışkan et al. 6).

2014

Ishihara et al. report an acute stroke patient taking rivaroxaban who received intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA). An 80-year-old man with a history of nonvalvular atrial fibrillation, who had been receiving 10 mg of rivaroxaban showed abrupt onset of aphasia and right hemiparesis. National Institutes of Health Stroke Scale score was 10. Onset of neurologic deficits occurred 4 hours after the last dose of rivaroxaban. Clinical data on admission were as follows: blood pressure, 170/90 mm Hg; prothrombin time (PT), 22.6 seconds (control, 12.9 seconds); international normalized ratio, 2.03; activated partial thromboplastin time, 46 seconds (normal, 23-32 seconds); and creatinine level, 1.11 mg/dL. Magnetic resonance angiography revealed occlusion of the superior trunk of the left middle cerebral artery. Intravenous infusion of .6 mg/kg of rt-PA (total dose, 36 mg) was performed 6 hours after the last rivaroxaban administration with informed consent. The neurologic deficit improved during infusion of rt-PA. Repeat brain computed tomography showed left frontal cortical infarction without hemorrhagic changes. In the case of rivaroxaban, it is difficult to accurately determine the drug activity. As the anticoagulant activity of rivaroxaban can be estimated from its pharmacokinetics and PT, it is clinically important to obtain accurate information about the timing of medication and blood sampling 7).


A 83-year-old woman had a medical history with ischemic stroke due to paroxysmal atrial fibrillation and was then administered 10 mg of rivaroxaban daily. Although she took rivaroxaban in the morning, ischemic stroke recurred at midnight of that day. Soon after transferring to the hospital, Kimura et al. confirmed right middle cerebral artery (MCA) occlusion in the patient and then initiated treatment with intravenous rt-PA. Although no hemorrhagic complication occurred, recovery of her symptoms was not seen, and endovascular thrombectomy was performed. Although the inferior branch of the MCA was recanalized, an infarct was seen in her left frontal lobe. Hemorrhagic transformation was not observed during or after these combined treatments 8).

1) Komotar RJ, Starke RM, Connolly ES Jr. Orally administered factor xa inhibitor, rivaroxaban: a novel thromboembolic prophylaxis agent. Neurosurgery. 2008 Oct;63(4):N10-1. doi: 10.1227/01.NEU.0000339454.55968.F0. PubMed PMID: 18981864.
2) , 8) Kimura S, Ogata T, Fukae J, Okawa M, Higashi T, Iwaasa M, Inoue T, Tsuboi Y. Revascularization for acute ischemic stroke is safe for rivaroxaban users. J Stroke Cerebrovasc Dis. 2014 Oct;23(9):e427-31. doi: 10.1016/j.jstrokecerebrovasdis.2014.05.015. Epub 2014 Aug 20. PubMed PMID:25149204.
3) , 6) Çalışkan F, Akdemir HU, Nurata H, Akdemir N, Başara G, Yavuz Y.Rıvaroxaban-induced severe diffuse ıntracerebral hemorrhage. Am J Emerg Med. 2015 Mar;33(3):475.e1-5. doi: 10.1016/j.ajem.2014.08.028. Epub 2014 Aug 21. PubMed PMID: 25218622.
4) , 5) Beynon C, Potzy A, Sakowitz OW, Unterberg AW. Rivaroxaban and intracranial haemorrhage after mild traumatic brain injury: A dangerous combination? Clin Neurol Neurosurg. 2015 May 30;136:73-78. doi: 10.1016/j.clineuro.2015.05.035. [Epub ahead of print] PubMed PMID: 26070116.
7) Ishihara H, Torii H, Imoto H, Oka F, Sadahiro H, Suzuki M. Intravenous thrombolysis with recombinant tissue plasminogen activator in a stroke patient treated with rivaroxaban. J Stroke Cerebrovasc Dis. 2014 Nov-Dec;23(10):e457-9. doi: 10.1016/j.jstrokecerebrovasdis.2014.07.008. Epub 2014 Oct 3. PubMed PMID: 25280819.

Beca Gebro Pharma

Gebro Pharma lanzó en el mercado español Gliolan para tumores cerebrales el 26 de mayo del 2011.

La Beca Gebro Pharma tiene por objetivo incentivar la formación complementaria en neurooncología de los residentes de neurocirugía.

La farmacéutica Gebro Pharma y la Sociedad Española de Neurocirugía (SENEC) se han unido con el objetivo de potenciar la formación en neuro-oncología de los residentes de neurocirugía de España.
Para ello, se ha creado la Beca Gebro-Pharma para estancias en el extranjero en centros de reconocida experiencia y trayectoria en esta especialidad.

Así, durante la Reunión anual del grupo de trabajo de neuro-oncología y neuroanatomía de la SENEC, que se ha celebrado en el Hospital Puerta de Hierro de Madrid, se ha anunciado la creación de la Beca de investigación Gebro-Pharma, que se otorgará a un médico residente de neurocirugía en los dos últimos años de especialidad o a un especialista en neurocirugía con menos de 5 años de ejercicio como especialista, con el mejor trabajo publicado de Neuro-Oncología en revistas nacionales o internacionales en los últimos dos años.

Según el Dr. Ángel Rodríguez de Lope, coordinador del Grupo de Neuro-Oncología de la SENEC, “nuestro mayor objetivo es fomentar la formación e investigación en el campo de la neurocirugía, generando nuevos conocimientos que nos ayuden en el tratamiento de los pacientes. Para nosotros es muy importante contar con la implicación de laboratorios, como Gebro Pharma, que reúnen recursos que nos permiten seguir avanzando en este campo”.

Gebro Pharma mantiene una estrecha relación con asociaciones y sociedades médicas, afianzando su compromiso con las áreas terapéuticas que cubre. Como afirma la responsable del Departamento de Market Access de Gebro Pharma, Carmen Sans, “nos sentimos muy orgullosos de anunciar esta unión. Nuestra compañía está muy comprometida con la salud de los pacientes, y somos plenamente conscientes de la gran importancia que tienen la formación e investigación médica. Para nosotros es muy gratificante colaborar con la SENEC y ayudar a incentivar la formación en el campo de la neuro-oncología”.

Gebro Pharma y el área neuro-oncológica

El año 2011 Gebro Pharma incorporó a su portfolio un marcador para el manejo de los pacientes con gliomas malignos.

Los gliomas malignos son los tumores más frecuentes del sistema nervioso (4 nuevos casos por 100.000 habitantes y año). Su mayor incidencia es a partir de los 65 años de edad y el tratamiento quirúrgico constituye el primer paso del tratamiento, que también incluye radioterapia y quimioterapia.